Defects in HLA-B are a cause of susceptibility toStevens-Johnson syndrome (STJOS) [MIM:608579]. A limited form oftoxic epidermal necrolysis characterized by destruction anddetachment of the skin epithelium and mucous membranes involvingless than 10% of the body surface area. It ranges from mild skinand mucous membrane lesions to a severe, sometimes fatal systemicdisorder. Ocular symptoms include ulcerative conjunctivitis,keratitis, iritis, uveitis and sometimes blindness. It can becaused by a severe adverse reaction to particular types ofmedication, although Mycoplasma infections may induce some cases.

Defects in HLA-B are a cause of susceptibility tospondyloarthropathy type 1 (SPDA1) [MIM:106300]. It is a chronicrheumatic disease with multifactorial inheritance. It includes aspectrum of related disorders comprising ankylosing spondylitis, asubset of psoriatic arthritis, reactive arthritis (e.g.,Reitersyndrome), arthritis associated with inflammatory bowel diseaseand undifferentiated spondyloarthropathy. These disorders mayoccur simultaneously or sequentially in the same patient, probablyrepresenting various phenotypic expressions of the same disease.Ankylosing spondylitis is the form of rheumatoid arthritisaffecting the spine and is considered the prototype ofseronegative spondyloarthropathies. It produces pain and stiffnessas a result of inflammation of the sacroiliac, intervertebral, andcostovertebral joints. Note=In the Greek Cypriot population, arestricted number of HLA-B27 subtypes are associated withankylosing spondylitis and other B27-related diseases and anelevated frequency of the B*2702 allele in ankylosing spondylitispatients is identified. The allele B*2707 seems to have aprotective role in this population because it was found only inthe healthy controls.

Genetic variations in HLA-C are a cause of susceptibilityto psoriasis type 1 (PSORS1) [MIM:177900]. Psoriasis is a common,chronic inflammatory disease of the skin with multifactorialetiology. It is characterized by red, scaly plaques usually foundon the scalp, elbows and knees. These lesions are caused byabnormal keratinocyte proliferation and infiltration ofinflammatory cells into the dermis and epidermis.

Defects in PPP2R2B are the cause of spinocerebellarataxia type 12 (SCA12) [MIM:604326]. Spinocerebellar ataxia is aclinically and genetically heterogeneous group of cerebellardisorders. Patients show progressive incoordination of gait andoften poor coordination of hands, speech and eye movements, due todegeneration of the cerebellum with variable involvement of thebrainstem and spinal cord. SCA12 is an autosomal dominantcerebellar ataxia (ADCA).

Genetic variation in HLA-DRB1 is a cause ofsusceptibility to sarcoidosis type 1 (SS1) [MIM:181000].Sarcoidosis is an idiopathic, systemic, inflammatory diseasecharacterized by the formation of immune granulomas in involvedorgans. Granulomas predominantly invade the lungs and thelymphatic system, but also skin, liver, spleen, eyes and otherorgans may be involved.

Defects in HSD3B2 are the cause of adrenal hyperplasiatype 2 (AH2) [MIM:201810]. AH2 is a form of congenital adrenalhyperplasia, a common recessive disease due to defective synthesisof cortisol. Congenital adrenal hyperplasia is characterized byandrogen excess leading to ambiguous genitalia in affectedfemales, rapid somatic growth during childhood in both sexes withpremature closure of the epiphyses and short adult stature. Fourclinical types: 'salt wasting' (SW, the most severe type), 'simplevirilizing' (SV, less severely affected patients), with normalaldosterone biosynthesis, 'non-classic form' or late onset (NC orLOAH), and 'cryptic' (asymptomatic). In AH2, virilization is muchless marked or does not occur. AH2 is frequently lethal in earlylife.

Note=Mild HSD3B2 deficiency in hyperandrogenic females isassociated with characteristic traits of polycystic ovarysyndrome, such as insulin resistance and luteinizing hormonhypersecretion.

Defects in HSD3B7 are the cause of congenital bile acidsynthesis defect type 1 (CBAS1) [MIM:607765], also known asneonatal progressive intrahepatic cholestasis. CBAS1 is due to aprimary defect in bile synthesis leading to progressive liverdisease. Clinical features include neonatal jaundice, severeintrahepatic cholestasis and cirrhosis.

Defects in SH3BP2 are the cause of cherubism (CRBM)[MIM:118400]. CRBM is an autosomal dominant inherited syndromecharacterized by excessive bone degradation of the upper and lowerjaws, which often begins around three years of age. It is followedby development of fibrous tissue masses, which causes acharacteristic facial swelling.

Defects in EPB41 are the cause of elliptocytosis type 1(EL1) [MIM:611804]. EL1 is a Rhesus-linked form of hereditaryelliptocytosis, a genetically heterogeneous, autosomal dominant,hematologic disorder. It is characterized by variable hemolyticanemia and elliptical or oval red cell shape.

Defects in EPB41 are a cause of hereditarypyropoikilocytosis (HPP) [MIM:266140]. HPP is an autosomalrecessive hematologic disorder characterized by hemolytic anemia,microspherocytosis, poikilocytosis, and an unusual thermalsensitivity of red cells.

Defects in NT5C3 are the cause of P5N deficiency (P5ND)[MIM:266120], also called hemolytic anemia due to P5N deficiencyor hemolytic anemia due to UMPH1 deficiency. P5ND is an autosomalrecessive condition causing hemolytic anemia characterized bymarked basophilic stipplig and the accumulation of highconcentrations of pyrimidine nucleotides within the erythrocyte.It is implicated in the anemia of lead poisoning and is possiblyassociated with learning difficulties.

Defects in NT5E are the cause of calcification of jointsand arteries (CAJA) [MIM:211800]. A condition characterized byadult-onset calcification of the lower extremity arteries,including the iliac, femoral and tibial arteries, and hand andfoot capsule joints. Age of onset has been reported as early asthe second decade of life, usually involving intense joint pain orcalcification in the hands.

Genetic variations in ATG16L1 are associated withsusceptibility to inflammatory bowel disease type 10 (IBD10)[MIM:611081]. IBD is characterized by a chronic relapsingintestinal inflammation. IBD is subdivided into Crohn disease (CD)and ulcerative colitis phenotypes. IBD10 individuals show thephenotype characteristic to CD. It may involve any part of thegastrointestinal tract, but most frequently the terminal ileum andcolon. CD is commonly classified as autoimmune disease.

Defects in SERPINA1 are the cause of alpha-1-antitrypsindeficiency (A1ATD) [MIM:613490]. A disorder whose most commonmanifestation is emphysema, which becomes evident by the third tofourth decade. A less common manifestation of the deficiency isliver disease, which occurs in children and adults, and may resultin cirrhosis and liver failure. Environmental factors,particularly cigarette smoking, greatly increase the risk ofemphysema at an earlier age.

Defects in SERPINF2 are the cause of alpha-2-plasmininhibitor deficiency (APLID) [MIM:262850]. APLID is an autosomalrecessive disorder resulting in severe hemorrhagic diathesis.

Defects in APP are the cause of Alzheimer disease type 1(AD1) [MIM:104300]. AD1 is a familial early-onset form ofAlzheimer disease. It can be associated with cerebral amyloidangiopathy. Alzheimer disease is a neurodegenerative disordercharacterized by progressive dementia, loss of cognitiveabilities, and deposition of fibrillar amyloid proteins asintraneuronal neurofibrillary tangles, extracellular amyloidplaques and vascular amyloid deposits. The major constituent ofthese plaques is the neurotoxic amyloid-beta-APP 40-42 peptide(s), derived proteolytically from the transmembrane precursorprotein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such asC31 derived from APP, are also implicated in neuronal death.

Defects in APP are the cause of cerebral amyloidangiopathy APP-related (CAA-APP) [MIM:605714]. A hereditarylocalized amyloidosis due to amyloid-beta A4 peptide(s) depositionin the cerebral vessels. The principal clinical characteristicsare recurrent cerebral and cerebellar hemorrhages, recurrentstrokes, cerebral ischemia, cerebral infarction, and progressivemental deterioration. Patients develop cerebral hemorrhage becauseof the severe cerebral amyloid angiopathy. Parenchymal amyloiddeposits are rare and largely in the form of pre-amyloid lesionsor diffuse plaque-like structures. They are Congo red negative andlack the dense amyloid cores commonly present in Alzheimerdisease. Some affected individuals manifest progressive aphasicdementia, leukoencephalopathy, and occipital calcifications.

Defects in AAAS are the cause of achalasia-addisonianism-alacrima syndrome (AAAS) [MIM:231550], also known as triple-Asyndrome or Allgrove syndrome. AAAS is an autosomal recessivedisorder characterized by adreno-corticotropic hormone (ACTH)-resistant adrenal failure, achalasia of the esophageal cardia andalacrima. The syndrome is associated with variable and progressiveneurological impairment involving the central, peripheral, andautonomic nervous system. Other features such as palmoplantarhyperkeratosis, short stature, facial dysmorphy and osteoporosismay also be present.

Defects in SERPINA3 may be a cause of chronic obstructivepulmonary disease (COPD) [MIM:107280].

Defects in PRKAG2 are the cause of Wolff-Parkinson-Whitesyndrome (WPWS) [MIM:194200], also known as preexcitationsyndrome. It is the second most common cause of paroxysmalsupraventricular tachycardia.

Defects in PRKAG2 are a cause of cardiomyopathy familialhypertrophic with Wolff-Parkinson-White syndrome (CMH-WPWS)[MIM:600858]. HCM due to PRKAG2 mutations is probably due topolysaccharide storage in the heart. Defects in PRKAG2 may not bea frequent cause of HCM where no features of pre-excitation arefound in affected individuals.

Defects in PRKAG2 are a cause of glycogen storage diseaseof heart lethal congenital (GSDH) [MIM:261740], also known asphosphorylase kinase deficiency of heart or congenitalnonlysosomal cardiac glycogenosis. GSDH is a rare disease whichleads to death within a few weeks to a few months after birth,through heart failure and respiratory compromise.

Defects in AASS are the cause of hyperlysinemia (HYPLYS)[MIM:238700]. Hyperlysinemia is an autosomal recessive conditioncharacterized by hyperlysinemia lysinuria and variablesaccharopinuria.

Defects in ABCA1 are a cause of high density lipoproteindeficiency type 1 (HDLD1) [MIM:205400], also known asanalphalipoproteinemia or Tangier disease (TGD). HDLD1 is arecessive disorder characterized by absence of high densitylipoprotein (HDL) cholesterol from plasma, accumulation ofcholesteryl esters, premature coronary artery disease (CAD),hepatosplenomegaly, recurrent peripheral neuropathy andprogressive muscle wasting and weakness.

Defects in ABCA1 are a cause of high density lipoproteindeficiency type 2 (HDLD2) [MIM:604091], also known as familialhypoalphalipoproteinemia (FHA). HDLD2 is inherited as autosomaldominant trait. It is characterized by moderately low HDLcholesterol, predilection toward premature coronary artery disease(CAD) and a reduction in cellular cholesterol efflux.

Defects in ABCA3 are the cause of pulmonary surfactantmetabolism dysfunction type 3 (SMDP3) [MIM:610921], also calledpulmonary alveolar proteinosis due to ABCA3 deficiency. A rarelung disorder due to impaired surfactant homeostasis. It ischaracterized by alveolar filling with floccular material thatstains positive using the periodic acid-Schiff method and isderived from surfactant phospholipids and protein components.Excessive lipoproteins accumulation in the alveoli results insevere respiratory distress.

Defects in ABCA4 are the cause of Stargardt disease type1 (STGD1) [MIM:248200]. STGD is one of the most frequent causes ofmacular degeneration in childhood. It is characterized by maculardystrophy with juvenile-onset, rapidly progressive course,alterations of the peripheral retina, and subretinal deposition oflipofuscin-like material. STGD1 inheritance is autosomalrecessive.

Defects in ABCA4 are the cause of fundus flavimaculatus(FFM) [MIM:248200]. FFM is an autosomal recessive retinal disordervery similar to Stargardt disease. In contrast to Stargardtdisease, FFM is characterized by later onset and slowlyprogressive course.

Defects in ABCA4 may be a cause of age-related maculardegeneration type 2 (ARMD2) [MIM:153800]. ARMD is a multifactorialeye disease and the most common cause of irreversible vision lossin the developed world. In most patients, the disease is manifestas ophthalmoscopically visible yellowish accumulations of proteinand lipid (known as drusen) that lie beneath the retinal pigmentepithelium and within an elastin-containing structure known asBruch membrane.

Defects in ABCA4 are the cause of cone-rod dystrophy type3 (CORD3) [MIM:604116]. CORDs are inherited retinal dystrophiesbelonging to the group of pigmentary retinopathies. CORDs arecharacterized by retinal pigment deposits visible on fundusexamination, predominantly in the macular region, and initial lossof cone photoreceptors followed by rod degeneration. This leads todecreased visual acuity and sensitivity in the central visualfield, followed by loss of peripheral vision. Severe loss ofvision occurs earlier than in retinitis pigmentosa.

Defects in ABCA4 are the cause of retinitis pigmentosatype 19 (RP19) [MIM:601718]. RP leads to degeneration of retinalphotoreceptor cells. Patients typically have night visionblindness and loss of midperipheral visual field. As theircondition progresses, they lose their far peripheral visual fieldand eventually central vision as well. RP19 is characterized bychoroidal atrophy. Inheritance is autosomal recessive.

Defects in ABCA12 are the cause of ichthyosis harlequin(HI) [MIM:242500], also known as harlequin fetus. HI is a verysevere skin disorder in which the neonate is born with a thickcovering of armor-like scales. The skin dries out to form harddiamond-shaped plaques separated by fissures, resembling 'armorplating'. The normal facial features are severely affected, withdistortion of the lips (eclabion), eyelids (ectropion), ears, andnostrils. Affected babies are often born prematurely and rarelysurvive the perinatal period.

Defects in ABCA12 are the cause of ichthyosis lamellartype 2 (LI2) [MIM:601277], also known as ichthyosis congenita IIB(ICR2B). LI is a non-bullous ichthyosis, a skin disordercharacterized by abnormal cornification of the epidermis. It isone the most severe forms of ichthyoses apparent at birth andpersisting throughout life. LI patients are born encased in atight, shiny, translucent covering called collodion membrane. Overthe first weeks of life, the collodion membrane is graduallyreplaced by generalized large, dark brown, plate-like scales withminimal to no erythroderma. Tautness of facial skin commonlyresults in ectropion, eclabium and scarring alopecia of the scalp.Common complications are severe heat intolerance and recurrent earinfections.

Defects in ABCB7 are the cause of X-linked sideroblasticanemia with ataxia (ASAT) [MIM:301310]. ASAT is a recessivedisorder characterized by an infantile to early childhood onset ofnonprogressive cerebellar ataxia and mild anemia with hypochromiaand microcytosis.

Defects in ABCB11 are the cause of progressive familialintrahepatic cholestasis type 2 (PFIC2) [MIM:601847]. PFIC2 is aninherited liver disease of childhood which is characterized bycholestasis and normal serum gamma-glutamyltransferase activity.Defects in ABCB11 are also found in cases of chronic intrahepaticcholestasis without obvious familial history of chronic liverdisease.

Defects in ABCB11 are the cause of benign recurrentintrahepatic cholestasis type 2 (BRIC2) [MIM:605479]. BRIC ischaracterized by intermittent episodes of cholestasis withoutprogression to liver failure. There is initial elevation of serumbile acids, followed by cholestatic jaundice which generallyspontaneously resolves after periods of weeks to months. Thecholestatic attacks vary in severity and duration and patients areasymptomatic between episodes, both clinically and biochemically.

Defects in ABCC8 are a cause of leucine-inducedhypoglycemia (LIH) [MIM:240800], also known as leucine-sensitivehypoglycemia of infancy. LIH is a rare cause of hypoglycemia andis described as a condition in which symptomatic hypoglycemia isprovoked by high protein feedings. Hypoglycemia is also elicitedby administration of oral or intravenous infusions of a singleamino acid, leucine.

Defects in ABCC8 are the cause of familialhyperinsulinemic hypoglycemia type 1 (HHF1) [MIM:256450], alsoknown as persistent hyperinsulinemic hypoglycemia of infancy(PHHI) or congenital hyperinsulinism. HHF is the most common causeof persistent hypoglycemia in infancy and is due to defectivenegative feedback regulation of insulin secretion by low glucoselevels. It causes nesidioblastosis, a diffuse abnormality of thepancreas in which there is extensive, often disorganized formationof new islets. Unless early and aggressive intervention isundertaken, brain damage from recurrent episodes of hypoglycemiamay occur.

Defects in ABCC8 are a cause of diabetes mellituspermanent neonatal (PNDM) [MIM:606176]. PNDM is a rare form ofdiabetes distinct from childhood-onset autoimmune diabetesmellitus type 1. It is characterized by insulin-requiringhyperglycemia that is diagnosed within the first months of life.Permanent neonatal diabetes requires lifelong therapy.

Defects in ABCC8 are the cause of transient neonataldiabetes mellitus type 2 (TNDM2) [MIM:610374]. Neonatal diabetesis a form of diabetes mellitus defined by the onset of mild-to-severe hyperglycemia within the first months of life. Transientneonatal diabetes remits early, with a possible relapse duringadolescence.

Defects in ABCC9 are the cause of cardiomyopathy dilatedtype 1O (CMD1O) [MIM:608569], also known as dilated cardiomyopathywith ventricular tachycardia. Dilated cardiomyopathy is a disordercharacterized by ventricular dilation and impaired systolicfunction, resulting in congestive heart failure and arrhythmia.Patients are at risk of premature death.

Defects in ABCD1 are the cause of adrenoleukodystrophy X-linked (X-ALD) [MIM:300100]. X-ALD is a peroxisomal metabolicdisorder characterized by progressive multifocal demyelination ofthe central nervous system and by peripheral adrenal insufficiency(Addison disease). It results in mental deterioration,corticospinal tract dysfunction, and cortical blindness. Differentclinical manifestations exist like: cerebral childhood ALD (CALD),adult cerebral ALD (ACALD), adrenomyeloneuropathy (AMN) and'Addison disease only' (ADO) phenotype.

Note=The promoter region of ABCD1 is deleted in thechromosome Xq28 deletion syndrome which involves ABCD1 and theneighboring gene BCAP31.

Defects in ABCG5 are a cause of sitosterolemia (SITOST)[MIM:210250], also known as phytosterolemia or shellfishsterolemia. It is a rare autosomal recessive disordercharacterized by increased intestinal absorption of all sterolsincluding cholesterol, plant and shellfish sterols, and decreasedbiliary excretion of dietary sterols into bile. Sitosterolemiapatients have hypercholesterolemia, very high levels of plantsterols in the plasma, and frequently develop tendon and tuberousxanthomas, accelerated atherosclerosis and premature coronaryartery disease.

Genetic variations in ABCG8 can be associated withsusceptibility to gallbladder disease type 4 (GBD4) [MIM:611465].With an overall prevalence of 10-20%, gallstone disease(cholelithiasis) represents one of the most frequent andeconomically relevant health problems of industrialized countries.

Defects in ABCG8 are a cause of sitosterolemia (SITOST)[MIM:210250], also known as phytosterolemia or shellfishsterolemia. It is a rare autosomal recessive disordercharacterized by increased intestinal absorption of all sterolsincluding cholesterol, plant and shellfish sterols, and decreasedbiliary excretion of dietary sterols into bile. Sitosterolemiapatients have hypercholesterolemia, very high levels of plantsterols in the plasma, and frequently develop tendon and tuberousxanthomas, accelerated atherosclerosis and premature coronaryartery disease.

Defects in ABHD12 are the cause of polyneuropathy hearingloss ataxia retinitis pigmentosa and cataract (PHARC)[MIM:612674]. PHARC is a slowly progressive neurologic disorderwith a variable phenotype resembling Refsum disease. Clinicalfeatures include sensorineural hearing loss, visual problemsrelated to cataracts, retinitis pigmentosa, pes cavus, ataxicand/or spastic gait disturbances with a progressive sensorimotorperipheral neuropathy. Other features include hyporeflexia,hyperreflexia, extensor plantar responses.

Defects in ABHD5 are the cause of Chanarin-Dorfmansyndrome (CDS) [MIM:275630], also called triglyceride storagedisease with impaired long-chain fatty acid oxidation or neutrallipid storage disease with ichthyosis. CDS is an autosomalrecessive inborn error of lipid metabolism with multisystemicaccumulation of triglycerides although plasma concentrations arenormal. Clinical characteristics are congenital generalizedichthyosis, vacuolated leukocytes, hepatomegaly, myopathy,cataracts, neurosensory hearing loss and developmental delay. Thedisorder presents at birth with generalized, fine, white scalingof the skin and a variable degree of erythema resembling non-bullous congenital ichthyosiform erythroderma.

Note=ABHD11 is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.

Note=A chromosomal aberration involving ABI1 is a causeof acute leukemias. Translocation t(10,11)(p11.2,q23) with MLL.ABI1 isoform 2 was found to be present in acute leukemia MLL-ABI1fusion transcript.

Note=A chromosomal aberration involving ABL1 is a causeof chronic myeloid leukemia. Translocation t(9,22)(q34,q11) withBCR. The translocation produces a BCR-ABL found also in acutemyeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

Defects in ACACA are a cause of acetyl-CoA carboxylase 1deficiency (ACACAD) [MIM:200350], also known as ACAC deficiency orACC deficiency. An inborn error of de novo fatty acid synthesisassociated with severe brain damage, persistent myopathy and poorgrowth.

Defects in ACAD8 are the cause of isobutyryl-CoAdehydrogenase deficiency (IBDD) [MIM:611283]. The symptoms of IBDDgenerally appear until late in infancy or in childhood and caninclude poor feeding and growth (failure to thrive), a weakenedand enlarged heart (dilated cardiomyopathy), seizures, and lownumbers of red blood cells (anemia).

Defects in ACAD9 are a cause of acyl-CoA dehydrogenasefamily member type 9 deficiency (ACAD9 deficiency) [MIM:611126].ACAD9 deficiency patients present with episodic liver dysfunctionduring otherwise mild illnesses or cardiomyopathy, along withchronic neurologic dysfunction.

Defects in ACADL are the cause of acyl-CoA dehydrogenaselong-chain deficiency (ACADLD) [MIM:201460]. ACADLD is an inbornerror of mitochondrial fatty acid beta-oxidation resulting inhepatic and cardiac dysfunction, non-ketotic hypoglycemia,hypotonia, muscle weakness.

Defects in ACADM are the cause of acyl-CoA dehydrogenasemedium-chain deficiency (ACADMD) [MIM:201450]. It is an autosomalrecessive disease which causes fasting hypoglycemia, hepaticdysfunction, and encephalopathy, often resulting in death ininfancy.

Defects in ACADS are the cause of acyl-CoA dehydrogenaseshort-chain deficiency (ACADSD) [MIM:201470]. It is an autosomalrecessive disorder resulting in acute acidosis and muscle weaknessin infants, and a form of lipid-storage myopathy in adults.

Defects in ACADVL are the cause of acyl-CoA dehydrogenasevery long chain deficiency (ACADVLD) [MIM:201475]. ACADVLD is anautosomal recessive disease which leads to impaired long-chainfatty acid beta-oxidation. It is clinically heterogeneous, withthree major phenotypes: a severe childhood form, with early onset,high mortality, and high incidence of cardiomyopathy, a milderchildhood form, with later onset, usually with hypoketotichypoglycemia as the main presenting feature, low mortality, andrare cardiomyopathy, and an adult form, with isolated skeletalmuscle involvement, rhabdomyolysis, and myoglobinuria, usuallytriggered by exercise or fasting.

Defects in SLC33A1 are the cause of spastic paraplegiaautosomal dominant type 42 (SPG42) [MIM:612539]. Spasticparaplegia is a neurodegenerative disorder characterized by aslow, gradual, progressive weakness and spasticity of the lowerlimbs. Rate of progression and the severity of symptoms are quitevariable. Initial symptoms may include difficulty with balance,weakness and stiffness in the legs, muscle spasms, and draggingthe toes when walking. In some forms of the disorder, bladdersymptoms (such as incontinence) may appear, or the weakness andstiffness may spread to other parts of the body.

Defects in ACADSB are the cause of short/branched-chainacyl-CoA dehydrogenase deficiency (SBCADD) [MIM:610006], alsoknown as 2-methylbutyryl-CoA dehydrogenase deficiency or 2-methylbutyryl glycinuria. SBCADD is an autosomal recessivedisorder and consists of a defect in catabolism of L-isoleucinewhich is characterized by an increase of 2-methylbutyrylglycineand 2-methylbutyrylcarnitine in blood and urine. Affectedindividuals have seizures and psychomotor delay as the mainclinical features.

Genetic variations in ACE may be a cause ofsusceptibility to ischemic stroke (ISCHSTR) [MIM:601367], alsoknown as cerebrovascular accident or cerebral infarction. A strokeis an acute neurologic event leading to death of neural tissue ofthe brain and resulting in loss of motor, sensory and/or cognitivefunction. Ischemic strokes, resulting from vascular occlusion, isconsidered to be a highly complex disease consisting of a group ofheterogeneous disorders with multiple genetic and environmentalrisk factors.

Defects in ACE are a cause of renal tubular dysgenesis(RTD) [MIM:267430]. RTD is an autosomal recessive severe disorderof renal tubular development characterized by persistent fetalanuria and perinatal death, probably due to pulmonary hypoplasiafrom early-onset oligohydramnios (the Potter phenotype).

Genetic variations in ACE are associated withsusceptibility to microvascular complications of diabetes type 3(MVCD3) [MIM:612624]. These are pathological conditions thatdevelop in numerous tissues and organs as a consequence ofdiabetes mellitus. They include diabetic retinopathy, diabeticnephropathy leading to end-stage renal disease, and diabeticneuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized byvascular permeability and increased tissue ischemia andangiogenesis.

Defects in CHRNA2 are the cause of nocturnal frontal lobeepilepsy type 4 (ENFL4) [MIM:610353]. ENFL4 is an autosomaldominant epilepsy characterized by nocturnal seizures associatedwith fear sensation, tongue movements, and nocturnal wandering,closely resembling nightmares and sleep walking.

Defects in CHRNA4 are the cause of nocturnal frontal lobeepilepsy type 1 (ENFL1) [MIM:600513], also symbolized ADNFLE.ENFL1 is an autosomal dominant epilepsy characterized by nocturnalseizures with hyperkinetic automatisms and poorly organizedstereotyped movements.

Defects in CHRNA1 are a cause of multiple pterygiumsyndrome lethal type (MUPSL) [MIM:253290]. Multiple pterygia arefound infrequently in children with arthrogryposis and in fetuseswith fetal akinesia syndrome. In lethal multiple pterygiumsyndrome there is intrauterine growth retardation, multiplepterygia, and flexion contractures causing severe arthrogryposisand fetal akinesia. Subcutaneous edema can be severe, causingfetal hydrops with cystic hygroma and lung hypoplasia.Oligohydramnios and facial anomalies are frequent.

Note=The alpha subunit is the main focus for antibodybinding in myasthenia gravis. Myasthenia gravis is characterizedby sporadic muscular fatigability and weakness, occurring chieflyin muscles innervated by cranial nerves, and characteristicallyimproved by cholinesterase-inhibiting drugs.

Defects in CHRNA1 are a cause of congenital myasthenicsyndrome slow-channel type (SCCMS) [MIM:601462]. SCCMS is the mostcommon congenital myasthenic syndrome. Congenital myasthenicsyndromes are characterized by muscle weakness affecting the axialand limb muscles (with hypotonia in early-onset forms), the ocularmuscles (leading to ptosis and ophthalmoplegia), and the facialand bulbar musculature (affecting sucking and swallowing, andleading to dysphonia). The symptoms fluctuate and worsen withphysical effort. SCCMS is caused by kinetic abnormalities of theAChR, resulting in prolonged endplate currents and prolonged AChRchannel opening episodes.

Defects in CHRNA1 are a cause of congenital myasthenicsyndrome fast-channel type (FCCMS) [MIM:608930]. FCCMS is acongenital myasthenic syndrome characterized by kineticabnormalities of the AChR. In most cases, FCCMS is due tomutations that decrease activity of the AChR by slowing the rateof opening of the receptor channel, speeding the rate of closureof the channel, or decreasing the number of openings of thechannel during ACh occupancy. The result is failure to achievethreshold depolarization of the endplate and consequent failure tofire an action potential.

Defects in CHRNB2 are the cause of nocturnal frontal lobeepilepsy type 3 (ENFL3) [MIM:605375]. ENFL3 is an autosomaldominant epilepsy characterized by nocturnal seizures withhyperkinetic automatisms and poorly organized stereotypedmovements.

Defects in CHRNB1 are a cause of congenital myasthenicsyndrome slow-channel type (SCCMS) [MIM:601462]. SCCMS is the mostcommon congenital myasthenic syndrome. Congenital myasthenicsyndromes are characterized by muscle weakness affecting the axialand limb muscles (with hypotonia in early-onset forms), the ocularmuscles (leading to ptosis and ophthalmoplegia), and the facialand bulbar musculature (affecting sucking and swallowing, andleading to dysphonia). The symptoms fluctuate and worsen withphysical effort. SCCMS is caused by kinetic abnormalities of theAChR, resulting in prolonged endplate currents and prolonged AChRchannel opening episodes.

Defects in CHRNB1 are a cause of congenital myasthenicsyndrome with acetylcholine receptor deficiency (ACHRDCMS)[MIM:608931]. ACHRDCMS is a post-synaptic congenital myasthenicsyndrome. Mutations underlying AChR deficiency cause a 'loss offunction' and show recessive inheritance.

Defects in CHRND are a cause of multiple pterygiumsyndrome lethal type (MUPSL) [MIM:253290]. Multiple pterygia arefound infrequently in children with arthrogryposis and in fetuseswith fetal akinesia syndrome. In lethal multiple pterygiumsyndrome there is intrauterine growth retardation, multiplepterygia, and flexion contractures causing severe arthrogryposisand fetal akinesia. Subcutaneous edema can be severe, causingfetal hydrops with cystic hygroma and lung hypoplasia.Oligohydramnios and facial anomalies are frequent.

Defects in CHRND are a cause of congenital myasthenicsyndrome slow-channel type (SCCMS) [MIM:601462]. SCCMS is the mostcommon congenital myasthenic syndrome. Congenital myasthenicsyndromes are characterized by muscle weakness affecting the axialand limb muscles (with hypotonia in early-onset forms), the ocularmuscles (leading to ptosis and ophthalmoplegia), and the facialand bulbar musculature (affecting sucking and swallowing, andleading to dysphonia). The symptoms fluctuate and worsen withphysical effort. SCCMS is caused by kinetic abnormalities of theAChR, resulting in prolonged endplate currents and prolonged AChRchannel opening episodes.

Defects in CHRND are a cause of congenital myasthenicsyndrome fast-channel type (FCCMS) [MIM:608930]. FCCMS is acongenital myasthenic syndrome characterized by kineticabnormalities of the AChR. In most cases, FCCMS is due tomutations that decrease activity of the AChR by slowing the rateof opening of the receptor channel, speeding the rate of closureof the channel, or decreasing the number of openings of thechannel during ACh occupancy. The result is failure to achievethreshold depolarization of the endplate and consequent failure tofire an action potential.

Note=The muscle AChR is the major target antigen in theautoimmune disease myasthenia gravis. Myasthenia gravis ischaracterized by sporadic muscular fatigability and weakness,occurring chiefly in muscles innervated by cranial nerves, andcharacteristically improved by cholinesterase-inhibiting drugs.

Defects in CHRNE are a cause of congenital myasthenicsyndrome slow-channel type (SCCMS) [MIM:601462]. SCCMS is the mostcommon congenital myasthenic syndrome. Congenital myasthenicsyndromes are characterized by muscle weakness affecting the axialand limb muscles (with hypotonia in early-onset forms), the ocularmuscles (leading to ptosis and ophthalmoplegia), and the facialand bulbar musculature (affecting sucking and swallowing, andleading to dysphonia). The symptoms fluctuate and worsen withphysical effort. SCCMS is caused by kinetic abnormalities of theAChR, resulting in prolonged endplate currents and prolonged AChRchannel opening episodes.

Defects in CHRNE are a cause of congenital myasthenicsyndrome fast-channel type (FCCMS) [MIM:608930]. FCCMS is acongenital myasthenic syndrome characterized by kineticabnormalities of the AChR. In most cases, FCCMS is due tomutations that decrease activity of the AChR by slowing the rateof opening of the receptor channel, speeding the rate of closureof the channel, or decreasing the number of openings of thechannel during ACh occupancy. The result is failure to achievethreshold depolarization of the endplate and consequent failure tofire an action potential.

Defects in CHRNE are a cause of congenital myasthenicsyndrome with acetylcholine receptor deficiency (ACHRDCMS)[MIM:608931]. ACHRDCMS is a post-synaptic congenital myasthenicsyndrome. Mutations underlying AChR deficiency cause a 'loss offunction' and show recessive inheritance.

Defects in CHRNG are a cause of multiple pterygiumsyndrome lethal type (MUPSL) [MIM:253290]. Multiple pterygia arefound infrequently in children with arthrogryposis and in fetuseswith fetal akinesia syndrome. In lethal multiple pterygiumsyndrome there is intrauterine growth retardation, multiplepterygia, and flexion contractures causing severe arthrogryposisand fetal akinesia. Subcutaneous edema can be severe, causingfetal hydrops with cystic hygroma and lung hypoplasia.Oligohydramnios and facial anomalies are frequent.

Defects in CHRNG are a cause of multiple pterygiumsyndrome Escobar variant (MUPSE) [MIM:265000], also known asnonlethal type multiple pterygium syndrome. Escobar syndrome is anon-lethal form of arthrogryposis multiplex congenita. It is anautosomal recessive condition characterized by excessive webbing(pterygia), congenital contractures (arthrogryposis), andscoliosis. Variable other features include intrauterine death,congenital respiratory distress, short stature, faciocranialdysmorphism, ptosis, low-set ears, arachnodactyly and cryptorchismin males. Congenital contractures are common and may be caused byreduced fetal movements at sensitive times of development.Possible causes of decreased fetal mobility include spaceconstraints such as oligohydramnion, drugs, metabolic conditionsor neuromuscular disorders including myasthenia gravis. is a.

Genetic variations in CHRM2 can influence susceptibilityto major depressive disorder (MDD) [MIM:608516]. MDD is one of themost common psychiatric disorders. MDD is a complex traitcharacterized by one or more major depressive episodes without ahistory of manic, mixed, or hypomanic episodes. A major depressiveepisode is characterized by at least 2 weeks during which there isa new onset or clear worsening of either depressed mood or loss ofinterest or pleasure in nearly all activities. Four additionalsymptoms must also be present including changes in appetite,weight, sleep, and psychomotor activity, decreased energy,feelings of worthlessness or guilt, difficulty thinking,concentrating, or making decisions, or recurrent thoughts of deathor suicidal ideation, plans, or attempts. The episode must beaccompanied by distress or impairment in social, occupational, orother important areas of functioning.

Defects in ACOX1 are the cause of adrenoleukodystrophypseudoneonatal (Pseudo-NALD) [MIM:264470], also known asperoxisomal acyl-CoA oxidase deficiency. Pseudo-NALD is aperoxisomal single-enzyme disorder. Clinical features includemental retardation, leukodystrophy, seizures, mild hepatomegaly,hearing deficit. Pseudo-NALD is characterized by increased plasmalevels of very-long chain fatty cids, due to decreased or absentperoxisome acyl-CoA oxidase activity. Peroxisomes are intact andfunctioning.

Defects in ACSL4 are the cause of mental retardation X-linked type 63 (MRX63) [MIM:300387]. Mental retardation is amental disorder characterized by significantly sub-average generalintellectual functioning associated with impairments in adaptativebehavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest otherclinical signs.

Defects in ACSL4 are involved in Alport syndrome withmental retardation midface hypoplasia and elliptocytosis (ATS-MR)[MIM:300194]. A X-linked contiguous gene deletion syndromecharacterized by glomerulonephritis, deafness, mental retardation,midface hypoplasia and elliptocytosis.

Note=A chromosomal aberration involving ACSL6 may be acause of myelodysplastic syndrome with basophilia. Translocationt(5,12)(q31,p13) with ETV6.

Note=A chromosomal aberration involving ACSL6 may be acause of acute myelogenous leukemia with eosinophilia.Translocation t(5,12)(q31,p13) with ETV6.

Note=A chromosomal aberration involving ACSL6 may be acause of acute eosinophilic leukemia (AEL). Translocationt(5,12)(q31,p13) with ETV6.

Defects in ACTA2 are the cause of aortic aneurysmfamilial thoracic type 6 (AAT6) [MIM:611788]. AATs arecharacterized by permanent dilation of the thoracic aorta usuallydue to degenerative changes in the aortic wall. They are primarilyassociated with a characteristic histologic appearance known as'medial necrosis' or 'Erdheim cystic medial necrosis' in whichthere is degeneration and fragmentation of elastic fibers, loss ofsmooth muscle cells, and an accumulation of basophilic groundsubstance.

Defects in ACTB are a cause of dystonia juvenile-onset(DYTJ) [MIM:607371]. DYTJ is a form of dystonia with juvenileonset. Dystonia is defined by the presence of sustainedinvoluntary muscle contraction, often leading to abnormalpostures. DYTJ patients manifest progressive, generalized, dopa-unresponsive dystonia, developmental malformations and sensoryhearing loss.

Defects in ACTC1 are the cause of cardiomyopathy dilatedtype 1R (CMD1R) [MIM:613424]. Dilated cardiomyopathy is a disordercharacterized by ventricular dilation and impaired systolicfunction, resulting in congestive heart failure and arrhythmia.Patients are at risk of premature death.

Defects in ACTC1 are the cause of cardiomyopathy familialhypertrophic type 11 (CMH11) [MIM:612098]. Familial hypertrophiccardiomyopathy is a hereditary heart disorder characterized byventricular hypertrophy, which is usually asymmetric and ofteninvolves the interventricular septum. The symptoms includedyspnea, syncope, collapse, palpitations, and chest pain. They canbe readily provoked by exercise. The disorder has inter- andintrafamilial variability ranging from benign to malignant formswith high risk of cardiac failure and sudden cardiac death.

Defects in ACTC1 are the cause of atrial septal defecttype 5 (ASD5) [MIM:612794]. A congenital heart malformationcharacterized by incomplete closure of the wall between the atriaresulting in blood flow from the left to the right atria.

Defects in ACTG1 are the cause of deafness autosomaldominant type 20 (DFNA20) [MIM:604717], also called autosomaldominant deafness type 26 (DFNA26). DFNA20 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in MC2R are the cause of glucocorticoiddeficiency type 1 (GCCD1) [MIM:202200], also known as familialglucocorticoid deficiency type 1 (FGD1). GCCD1 is an autosomalrecessive disorder due to congenital insensitivity or resistanceto adrenocorticotropin (ACTH). It is characterized by progressiveprimary adrenal insufficiency, without mineralocorticoiddeficiency.

Defects in ACTN2 are the cause of cardiomyopathy dilatedtype 1AA (CMD1AA) [MIM:612158]. Dilated cardiomyopathy is adisorder characterized by ventricular dilation and impairedsystolic function, resulting in congestive heart failure andarrhythmia. Patients are at risk of premature death.

Defects in ACTN4 are the cause of focal segmentalglomerulosclerosis type 1 (FSGS1) [MIM:603278]. A renal pathologydefined by the presence of segmental sclerosis in glomeruli andresulting in proteinuria, reduced glomerular filtration rate andedema. Renal insufficiency often progresses to end-stage renaldisease, a highly morbid state requiring either dialysis therapyor kidney transplantation.

Defects in ACTA1 are the cause of nemaline myopathy type3 (NEM3) [MIM:161800]. A form of nemaline myopathy. Nemalinemyopathies are muscular disorders characterized by muscle weaknessof varying severity and onset, and abnormal thread-or rod-likestructures in muscle fibers on histologic examination.

Defects in ACTA1 are a cause of congenital myopathy withexcess of thin myofilaments (CM) [MIM:102610].

Defects in ACTA1 are a cause of congenital myopathy withfiber-type disproportion (CFTD) [MIM:255310], also known ascongenital fiber-type disproportion myopathy (CFTDM). CFTD is agenetically heterogeneous disorder in which there is relativehypotrophy of type 1 muscle fibers compared to type 2 fibers onskeletal muscle biopsy. However, these findings are not specificand can be found in many different myopathic and neuropathicconditions.

Defects in ACVRL1 are the cause of hereditary hemorrhagictelangiectasia type 2 (HHT2) [MIM:600376], also known as Osler-Rendu-Weber syndrome 2 (ORW2). HHT2 is an autosomal dominantmultisystemic vascular dysplasia, characterized by recurrentepistaxis, muco-cutaneous telangiectases, gastro-intestinalhemorrhage, and pulmonary, cerebral and hepatic arteriovenousmalformations, all secondary manifestations of the underlyingvascular dysplasia.

Defects in ACVR1 are a cause of fibrodysplasia ossificansprogressiva (FOP) [MIM:135100]. FOP is a rare autosomal dominantdisorder of skeletal malformations and progressive extraskeletalossification. Heterotopic ossification in FOP begins in childhoodand can be induced by trauma or may occur without warning. Boneformation is episodic and progressive, leading to extra-articularankylosis of all major joints of the axial and appendicularskeleton, rendering movement impossible.

Defects in ACY1 are the cause of aminoacylase-1deficiency (ACY1D) [MIM:609924]. ACY1D results in a metabolicdisorder manifesting with encephalopathy, unspecific psychomotordelay, psychomotor delay with atrophy of the vermis andsyringomyelia, marked muscular hypotonia or normal clinicalfeatures. Epileptic seizures are a frequent feature. All affectedindividuals exhibit markedly increased urinary excretion ofseveral N-acetylated amino acids.

Defects in ASPA are the cause of Canavan disease (CAND)[MIM:271900], also known as spongy degeneration of the brain. CANDis a rare neurodegenerative condition of infancy or childhoodcharacterized by white matter vacuolization and demeylination thatgives rise to a spongy appearance. The clinical features are onsetin early infancy, atonia of neck muscles, hypotonia,hyperextension of legs and flexion of arms, blindness, severemental defect, megalocephaly, and death by 18 months on theaverage.

Genetic variations in ADAM33 are associated withsusceptibility to asthma (ASTHMA) [MIM:600807]. The most commonchronic disease affecting children and young adults. It is acomplex genetic disorder with a heterogeneous phenotype, largelyattributed to the interactions among many genes and between thesegenes and the environment. It is characterized by recurrentattacks of paroxysmal dyspnea, with weezing due to spasmodiccontraction of the bronchi.

Defects in ADAM9 are the cause of cone-rod dystrophy type9 (CORD9) [MIM:612775]. An inherited retinal dystrophycharacterized by retinal pigment deposits visible on fundusexamination, predominantly in the macular region, and initial lossof cone photoreceptors followed by rod degeneration. This leads todecreased visual acuity and sensitivity in the central visualfield, followed by loss of peripheral vision. Severe loss ofvision occurs earlier than in retinitis pigmentosa.

Defects in AGPS are the cause of rhizomelicchondrodysplasia punctata type 3 (RCDP3) [MIM:600121]. RCDP3 ischaracterized by rhizomelic shortening of femur and humerus,vertebral disorders, cataract, cutaneous lesions and severe mentalretardation.

Defects in ADA are the cause of severe combinedimmunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-negative due to adenosine deaminase deficiency(ADASCID) [MIM:102700]. SCID refers to a genetically andclinically heterogeneous group of rare congenital disorderscharacterized by impairment of both humoral and cell-mediatedimmunity, leukopenia, and low or absent antibody levels. Patientswith SCID present in infancy with recurrent, persistent infectionsby opportunistic organisms. The common characteristic of all typesof SCID is absence of T-cell-mediated cellular immunity due to adefect in T-cell development. ADA-SCID is an autosomal recessiveform accounting for about 50% of non-X-linked SCIDs. ADAdeficiency has been diagnosed in chronically ill teenagers andadults (late or adult onset). Population and newborn screeningprograms have also identified several healthy individuals withnormal immunity who have partial ADA deficiency.

Defects in ADCK3 are a cause of coenzyme Q10 deficiency(CoQ10 deficiency) [MIM:607426]. CoQ10 deficiency is an autosomalrecessive disorder with variable manifestations. It can beassociated with three main clinical phenotypes: a predominantlymyopathic form with central nervous system involvement, aninfantile encephalomyopathy with renal dysfunction and an ataxicform with cerebellar atrophy.

Defects in ADCK3 are the cause of spinocerebellar ataxiaautosomal recessive type 9 (SCAR9) [MIM:612016], also known asautosomal recessive cerebellar ataxia type 2 (ARCA2).Spinocerebellar ataxia is a clinically and geneticallyheterogeneous group of cerebellar disorders. Patients showprogressive incoordination of gait and often poor coordination ofhands, speech and eye movements, due to degeneration of thecerebellum with variable involvement of the brainstem and spinalcord. SCAR9 is an autosomal recessive form characterized by gaitataxia and cerebellar atrophy with slow progression and fewassociated features. Patients can manifest brisk tendon reflexesand Hoffmann sign, mild psychomotor retardation, mild axonaldegeneration of the sural nerve, exercise intolerance and elevatedserum lactate.

Genetic variations in ADCY10 are a cause ofsusceptibility to hypercalciuria absorptive type 2 (HCA2)[MIM:143870]. Absorptive hypercalciuria is a common type ofhypercalciuria, a condition characterized by excessive urinarycalcium excretion. Absorptive hypercalciuria is due togastrointestinal hyperabsorption of calcium and is a frequentcause of calcium oxalate nephrolithiasis.

Defects in ADIPOQ are the cause of adiponectin deficiency(ADPND) [MIM:612556]. ADPND results in very low concentrations ofplasma adiponectin.

Genetic variations in ADIPOQ are associated with non-insulin-dependent diabetes mellitus (NIDDM) [MIM:125853], alsoknown as diabetes mellitus type 2. NIDDM is characterized by anautosomal dominant mode of inheritance, onset during adulthood andinsulin resistance.

Defects in SLC25A4 are a cause of progressive externalophthalmoplegia with mitochondrial DNA deletions autosomaldominant type 2 (PEOA2) [MIM:609283]. Progressive externalophthalmoplegia is characterized by progressive weakness of ocularmuscles and levator muscle of the upper eyelid. In a minority ofcases, it is associated with skeletal myopathy, whichpredominantly involves axial or proximal muscles and which causesabnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A largeproportion of chronic ophthalmoplegias are associated with othersymptoms, leading to a multisystemic pattern of this disease.Additional symptoms are variable, and may include cataracts,hearing loss, sensory axonal neuropathy, ataxia, depression,hypogonadism, and parkinsonism.

Note=A chromosomal aberration involving MLLT10 isassociated with acute leukemias. Translocation t(10,11)(p12,q23)with MLL/HRX. The result is a rogue activator protein.

Note=A chromosomal aberration involving MLLT10 isassociated with diffuse histiocytic lymphomas. Translocationt(10,11)(p13,q14) with PICALM.

Note=A chromosomal aberration involving MLLT6 isassociated with acute leukemias. Translocation t(11,17)(q23,q21)with MLL/HRX. The result is a rogue activator protein.

Note=A chromosomal aberration involving MLLT11 is foundin acute leukemias. Translocation t(1,11)(q21,q23) with MLL.

Note=A chromosomal aberration involving MLLT3 isassociated with acute leukemias. Translocation t(9,11)(p22,q23)with MLL/HRX. The result is a rogue activator protein.

Note=A chromosomal aberration involving MLLT4 isassociated with acute leukemias. Translocation t(6,11)(q27,q23)with MLL/HRX. The result is a rogue activator protein.

Note=A chromosomal aberration involving AFF1 isassociated with acute leukemias. Translocation t(4,11)(q21,q23)with MLL/HRX. The result is a rogue activator protein.

Defects in AFF2 are the cause of fragile X-E mentalretardation syndrome (FRAXE) [MIM:309548]. FRAXE is an X-linkedform of mental retardation. Loss of FMR2 expression is correlatedwith FRAXE CCG(N) expansion. Normal individuals have 6-35 copiesof the repeat, whereas cytogenetically positive, developmentallydelayed males have more than 200 copies and show methylation ofthe associated CPG island.

Note=A chromosomal aberration involving AFF4 is found inacute lymphoblastic leukemia (ALL). Insertionins(5,11)(q31,q13q23) that forms a MLL-AFF4 fusion protein.

Defects in AFG3L2 are the cause of spinocerebellar ataxiatype 28 (SCA28) [MIM:610246]. It is a clinically and geneticallyheterogeneous group of cerebellar disorders. Patients showprogressive incoordination of gait and often poor coordination ofhands, speech and eye movements, due to degeneration of thecerebellum with variable involvement of the brainstem and spinalcord. SCA28 is an autosomal dominant cerebellar ataxia (ADCA) witha slow progressive course and no evidence of sensory involvementor cognitive impairment.

Defects in GLA are the cause of Fabry disease (FD)[MIM:301500]. FD is a rare X-linked sphingolipidosis disease whereglycolipid accumulates in many tissues. The disease consists of aninborn error of glycosphingolipid catabolism. FD patients showsystemic accumulation of globotriaoslyceramide (Gb3) and relatedglycosphingolipids in the plasma and cellular lysosomes throughoutthe body. Clinical recognition in males results fromcharacteristic skin lesions (angiokeratomas) over the lower trunk.Patients may show ocular deposits, febrile episodes, and burningpain in the extremities. Death results from renal failure, cardiacor cerebral complications of hypertension or other vasculardisease. Heterozygous females may exhibit the disorder in anattenuated form, they are more likely to show corneal opacities.

Defects in AGGF1 are a cause of Klippel-Trenaunaysyndrome (KTS) [MIM:149000]. KTS is a congenital diseasecharacterized by malformations of capillary (98% of KTS patients),venous (72%) and lymphatic (11%) vessels, and bony and soft tissuehypertrophy that leads to large cutaneous hemangiomata withhypertrophy of the related bones and soft tissues.

Genetic variations in AGRP may be a cause of obesity(OBESITY) [MIM:601665]. It is a condition characterized by anincrease of body weight beyond the limitation of skeletal andphysical requirements, as the result of excessive accumulation ofbody fat.

Defects in AHI1 are the cause of Joubert syndrome type 3(JBTS3) [MIM:608629]. JBTS is an autosomal recessive disorderpresenting with cerebellar ataxia, oculomotor apraxia, hypotonia,neonatal breathing abnormalities and psychomotor delay.Neuroradiologically, it is characterized by cerebellar vermianhypoplasia/aplasia, thickened and reoriented superior cerebellarpeduncles, and an abnormally large interpeduncular fossa, givingthe appearance of a molar tooth on transaxial slices (molar toothsign). Additional variable features include retinal dystrophy andrenal disease. JBTS3 shows minimal extra central nervous systeminvolvement and appears not to be associated with renaldysfunction.

Defects in AICDA are the cause of hyper-IgMimmunodeficiency syndrome type 2 (HIGM2) [MIM:605258], also knownas hyper-IgM syndrome 2. HIGM2 is an autosomal recessive disordercharacterized by normal or elevated serum IgM levels with absenceof IgG, IgA, and IgE, resulting in a profound susceptibility tobacterial infections. HIGM2 causes the absence of Ig class switchrecombination (CSR), the lack of Ig somatic hypermutations, andlymph node hyperplasia caused by the presence of giant germinalcenters.

Defects in AIFM1 are the cause of combined oxidativephosphorylation deficiency type 6 (COXPD6) [MIM:300816]. It is amitochondrial disease resulting in a neurodegenerative disordercharacterized by psychomotor delay, hypotonia, areflexia, muscleweakness and wasting.

Defects in AIMP1 are the cause of leukodystrophyhypomyelinating type 3 (HLD3) [MIM:260600]. A severe autosomalrecessive hypomyelinating leukodystrophy characterized by earlyinfantile onset of global developmental delay, lack ofdevelopment, lack of speech acquisition, and peripheral spasticityassociated with decreased myelination in the central nervoussystem.

Defects in AIPL1 are the cause of Leber congenitalamaurosis type 4 (LCA4) [MIM:604393]. LCA designates a clinicallyand genetically heterogeneous group of childhood retinaldegenerations, generally inherited in an autosomal recessivemanner. Affected infants have little or no retinal photoreceptorfunction as tested by electroretinography. LCA represents the mostcommon genetic cause of congenital visual impairment in infantsand children.

Defects in AIRE are a cause of autoimmune poly-endocrinopathy candidiasis ectodermal dystrophy (APECED)[MIM:240300], also known as autoimmune polyglandular syndrome typeI (APS-1). APECED is an autosomal recessive disease characterizedby: (1) autoimmune polyendocrinopathies: hypoparathyroidism,adrenocortical failure, IDDM, gonadal failure, hypothyroidism,pernicious anemia, and hepatitis, (2) chronic mucocutaneouscandidiasis, (3) ectodermal dystrophies: vitiligo, alopecia,keratopathy, dystrophy of dental enamel, nails and tympanicmembranes. In addition, a high proportion of patients developsquamous cell carcinoma of the oral mucosa. The disease isreported worldwide but is exceptionally prevalent among theFinnish population (incidence 1:25000) and the Iranian jews(incidence 1:9000).

Note=Most of the mutations alter the nucleus-cytoplasmdistribution of AIRE and disturb its association with nuclear dotsand cytoplasmic filaments. Most of the mutations also decreasetransactivation of the protein. The HSR domain is responsible forthe homomultimerization activity of AIRE. All the missensemutations of the HSR and the SAND domains decrease this activity,but those in other domains do not. The AIRE protein is present insoluble high-molecular-weight complexes. Mutations in the HSRdomain and deletion of PHD zinc fingers disturb the formation ofthese complexes.

Defects in AKR1D1 are the cause of congenital bile acidsynthesis defect type 2 (CBAS2) [MIM:235555], also known ascholestasis with delta(4)-3-oxosteroid 5-beta-reductasedeficiency. Patients with this liver disease show absence or lowlevels of chenodeoxycholic acid and cholic acid in plasma andurine.

Defects in AKAP9 are the cause of long QT syndrome type11 (LQT11) [MIM:611820]. Long QT syndromes are heart disorderscharacterized by a prolonged QT interval on the ECG andpolymorphic ventricular arrhythmias. They cause syncope and suddendeath in response to excercise or emotional stress. They canpresent with a sentinel event of sudden cardiac death in infancy.

Defects in AKT1 are a cause of susceptibility to breastcancer (BC) [MIM:114480]. A common malignancy originating frombreast epithelial tissue. Breast neoplasms can be distinguished bytheir histologic pattern. Invasive ductal carcinoma is by far themost common type. Breast cancer is etiologically and geneticallyheterogeneous. Important genetic factors have been indicated byfamilial occurrence and bilateral involvement. Mutations at morethan one locus can be involved in different families or even inthe same case.

Defects in AKT1 are associated with colorectal cancer(CRC) [MIM:114500].

Defects in AKT1 are associated with susceptibility toovarian cancer [MIM:604370], also called susceptibility tofamilial breast-ovarian cancer type 1 (BROVCA1).

Defects in ALDH3A2 are the cause of Sjoegren-Larssonsyndrome (SLS) [MIM:270200]. SLS is an autosomal recessiveneurocutaneous disorder characterized by a combination of severemental retardation, spastic di- or tetraplegia and congenitalichthyosis (increased keratinization). Ichthyosis is usuallyevident at birth, neurologic symptoms appear in the first orsecond year of life. Most patients have an IQ of less than 60.Additional clinical features include glistening white spots on theretina, seizures, short stature and speech defects.

Defects in ALDH4A1 are the cause of hyperprolinemia type2 (HP-2) [MIM:239510]. HP-2 is characterized by the accumulationof delta-1-pyrroline-5-carboxylate (P5C) and proline. The disordermay be causally related to neurologic manifestations, includingseizures and mental retardation.

Genetic variations in ALOX5AP may be a cause ofsusceptibility to ischemic stroke (ISCHSTR) [MIM:601367], alsoknown as cerebrovascular accident or cerebral infarction. A strokeis an acute neurologic event leading to death of neural tissue ofthe brain and resulting in loss of motor, sensory and/or cognitivefunction. Ischemic strokes, resulting from vascular occlusion, isconsidered to be a highly complex disease consisting of a group ofheterogeneous disorders with multiple genetic and environmentalrisk factors.

Note=Genetic variations in ALOX5AP may be associated withsusceptibility to myocardial infarction. Involvement in myocardialinfarction is however unclear: according to some authors(PubMed:14770184), a 4-SNP haplotype in ALOX5AP confers risk ofmyocardial infarction, while according to other (PubMed:17304054)ALOX5AP is not implicated in this condition.

Defects in ALDH7A1 are the cause of pyridoxine-dependentepilepsy (PDE) [MIM:266100]. PDE is characterized by a combinationof various seizure types. It usually occurs in the first hours oflife and is unresponsive to standard anticonvulsants, respondingonly to immediate administration of pyridoxine hydrochloride.

Defects in ALB are a cause of familial dysalbuminemichyperthyroxinemia (FDH) [MIM:103600]. FDH is a form of euthyroidhyperthyroxinemia that is due to increased affinity of ALB forT(4). It is the most common cause of inherited euthyroidhyperthyroxinemia in Caucasian population.

Defects in ALDOA are the cause of glycogen storagedisease type 12 (GSD12) [MIM:611881], also known as red cellaldolase deficiency. A metabolic disorder associated withincreased hepatic glycogen and hemolytic anemia. It may lead tomyopathy with exercise intolerance and rhabdomyolysis.

Defects in ALDOB are the cause of hereditary fructoseintolerance (HFI) [MIM:229600]. HFI is an autosomal recessivedisease that results in an inability to metabolize fructose andrelated sugars. Complete exclusion of fructose results in dramaticrecovery, however, if not treated properly, HFI subjects sufferepisodes of hypoglycemia, general ill condition, and risk of deaththe remainder of life.

Defects in GNAS are the cause of GNAS hyperfunction(GNASHYP) [MIM:139320]. This condition is characterized byincreased trauma-related bleeding tendency, prolonged bleedingtime, brachydactyly and mental retardation. Both the XLas isoformsand the ALEX protein are mutated which strongly reduces theinteraction between them and this may allow unimpeded activationof the XLas isoforms.

Defects in GNAS are a cause of ACTH-independentmacronodular adrenal hyperplasia (AIMAH) [MIM:219080], also knownas adrenal Cushing syndrome due to AIMAH. A rare adrenal defectcharacterized by multiple, bilateral, non-pigmented, benign,adrenocortical nodules. It results in excessive production ofcortisol leading to ACTH-independent Cushing syndrome. Clinicalmanifestations of Cushing syndrome include facial and trunkalobesity, abdominal striae, muscular weakness, osteoporosis,arterial hypertension, diabetes.

Genetic variations in GNAS are the cause ofpseudohypoparathyroidism type 1B (PHP1B) [MIM:603233]. PHP1B ischaracterized by parathyroid hormone (PTH)-resistant hypocalcemiaand hyperphosphatemia. Patients affected with PHP1B have normalactivity of the product of GNAS, lack developmental defectscharacteristic of AHO, and typically show no other endocrineabnormalities besides resistance to PTH. Most affected individualshave defects in methylation of the gene. In some casesmicrodeletions involving the STX16 appear to cause loss ofmethylation at exon A/B of GNAS, resulting in PHP1B. Paternaluniparental isodisomy have also been observed.

Defects in GNAS may be a cause of colorectal cancer (CRC)[MIM:114500].

Defects in ALG11 are the cause of congenital disorder ofglycosylation type 1P (CDG1P) [MIM:613661]. A multisystem disordercaused by a defect in glycoprotein biosynthesis and characterizedby under-glycosylated serum glycoproteins. Congenital disorders ofglycosylation result in a wide variety of clinical features, suchas defects in the nervous system development, psychomotorretardation, dysmorphic features, hypotonia, coagulationdisorders, and immunodeficiency. The broad spectrum of featuresreflects the critical role of N-glycoproteins during embryonicdevelopment, differentiation, and maintenance of cell functions.

Defects in ALG12 are the cause of congenital disorder ofglycosylation type 1G (CDG1G) [MIM:607143]. CDGs are a family ofsevere inherited diseases caused by a defect in protein N-glycosylation. They are characterized by under-glycosylated serumproteins. These multisystem disorders present with a wide varietyof clinical features, such as disorders of the nervous systemdevelopment, psychomotor retardation, dysmorphic features,hypotonia, coagulation disorders, and immunodeficiency. The broadspectrum of features reflects the critical role of N-glycoproteinsduring embryonic development, differentiation, and maintenance ofcell functions.

Defects in ALG1 are the cause of congenital disorder ofglycosylation type 1K (CDG1K) [MIM:608540]. CDGs are a family ofsevere inherited diseases caused by a defect in protein N-glycosylation. They are characterized by under-glycosylated serumproteins. These multisystem disorders present with a wide varietyof clinical features, such as disorders of the nervous systemdevelopment, psychomotor retardation, dysmorphic features,hypotonia, coagulation disorders, and immunodeficiency. The broadspectrum of features reflects the critical role of N-glycoproteinsduring embryonic development, differentiation, and maintenance ofcell functions.

Defects in ALG2 are the cause of congenital disorder ofglycosylation type 1I (CDG1I) [MIM:607906]. CDGs are a family ofsevere inherited diseases caused by a defect in protein N-glycosylation. They are characterized by under-glycosylated serumproteins. These multisystem disorders present with a wide varietyof clinical features, such as disorders of the nervous systemdevelopment, psychomotor retardation, dysmorphic features,hypotonia, coagulation disorders, and immunodeficiency. The broadspectrum of features reflects the critical role of N-glycoproteinsduring embryonic development, differentiation, and maintenance ofcell functions.

Defects in ALG3 are the cause of congenital disorder ofglycosylation type 1D (CDG1D) [MIM:601110], also known ascarbohydrate-deficient glycoprotein syndrome type IV (CDGS4). CDGsare metabolic deficiencies in glycoprotein biosynthesis thatusually cause severe mental and psychomotor retardation. They arecharacterized by under-glycosylated serum glycoproteins.

Defects in ALG6 are the cause of congenital disorder ofglycosylation type 1C (CDG1C) [MIM:603147], also known ascarbohydrate-deficient glycoprotein syndrome type V. CDGs aremetabolic deficiencies in glycoprotein biosynthesis that usuallycause severe mental and psychomotor retardation. They arecharacterized by under-glycosylated serum glycoproteins. CDG1Cpatients have muscular hypotonia, show a delayed statomotordevelopment and are mentally retarded. CDG1C is biochemicallycharacterized by an accumulation of dolichyl pyrophosphate-linkedMan(9)GlcNAc(2) in the endoplasmic reticulum.

Defects in ALG8 are the cause of congenital disorder ofglycosylation type 1H (CDG1H) [MIM:608104]. CDGs are a family ofsevere inherited diseases caused by a defect in protein N-glycosylation. They are characterized by under-glycosylated serumproteins. These multisystem disorders present with a wide varietyof clinical features, such as disorders of the nervous systemdevelopment, psychomotor retardation, dysmorphic features,hypotonia, coagulation disorders, and immunodeficiency. The broadspectrum of features reflects the critical role of N-glycoproteinsduring embryonic development, differentiation, and maintenance ofcell functions.

Note=A chromosomal aberration involving ALG9 is found ina family with bipolar affective disorder. Translocationt(9,11)(p24,q23). However, common variations in ALG9 do not play amajor role in predisposition to bipolar affective disorder.

Defects in ALG9 are the cause of congenital disorder ofglycosylation type 1L (CDG1L) [MIM:608776]. CDGs are a family ofsevere inherited diseases caused by a defect in protein N-glycosylation. They are characterized by under-glycosylated serumproteins. These multisystem disorders present with a wide varietyof clinical features, such as disorders of the nervous systemdevelopment, psychomotor retardation, dysmorphic features,hypotonia, coagulation disorders, and immunodeficiency. The broadspectrum of features reflects the critical role of N-glycoproteinsduring embryonic development, differentiation, and maintenance ofcell functions.

Note=A chromosomal aberration involving ALK is found in aform of non-Hodgkin lymphoma. Translocation t(2,5)(p23,q35) withNPM1. The resulting chimeric NPM1-ALK protein homodimerize and thekinase becomes constitutively activated. The constitutively activefusion proteins are responsible for 5-10% of non-Hodgkinlymphomas.

Note=A chromosomal aberration involving ALK is associatedwith inflammatory myofibroblastic tumors (IMTs). Translocationt(2,11)(p23,p15) with CARS, translocation t(2,4)(p23,q21) withSEC31A.

Note=A chromosomal aberration involving ALK is associatedwith anaplastic large-cell lymphoma (ALCL). Translocationt(2,17)(p23,q25) with ALO17.

Defects in ALK are the cause of susceptibility toneuroblastoma type 3 (NBLST3) [MIM:613014]. Neuroblastoma is acommon neoplasm of early childhood arising from embryonic cellsthat form the primitive neural crest and give rise to the adrenalmedulla and the sympathetic nervous system.

Defects in ALMS1 are the cause of Alstrom syndrome (ALMS)[MIM:203800]. Alstrom syndrome is a rare autosomal recessivedisorder characterized by progressive cone-rod retinal dystrophy,neurosensory hearing loss, early childhood obesity and type 2diabetes mellitus. Dilated cardiomyopathy, acanthosis nigricans,male hypogonadism, hypothyroidism, developmental delay and hepaticdysfunction can also be associated with the syndrome.

Note=A chromosomal aberration involving ALO17 isassociated with anaplastic large-cell lymphoma (ALCL).Translocation t(2,17)(p23,q25) with ALK.

Defects in GFER are a cause of mitochondrial progressivemyopathy with congenital cataract hearing loss and developmentaldelay (MPMCHD) [MIM:613076], also called combined mitochondrialcomplex deficiency.

Defects in ALS2 are the cause of amyotrophic lateralsclerosis type 2 (ALS2) [MIM:205100]. ALS2 is a familial form ofamyotrophic lateral sclerosis, a neurodegenerative disorderaffecting upper and lower motor neurons and resulting in fatalparalysis. Sensory abnormalities are absent. Death usually occurswithin 2 to 5 years. The etiology of amyotrophic lateral sclerosisis likely to be multifactorial, involving both genetic andenvironmental factors. The disease is inherited in 5-10% of casesleading to familial forms.

Defects in ALS2 are the cause of juvenile primary lateralsclerosis (JPLS) [MIM:606353]. JPLS is a neurodegenerativedisorder which is closely related to but clinically distinct fromamyotrophic lateral sclerosis. It is a progressive paralyticdisorder which results from dysfunction of the upper motor neuronsof the motor cortex while the lower neurons are unaffected.

Defects in ALS2 are the cause of infantile-onsetascending spastic paralysis (IAHSP) [MIM:607225]. IAHSP ischaracterized by progressive spasticity and weakness of limbs.

Defects in ALX1 are the cause of frontonasal dysplasiatype 3 (FND3) [MIM:613456]. The term frontonasal dysplasiadescribes an array of abnormalities affecting the eyes, foreheadand nose and linked to midfacial dysraphia. The clinical pictureis highly variable. Major findings include true ocularhypertelorism, broadening of the nasal root, median facial cleftaffecting the nose and/or upper lip and palate, unilateral orbilateral clefting of the alae nasi, lack of formation of thenasal tip, anterior cranium bifidum occultum, a V-shaped orwidow's peak frontal hairline.

Defects in ALX3 are the cause of frontonasal dysplasiatype 1 (FND1) [MIM:136760], also called frontonasal malformation(FNM) or frontorhiny. The term frontonasal dysplasia describes anarray of abnormalities affecting the eyes, forehead and nose andlinked to midfacial dysraphia. The clinical picture is highlyvariable. Major findings include true ocular hypertelorism,broadening of the nasal root, median facial cleft affecting thenose and/or upper lip and palate, unilateral or bilateral cleftingof the alae nasi, lack of formation of the nasal tip, anteriorcranium bifidum occultum, a V-shaped or widow's peak frontalhairline.

Defects in ALX4 are the cause of parietal foramina 2(PFM2) [MIM:609597], also known as foramina parietalia permagna(FPP). PFM2 is an autosomal dominant disease characterized by ovaldefects of the parietal bones caused by deficient ossificationaround the parietal notch, which is normally obliterated duringthe fifth fetal month. PFM2 is also a clinical feature of Potocki-Shaffer syndrome.

Defects in ALX4 are the cause of frontonasal dysplasiatype 2 (FND2) [MIM:613451]. The term frontonasal dysplasiadescribes an array of abnormalities affecting the eyes, foreheadand nose and linked to midfacial dysraphia. The clinical pictureis highly variable. Major findings include true ocularhypertelorism, broadening of the nasal root, median facial cleftaffecting the nose and/or upper lip and palate, unilateral orbilateral clefting of the alae nasi, lack of formation of thenasal tip, anterior cranium bifidum occultum, a V-shaped orwidow's peak frontal hairline.

Involved in Potocki-Shaffer syndrome (PSS) [MIM:601224].PSS is a contiguous gene syndrome caused by deletion of the11p11.2 region.

Defects in AMACR are the cause of alpha-methylacyl-CoAracemase deficiency (AMACRD) [MIM:604489]. AMACRD results inelevated plasma concentrations of pristanic acid C27-bile-acidintermediates. It can be associated with polyneuropathy, retinitispigmentosa, epilepsy.

Defects in AMACR are the cause of congenital bile acidsynthesis defect type 4 (CBAS4) [MIM:214950], also known ascholestasis, intrahepatic, with defective conversion oftrihydroxycoprostanic acid to cholic acid or trihydroxycoprostanicacid in bile. Clinical features include neonatal jaundice,intrahepatic cholestasis, bile duct deficiency and absence ofcholic acid from bile.

Defects in AMELX are the cause of amelogenesis imperfectahypoplastic type 1 (AIH1) [MIM:301200]. AIH1 is a X-linked defectof dental enamel formation. Teeth have only a thin layer of enamelwith normal hardness. The thinness of the enamel makes the teethappear small.

Defects in AMMECR1 are involved in Alport syndrome withmental retardation midface hypoplasia and elliptocytosis (ATS-MR)[MIM:300194]. A X-linked contiguous gene deletion syndromecharacterized by glomerulonephritis, deafness, mental retardation,midface hypoplasia and elliptocytosis.

Defects in AMHR2 are the cause of persistent Muellerianduct syndrome type 2 (PMDS2) [MIM:261550]. PMDS2 is a form of malepseudohermaphroditism characterized by a failure of Muellerianduct regression in otherwise normal males.

Defects in AMN are a cause of recessive hereditarymegaloblastic anemia 1 (RH-MGA1) [MIM:261100], also known as MGA1Norwegian type or Imerslund-Grasbeck syndrome (I-GS). RH-MGA1 isdue to selective malabsorption of vitamin B12. Defects in vitaminB12 absorption lead to impaired function of thymidine synthase. Asa consequence DNA synthesis is interrupted. Rapidly dividing cellsinvolved in erythropoiesis are particularly affected.

Defects in AMPD1 are the cause of adenosine monophosphatedeaminase deficiency muscle type (AMPDDM) [MIM:102770]. AMPDDM isa metabolic disorder resulting in exercise-related myopathy. It ischaracterized by exercise-induced muscle aches, cramps, and earlyfatigue.

Defects in AMPD3 are the cause of adenosine monophosphatedeaminase deficiency erythrocyte type (AMPDDE) [MIM:612874], alsoknown as erythrocyte AMP deaminase deficiency. AMPDDE is ametabolic disorder due to lack of activity of the erythrocyteisoform of AMP deaminase. It is a clinically asymptomaticcondition characterized by a 50% increase in steady-state levelsof ATP in affected cells. Individuals with complete deficiency oferythrocyte AMP deaminase are healthy and have no hematologicdisorders.

Note=In complex with the alpha-2-MR or gp330, it may havesome role in the pathogenesis of membrane glomerular nephritis.

Defects in NAGLU are the cause of mucopolysaccharidosistype 3B (MPS3B) [MIM:252920], also known as Sanfilippo syndrome B.MPS3B is a form of mucopolysaccharidosis type 3, an autosomalrecessive lysosomal storage disease due to impaired degradation ofheparan sulfate. MPS3 is characterized by severe central nervoussystem degeneration, but only mild somatic disease. Onset ofclinical features usually occurs between 2 and 6 years, severeneurologic degeneration occurs in most patients between 6 and 10years of age, and death occurs typically during the second orthird decade of life.

Defects in AR are the cause of androgen insensitivitysyndrome (AIS) [MIM:300068], previously known as testicularfeminization syndrome (TFM). AIS is an X-linked recessive form ofpseudohermaphroditism due end-organ resistance to androgen.Affected males have female external genitalia, female breastdevelopment, blind vagina, absent uterus and female adnexa, andabdominal or inguinal testes, despite a normal 46,XY karyotype.

Defects in AR are the cause of spinal and bulbar muscularatrophy X-linked type 1 (SMAX1) [MIM:313200], also known asKennedy disease. SMAX1 is an X-linked recessive form of spinalmuscular atrophy. Spinal muscular atrophy refers to a group ofneuromuscular disorders characterized by degeneration of theanterior horn cells of the spinal cord, leading to symmetricalmuscle weakness and atrophy. SMAX1 occurs only in men. Age atonset is usually in the third to fifth decade of life, but earlierinvolvement has been reported. It is characterized by slowlyprogressive limb and bulbar muscle weakness with fasciculations,muscle atrophy, and gynecomastia. The disorder is clinicallysimilar to classic forms of autosomal spinal muscular atrophy.Note=Caused by trinucleotide CAG repeat expansion. In SMAX1patients the number of Gln ranges from 38 to 62. Longer expansionsresult in earlier onset and more severe clinical manifestations ofthe disease.

Note=Defects in AR may play a role in metastatic prostatecancer. The mutated receptor stimulates prostate growth andmetastases development despite of androgen ablation. Thistreatment can reduce primary and metastatic lesions probably byinducing apoptosis of tumor cells when they express the wild-typereceptor.

Defects in AR are the cause of androgen insensitivitysyndrome partial (PAIS) [MIM:312300], also known as Reifensteinsyndrome. PAIS is characterized by hypospadias, hypogonadism,gynecomastia, genital ambiguity, normal XY karyotype, and apedigree pattern consistent with X-linked recessive inheritance.Some patients present azoospermia or severe oligospermia withoutother clinical manifestations.

Defects in NPPA are the cause of atrial fibrillationfamilial type 6 (ATFB6) [MIM:612201]. Atrial fibrillation is acommon disorder of cardiac rhythm that is hereditary in a smallsubgroup of patients. It is characterized by disorganized atrialelectrical activity, progressive deterioration of atrialelectromechanical function and ineffective pumping of blood intothe ventricles. It can be associated with palpitations, syncope,thromboembolic stroke, and congestive heart failure.

Defects in ANG are the cause of susceptibility toamyotrophic lateral sclerosis type 9 (ALS9) [MIM:611895]. ALS is adegenerative disorder of motor neurons in the cortex, brain stemand spinal cord. ALS is characterized by muscular weakness andatrophy.

Genetic variations in AGT are a cause of susceptibilityto essential hypertension (EHT) [MIM:145500]. Essentialhypertension is a condition in which blood pressure isconsistently higher than normal with no identifiable cause.

Defects in AGT are a cause of renal tubular dysgenesis(RTD) [MIM:267430]. RTD is an autosomal recessive severe disorderof renal tubular development characterized by persistent fetalanuria and perinatal death, probably due to pulmonary hypoplasiafrom early-onset oligohydramnios (the Potter phenotype).

Defects in ANK1 are a cause of spherocytosis type 1(SPH1) [MIM:182900], also called hereditary spherocytosis type 1(HS1). Spherocytosis is a hematologic disorder leading to chronichemolytic anemia and characterized by numerous abnormally shapederythrocytes which are generally spheroidal. Inheritance can beautosomal dominant or recessive.

Defects in ANK2 are the cause of long QT syndrome type 4(LQT4) [MIM:600919], also known as sick sinus syndrome withbradycardia. Long QT syndromes are heart disorders characterizedby a prolonged QT interval on the ECG and polymorphic ventriculararrhythmias. They cause syncope and sudden death in response toexercise or emotional stress. LQT4 displays many atypical featurescompared to classical long QT syndromes, including pronouncedsinus bradycardia, polyphasic T waves and atrial fibrillation.Cardiac repolarization defects may be not as severe as inclassical LQT syndromes and prolonged QT interval on EKG is not aconsistent feature.

Defects in ANKH are the cause of chondrocalcinosis 2(CCAL2) [MIM:118600]. Chondrocalcinosis is a common cause of jointpain and arthritis caused by calcium deposition in articularcartilage and the presence of calcium hypophosphate crystals insynovial fluid, cartilage and periarticular soft tissue. CCAL2inheritance is autosomal dominant.

Defects in ANKH are the cause of craniometaphysealdysplasia Jackson type (CMDJ) [MIM:123000]. CMDJ is a rareautosomal dominant skeletal disorder characterized by abnormalbone formation and mineralization in membranous as well asendochondral bones. Progressive thickening of the bones can causenarrowing of cranial foramina and can lead to severe visual andneurological impairment, such as facial palsy and deafness.

Defects in ANKRD1 may be a cause of total anomalouspulmonary venous return (TAPVR) [MIM:106700]. TAPVR is a rarecongenital heart disease (CHD) in which the pulmonary veins failto connect to the left atrium during cardiac development, draininginstead into either the right atrium or one of its venoustributaries. This disease accounts for 1.5% of all CHDs and has aprevalence of approximately 1 out of 15'000 live births.

Defects in ANO10 are the cause of spinocerebellar ataxiaautosomal recessive type 10 (SCAR10) [MIM:613728]. Spinocerebellarataxia is a clinically and genetically heterogeneous group ofcerebellar disorders. Patients show progressive incoordination ofgait and often poor coordination of hands, speech and eyemovements, due to degeneration of the cerebellum with variableinvolvement of the brainstem and spinal cord. SCAR10 ischaracterized by onset in the teenage or young adult years of gaitand limb ataxia, dysarthria, and nystagmus associated with markedcerebellar atrophy on brain imaging.

Defects in ANO5 are the cause of gnathodiaphysealdysplasia (GDD) [MIM:166260], also known as osteogenesisimperfecta with unusual skeletal lesions or gnathodiaphysealsclerosis. GDD is a rare skeletal syndrome characterized by bonefragility, sclerosis of tubular bones, and cemento-osseous lesionsof the jawbone. Patients experience frequent bone fractures causedby trivial accidents in childhood, however the fractures healnormally without bone deformity. The jaw lesions replace thetooth-bearing segments of the maxilla and mandible with fibrousconnective tissues, including various amounts of cementum-likecalcified mass, sometimes causing facial deformities. Patientsalso have a propensity for jaw infection and often suffer frompurulent osteomyelitis-like symptoms, such as swelling of and pusdischarge from the gums, mobility of the teeth, insufficienthealing after tooth extraction and exposure of the lesions intothe oral cavity.

Defects in ANO5 are the cause of limb-girdle musculardystrophy type 2L dysplasia (LGMD2L) [MIM:611307]. It is anautosomal recessive degenerative myopathy characterized byproximal weakness, weakness of the hip and shoulder girdles andprominent asymmetrical quadriceps femoris and biceps brachiiatrophy.

Defects in ANO5 are the cause of miyoshi musculardystrophy type 3 (MMD3) [MIM:613319]. It is a late-onset musculardystrophy characterized by distal muscle weakness of the lowerlimbs, calf muscle discomfort and weakness, quadriceps atrophy.Muscle weakness and atrophy may be asymmetric.

Defects in ANO6 are the cause of Scott syndrome (SCOTTS)[MIM:262890]. A mild bleeding disorder due to impaired surfaceexposure of procoagulant phosphatidylserine (PS) on platelets andother blood cells, following activation with Ca(2+)-elevatingagents.

Defects in NPR2 are the cause of acromesomelic dysplasiaMaroteaux type (AMDM) [MIM:602875]. Acromesomelicchondrodysplasias are rare hereditary skeletal disorderscharacterized by short stature, very short limbs, and hand/footmalformations. The severity of limb abnormalities increases fromproximal to distal with profoundly affected hands and feet showingbrachydactyly and/or rudimentary fingers (knob-like fingers). AMDMis an autosomal recessive form characterized by axial skeletalinvolvement with wedging of vertebral bodies. In AMDM all skeletalelements are present but show abnormal rates of linear growth.

Defects in SERPINC1 are the cause of antithrombin IIIdeficiency (AT3D) [MIM:613118]. AT3D is an important risk factorfor hereditary thrombophilia, a hemostatic disorder characterizedby a tendency to recurrent thrombosis. AT3D is classified into 4types. Type I: characterized by a 50% decrease in antigenic andfunctional levels. Type II: has defects affecting the thrombin-binding domain. Type III: alteration of the heparin-bindingdomain. Plasma AT-III antigen levels are normal in type II andIII. Type IV: consists of miscellaneous group of unclassifiablemutations.

Defects in ANTXR1 are associated with susceptibility tohemangioma capillary infantile (HCI) [MIM:602089]. HCI are benign,highly proliferative lesions involving aberrant localized growthof capillary endothelium. They are the most common tumor ofinfancy, occurring in up to 10% of all births. Hemangiomas tend toappear shortly after birth and show rapid neonatal growth for upto 12 months characterized by endothelial hypercellularity andincreased numbers of mast cells. This phase is followed by slowinvolution at a rate of about 10% per year and replacement byfibrofatty stroma.

Defects in ANTXR2 are the cause of infantile systemichyalinosis (ISH) [MIM:236490]. This autosomal recessive syndromeis similar to JHF, but has an earlier onset and a more severecourse. Symptoms appear at birth or within the first months oflife, with painful, swollen joint contractures, osteopenia,osteoporosis and livid red hyperpigmentation over bonyprominences. Patients develop multiple subcutaneous skin tumorsand gingival hypertrophy. Hyaline deposits in multiple organs,recurrent infections and intractable diarrhea often lead to deathwithin the first 2 years of life. Surviving children may sufferfrom severely reduced mobility due to joint contractures.

Defects in ANTXR2 are the cause of juvenile hyalinefibromatosis (JHF) [MIM:228600]. JHF is an autosomal recessivesyndrome that is similar to ISH but takes a milder course. It ischaracterized by hyaline deposition in the dermis, multiplesubcutaneous skin tumors and gingival hypertrophy, followed byprogressive joint contractions, osteopenia and osteoporosis thatmay lead to a severe limitation of mobility.

Defects in MAOA are the cause of Brunner syndrome (BRUNS)[MIM:300615]. Brunner syndrome is a form of X-linked non-dysmorphic mild mental retardation. Male patients are affected bya syndrome of borderline mental retardation and exhibit abnormalbehavior, including disturbed regulation of impulsive aggression.Obligate female carriers have normal intelligence and behavior.

Defects in AP1S2 are the cause of mental retardation X-linked type 59 (MRX59) [MIM:300630]. It is characterized bysignificantly sub-average general intellectual functioningassociated with impairments in adaptative behavior and manifestedduring the developmental period. In contrast to syndromic orspecific X-linked mental retardation which also present withassociated physical, neurological and/or psychiatricmanifestations, intellectual deficiency is the only primarysymptom of non-syndromic X-linked mental retardation. MRX59consists of a mild-to-profound mental retardation. Other featuresincludes hypotonia early in life and delay in walking.

Defects in TFAP2A are the cause of branchiooculofacialsyndrome (BOFS) [MIM:113620], also known as branchial clefts withcharacteristic facies, growth retardation, imperforatenasolacrimal duct, and premature aging or lip pseudocleft-hemangiomatous branchial cyst syndrome. BOFS is a rare autosomaldominant cleft palate craniofacial disorder with variableexpressivity. The major features include cutaneous anomalies,ocular anomalies, characteristic facial appearance (malformedpinnae, oral clefts), and, less commonly, renal and ectodermal(dental and hair) anomalies.

Defects in TFAP2B are the cause of Char syndrome (CHAR)[MIM:169100]. CHAR is an autosomal dominant disorder characterizedby patent ductus arteriosus (PDA), facial dysmorphism and handanomalies.

Defects in AP3B1 are the cause of Hermansky-Pudlaksyndrome type 2 (HPS2) [MIM:608233]. Hermansky-Pudlak syndrome(HPS) is a genetically heterogeneous, rare, autosomal recessivedisorder characterized by oculocutaneous albinism, bleeding due toplatelet storage pool deficiency, and lysosomal storage defects.This syndrome results from defects of diverse cytoplasmicorganelles including melanosomes, platelet dense granules andlysosomes. Ceroid storage in the lungs is associated withpulmonary fibrosis, a common cause of premature death inindividuals with HPS. HPS2 differs from the other forms of HPS inthat it includes immunodeficiency in its phenotype and patientswith HPS2 have an increased susceptibility to infections.

Defects in AP4M1 are the cause of cerebral palsy spasticquadriplegic type 3 (CPSQ3) [MIM:612936]. A non-progressivedisorder of movement and/or posture resulting from defects in thedeveloping central nervous system. Affected individuals presentpostnatally with early infantile hypotonia, delayed psychomotordevelopment, strabismus, lack of independent walking and severemental retardation. They develop progressive spasticity of alllimbs with generalized hypertonia, hyperreflexia, and extensorplantar responses by the end of the first year of life. Speech isabsent or limited. Pseudobulbar signs, such as drooling,stereotypic laughter, and exaggerated jaw jerk, are part of theclinical picture.

Defects in APCDD1 are a cause of hypotrichosis simplex(HTS) [MIM:605389]. HTS is a rare form of non-syndromic hereditaryhypotrichosis without characteristic hair shaft anomalies.Affected individuals typically show normal hair at birth, but hairloss and thinning of the hair shaft start during early childhoodand progress with age.

Defects in APC are a cause of familial adenomatouspolyposis (FAP) [MIM:175100], which includes also Gardner syndrome(GS). FAP and GS contribute to tumor development in patients withuninherited forms of colorectal cancer. FAP is characterized byadenomatous polyps of the colon and rectum, but also of uppergastrointestinal tract (ampullary, duodenal and gastric adenomas).This is a viciously premalignant disease with one or more polypsprogressing through dysplasia to malignancy in untreated genecarriers with a median age at diagnosis of 40 years.

Defects in APC are a cause of hereditary desmoid disease(HDD) [MIM:135290], also known as familial infiltrativefibromatosis (FIF). HDD is an autosomal dominant trait with 100%penetrance and possible variable expression among affectedrelatives. HDD patients show multifocal fibromatosis of theparaspinal muscles, breast, occiput, arms, lower ribs, abdominalwall, and mesentery. Desmoid tumors appears also as a complicationof familial adenomatous polyposis.

Defects in APC are a cause of medulloblastoma (MDB)[MIM:155255]. MDB is a malignant, invasive embryonal tumor of thecerebellum with a preferential manifestation in children. Althoughthe majority of medulloblastomas occur sporadically, some manifestwithin familial cancer syndromes such as Turcot syndrome and basalcell nevus syndrome (Gorlin syndrome).

Defects in APC are a cause of mismatch repair cancersyndrome (MMRCS) [MIM:276300], also known as Turcot syndrome orbrain tumor-polyposis syndrome 1 (BTPS1). MMRCS is an autosomaldominant disorder characterized by malignant tumors of the brainassociated with multiple colorectal adenomas. Skin featuresinclude sebaceous cysts, hyperpigmented and cafe au lait spots.

Defects in APC are a cause of gastric cancer (GASC)[MIM:613659], also called gastric cancer intestinal or stomachcancer. Gastric cancer is a malignant disease which starts in thestomach, can spread to the esophagus or the small intestine, andcan extend through the stomach wall to nearby lymph nodes andorgans. It also can metastasize to other parts of the body. Theterm gastric cancer or gastric carcinoma refers to adenocarcinomaof the stomach that accounts for most of all gastric malignanttumors. Two main histologic types are recognized, diffuse type andintestinal type carcinomas. Diffuse tumors are poorlydifferentiated infiltrating lesions, resulting in thickening ofthe stomach. In contrast, intestinal tumors are usually exophytic,often ulcerating, and associated with intestinal metaplasia of thestomach, most often observed in sporadic disease.

Defects in APC are a cause of hepatocellular carcinoma(HCC) [MIM:114550]. This defect includes also the disease entitytermed hepatoblastoma.

Defects in APOA1 are a cause of high density lipoproteindeficiency type 2 (HDLD2) [MIM:604091], also known as familialhypoalphalipoproteinemia (FHA). Inheritance is autosomal dominant.

Defects in APOA1 are a cause of the low HDL levelsobserved in high density lipoprotein deficiency type 1 (HDLD1)[MIM:205400], also known as analphalipoproteinemia or Tangierdisease (TGD). HDLD1 is a recessive disorder characterized by theabsence of plasma HDL, accumulation of cholesteryl esters,premature coronary artery disease, hepatosplenomegaly, recurrentperipheral neuropathy and progressive muscle wasting and weakness.In HDLD1 patients, ApoA-I fails to associate with HDL probablybecause of the faulty conversion of pro-ApoA-I molecules intomature chains, either due to a defect in the converting enzymeactivity or a specific structural defect in Tangier ApoA-I.

Defects in APOA1 are the cause of amyloid polyneuropathy-nephropathy Iowa type (AMYLIOWA) [MIM:107680], also known asamyloidosis van Allen type or familial amyloid polyneuropathy typeIII. AMYLIOWA is a hereditary generalized amyloidosis due todeposition of amyloid mainly constituted by apolipoprotein A1. Theclinical picture is dominated by neuropathy in the early stages ofthe disease and nephropathy late in the course. Death is due inmost cases to renal amyloidosis. Severe peptic ulcer disease canoccurr in some and hearing loss is frequent. Cataracts is presentin several, but vitreous opacities are not observed.

Defects in APOA1 are a cause of amyloidosis type 8(AMYL8) [MIM:105200], also known as systemic non-neuropathicamyloidosis or Ostertag-type amyloidosis. AMYL8 is a hereditarygeneralized amyloidosis due to deposition of apolipoprotein A1,fibrinogen and lysozyme amyloids. Viscera are particularlyaffected. There is no involvement of the nervous system. Clinicalfeatures include renal amyloidosis resulting in nephroticsyndrome, arterial hypertension, hepatosplenomegaly, cholestasis,petechial skin rash.

Defects in APOA5 are a cause of susceptibility tofamilial hypertriglyceridemia (FHTR)[MIM:145750].mFamilialhypertriglyceridemia is a common inherited disorder in which theconcentration of very low density lipoprotein (VLDL) is elevatedin the plasma. This leads to increased risk of heart disease,obesity, and pancreatitis.

Defects in APOA5 are a cause of hyperlipoproteinemia type5 (HLPP5) [MIM:144650]. HLPP5 is characterized by increasedamounts of chylomicrons and very low density lipoprotein (VLDL)and decreased low density lipoprotein (LDL) and high densitylipoprotein (HDL) in the plasma after a fast. Numerous conditionscause this phenotype, including insulin-dependent diabetesmellitus, contraceptive steroids, alcohol abuse, and glycogenstorage disease type 1A (GSD1A) [MIM:232200].

Defects in APOB are a cause of hypobetalipoproteinemiafamilial type 1 (FHBL1) [MIM:107730]. A disorder characterized byhighly reduced plasma concentrations of low density lipoproteins,and dietary fat malabsorption. Clinical presentation may vary fromno symptoms to severe gastrointestinal and neurologicaldysfunction similar to abetalipoproteinemia.

Defects in APOB are a cause of familial ligand-defectiveapolipoprotein B-100 (FDB) [MIM:144010]. FDB is a dominantlyinherited disorder of lipoprotein metabolism leading tohypercholesterolemia and increased proneness to coronary arterydisease (CAD). The plasma cholesterol levels are dramaticallyelevated due to impaired clearance of LDL particles by defectiveAPOB/E receptors.

Note=Defects in APOB associated with defects in othergenes (polygenic) can contribute to hypocholesterolemia.

Defects in APOC2 are the cause of hyperlipoproteinemiatype 1B (HLPP1B) [MIM:207750]. It is an autosomal recessive traitcharacterized by hypertriglyceridemia, xanthomas, and increasedrisk of pancreatitis and early atherosclerosis.

Defects in APOC3 may be a cause ofhyperalphalipoproteinemia (HYPALIP) [MIM:143470]. Affectedindividuals show high levels of alpha-lipoprotein (high densitylipoprotein/HDL).

Defects in APOE are a cause of hyperlipoproteinemia type3 (HLPP3) [MIM:107741], also known as familialdysbetalipoproteinemia. Individuals with HLPP3 are clinicallycharacterized by xanthomas, yellowish lipid deposits in the palmarcrease, or less specific on tendons and on elbows. The disorderrarely manifests before the third decade in men. In women, it isusually expressed only after the menopause. The vast majority ofthe patients are homozygous for APOE*2 alleles. More severe casesof HLPP3 have also been observed in individuals heterozygous forrare APOE variants. The influence of APOE on lipid levels is oftensuggested to have major implications for the risk of coronaryartery disease (CAD). Individuals carrying the common APOE*4variant are at higher risk of CAD.

Genetic variations in APOE are associated with Alzheimerdisease type 2 (AD2) [MIM:104310]. It is a late-onsetneurodegenerative disorder characterized by progressive dementia,loss of cognitive abilities, and deposition of fibrillar amyloidproteins as intraneuronal neurofibrillary tangles, extracellularamyloid plaques and vascular amyloid deposits. The majorconstituent of these plaques is the neurotoxic amyloid-beta-APP40-42 peptide (s), derived proteolytically from the transmembraneprecursor protein APP by sequential secretase processing. Thecytotoxic C-terminal fragments (CTFs) and the caspase-cleavedproducts such as C31 derived from APP, are also implicated inneuronal death. Note=The APOE*4 allele is genetically associatedwith the common late onset familial and sporadic forms ofAlzheimer disease. Risk for AD increased from 20% to 90% and meanage at onset decreased from 84 to 68 years with increasing numberof APOE*4 alleles in 42 families with late onset AD. Thus APOE*4gene dose is a major risk factor for late onset AD and, in thesefamilies, homozygosity for APOE*4 was virtually sufficient tocause AD by age 80. The mechanism by which APOE*4 participates inpathogenesis is not known.

Defects in APOE are a cause of sea-blue histiocytedisease (SBHD) [MIM:269600], also known as sea-blue histiocytosis.This disorder is characterized by splenomegaly, mildthrombocytopenia and, in the bone marrow, numerous histiocytescontaining cytoplasmic granules which stain bright blue with theusual hematologic stains. The syndrome is the consequence of aninherited metabolic defect analogous to Gaucher disease and othersphingolipidoses.

Defects in APOE are a cause of lipoprotein glomerulopathy(LPG) [MIM:611771]. LPG is an uncommon kidney diseasecharacterized by proteinuria, progressive kidney failure, anddistinctive lipoprotein thrombi in glomerular capillaries. Itmainly affects people of Japanese and Chinese origin. The disorderhas rarely been described in Caucasians.

Defects in APOL1 are the cause of focal segmentalglomerulosclerosis type 4 (FSGS4) [MIM:612551]. It is a renalpathology defined by the presence of segmental sclerosis inglomeruli and resulting in proteinuria, reduced glomerularfiltration rate and edema. Renal insufficiency often progresses toend-stage renal disease, a highly morbid state requiring eitherdialysis therapy or kidney transplantation.

Defects in APTX are the cause of ataxia-oculomotorapraxia syndrome (AOA) [MIM:208920]. AOA is an autosomal recessivesyndrome characterized by early-onset cerebellar ataxia,oculomotor apraxia, early areflexia and late peripheralneuropathy.

Defects in APTX are a cause of coenzyme Q10 deficiency[MIM:607426]. Coenzyme Q10 deficiency is an autosomal recessivedisorder with variable manifestations. It can be associated withthree main clinical phenotypes: a predominantly myopathic formwith central nervous system involvement, an infantileencephalomyopathy with renal dysfunction and an ataxic form withcerebellar atrophy. Coenzyme Q10 deficiency due to APTX mutationsis typically associated with cerebellar ataxia.

Defects in APRT are the cause of adeninephosphoribosyltransferase deficiency (APRTD) [MIM:102600], alsoknown as 2,8-dihydroxyadenine urolithiasis. An enzymaticdeficiency that can lead to urolithiasis and renal failure.Patients have 2,8-dihydroxyadenine (DHA) urinary stones.

Defects in AQP2 are the cause of diabetes insipidusnephrogenic autosomal (ANDI) [MIM:125800], also known as diabetesinsipidus nephrogenic type 2. ANDI is caused by the inability ofthe renal collecting ducts to absorb water in response to argininevasopressin. It is characterized by excessive water drinking(polydypsia), excessive urine excretion (polyuria), persistenthypotonic urine, and hypokalemia. Inheritance can be autosomaldominant or recessive.

Defects in ARL13B are the cause of Joubert syndrome type8 (JBTS8) [MIM:612291]. JBTS is an autosomal recessive disorderpresenting with cerebellar ataxia, oculomotor apraxia, hypotonia,neonatal breathing abnormalities and psychomotor delay.Neuroradiologically, it is characterized by cerebellar vermishypoplasia/aplasia, thickened and reoriented superior cerebellarpeduncles, and an abnormally large interpeduncular fossa, givingthe appearance of a molar tooth on transaxial slices (molar toothsign). Additional variable features include retinal dystrophy andrenal disease.

Defects in ARG1 are the cause of argininemia (ARGIN)[MIM:207800], also known as hyperargininemia. Argininemia is arare autosomal recessive disorder of the urea cycle. Arginine iselevated in the blood and cerebrospinal fluid, and periodichyperammonemia occurs. Clinical manifestations includedevelopmental delay, seizures, mental retardation, hypotonia,ataxia, progressive spastic quadriplegia.

Defects in ARHGEF6 are the cause of mental retardation X-linked type 46 (MRX46) [MIM:300436]. Mental retardation is amental disorder characterized by significantly sub-average generalintellectual functioning associated with impairments in adaptativebehavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest otherclinical signs.

Defects in ARHGEF9 are a cause of startle disease withepilepsy (STHEE) [MIM:300607], also known as hyperekplexia withepilepsy. Startle disease is a genetically heterogeneousneurologic disorder. STHE is characterized by muscular rigidity ofcentral nervous system origin, particularly in the neonatalperiod, and by an exaggerated startle response to unexpectedacoustic or tactile stimuli.

Defects in ARHGEF10 are the cause of slowed nerveconduction velocity (SNCV) [MIM:608236]. Affected individualspresent a reduction in nerve conduction velocities without anyclinical signs of peripheral or central nervous systemdysfunction. SNCV inheritance is autosomal dominant.

Note=A chromosomal aberration involving ARHGEF12 may be acause of acute leukemia. Translocation t(11,11)(q23,23) with MLL.

Defects in LDLRAP1 are the cause of autosomal recessivehypercholesterolemia (ARH) [MIM:603813]. ARH is a disorder causedby defective internalization of LDL receptors (LDLR) in the liver.ARH has the clinical features of familial hypercholesterolemia(FH) [MIM:143890] homozygotes, including severely elevated plasmaLDL cholesterol, tuberous and tendon xanthomata, and prematureatherosclerosis. LDL receptor (LDLR) activity measured in skinfibroblasts is normal, as the LDL binding ability.

Defects in ARL11 may be a cause of susceptibility tochronic lymphocytic leukemia (CLL) [MIM:151400].

Defects in ARL6 are a cause of Bardet-Biedl syndrome type3 (BBS3) [MIM:209900]. Bardet-Biedl syndrome (BBS) is agenetically heterogeneous disorder characterized by usually severepigmentary retinopathy, early onset obesity, polydactyly,hypogenitalism, renal malformation and mental retardation.Secondary features include diabetes mellitus, hypertension andcongenital heart disease.

Defects in ARL6 are the cause of retinitis pigmentosatype 55 (RP55) [MIM:613575]. RP55 is a retinal dystrophy belongingto the group of pigmentary retinopathies. Retinitis pigmentosa ischaracterized by retinal pigment deposits visible on fundusexamination and primary loss of rod photoreceptor cells followedby secondary loss of cone photoreceptors. Patients typically havenight vision blindness and loss of midperipheral visual field. Astheir condition progresses, they lose their far peripheral visualfield and eventually central vision as well.

Defects in ASL are the cause of arginosuccinicaciduria(ARGINSA) [MIM:207900]. Arginosuccinicaciduria is an autosomalrecessive disorder of the urea cycle. The disease is characterizedby mental and physical retardation, liver enlargement, skinlesions, dry and brittle hair showing trichorrhexis nodosamicroscopically and fluorescing red, convulsions, and episodicunconsciousness.

Defects in ARMS2 influence susceptibility to age-relatedmacular degeneration type 8 (ARMD8) [MIM:611313]. ARMD is the mostcommon cause of irreversible vision loss in the developed world.In most patients, the disease is manifest as ophthalmoscopicallyvisible yellowish accumulations of protein and lipid (known asdrusen) that lie beneath the retinal pigment epithelium and withinan elastin-containing structure known as Bruch's membrane. ARMD islikely to be a mechanistically heterogeneous group of disorders,and the specific disease mechanisms that underlie the vastmajority of cases are currently unknown. However, a number ofstudies have suggested that both genetic and environmental factorsare likely to play a role.

Defects in SAG are a cause of congenital stationary nightblindness Oguchi type 1 (CSNBO1) [MIM:258100], also known asOguchi disease. Congenital stationary night blindness is a non-progressive retinal disorder characterized by impaired nightvision. CSNBO is an autosomal recessive form associated withfundus discoloration and abnormally slow dark adaptation.

Defects in ARSA are a cause of leukodystrophymetachromatic (MLD) [MIM:250100]. MLD is a disease due to alysosomal storage defect. It is characterized by intralysosomalstorage of cerebroside-3-sulfate in neural and non-neural tissues,with a diffuse loss of myelin in the central nervous system.Progressive demyelination causes a variety of neurologicalsymptoms, including gait disturbances, ataxias, optical atrophy,dementia, seizures, and spastic tetraparesis. Three forms of thedisease can be distinguished according to the age at onset: late-infantile, juvenile and adult.

Arylsulfatase A activity is defective in multiplesulfatase deficiency (MSD) [MIM:272200]. MSD is a disordercharacterized by decreased activity of all known sulfatases. MSDis due to defects in SUMF1 resulting in the lack of post-translational modification of a highly conserved cysteine into 3-oxoalanine. It combines features of individual sulfatasedeficiencies such as metachromatic leukodystrophy,mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus,ichthyosis, neurologic deterioration and developmental delay.

Defects in ARSB are the cause of mucopolysaccharidosistype 6 (MPS6) [MIM:253200], also known as Maroteaux-Lamy syndrome.MPS6 is an autosomal recessive lysosomal storage diseasecharacterized by intracellular accumulation of dermatan sulfate.Clinical features can include abnormal growth, short stature,stiff joints, skeletal malformations, corneal clouding,hepatosplenomegaly, and cardiac abnormalities. A wide variation inclinical severity is observed.

Arylsulfatase B activity is defective in multiplesulfatase deficiency (MSD) [MIM:272200]. MSD is a disordercharacterized by decreased activity of all known sulfatases. MSDis due to defects in SUMF1 resulting in the lack of post-translational modification of a highly conserved cysteine into 3-oxoalanine. It combines features of individual sulfatasedeficiencies such as metachromatic leukodystrophy,mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus,ichthyosis, neurologic deterioration and developmental delay.

Defects in ARSE are the cause of chondrodysplasiapunctata X-linked recessive type 1 (CDPX1) [MIM:302950]. CDP is aclinically and genetically heterogeneous disorder characterized bypunctiform calcification of the bones. CDPX1 is a congenitaldefect of bone and cartilage development characterized by aberrantbone mineralization, severe underdevelopment of nasal cartilage,and distal phalangeal hypoplasia. This disease can also be inducedby inhibition with the drug warfarin.

Defects in ARX are the cause of lissencephaly X-linkedtype 2 (LISX2) [MIM:300215], also known as lissencephaly X-linkedwith ambiguous genitalia (XLAG). LISX2 is a classic typelissencephaly associated with abnormal genitalia. LISX2 patientshave severe congenital or postnatal microcephaly, lissencephaly,agenesis of the corpus callosum, neonatal-onset intractableepilepsy, poor temperature regulation, chronic diarrhea, andambiguous or underdeveloped genitalia.

Defects in ARX are the cause of epileptic encephalopathyearly infantile type 1 (EIEE1) [MIM:308350], also known asmyoclonic epilepsy X-linked with intellectual disability andspasticity, X-linked West syndrome or X-linked infantile spasmsyndrome (ISSX). EIEE1 is a severe form of epilepsy characterizedby frequent tonic seizures or spasms beginning in infancy with aspecific EEG finding of suppression-burst patterns, characterizedby high-voltage bursts alternating with almost flat suppressionphases. Patients may progress to West syndrome, which ischaracterized by tonic spasms with clustering, arrest ofpsychomotor development, and hypsarrhythmia on EEG.

Defects in ARX are a cause of Partington syndrome (PRTS)[MIM:309510], also known as X-linked syndromic mental retardation1 (MRXS1). PRTS is characterized by mental retardation, episodicdystonic hand movements, and dysarthria.

Defects in ARX are the cause of mental retardation X-linked ARX-related (MRXARX) [MIM:300419]. Mental retardation is amental disorder characterized by significantly sub-average generalintellectual functioning associated with impairments in adaptativebehavior and manifested during the developmental period.

Defects in ARX are the cause of agenesis of the corpuscallosum with abnormal genitalia (ACCAG) [MIM:300004]. A X-linkedsyndrome with variable expression in females. It is characterizedby agenesis of corpus callosum, mental retardation and seizures.Manifestations in surviving males include severe acquiredmicrencephaly, mental retardation, limb contractures, scoliosis,tapered fingers with hyperconvex nails, a characteristic face withlarge eyes, prominent supraorbital ridges, synophrys, opticatrophy, broad alveolar ridges, and seizures. Urologic anomaliesinclude renal dysplasia, cryptorchidism, and hypospadias.

Defects in ASAH1 are the cause of Farberlipogranulomatosis (FL) [MIM:228000], also known as Farber disease(FD). This sphingolipid disease is characterized by subcutaneouslipid-loaded nodules, excruciating pain in the joints andextremities, marked accumulation of ceramide in lysosomes, anddeath by three years of age.

Defects in SMPD1 are the cause of Niemann-Pick diseasetype A (NPDA) [MIM:257200], also known as Niemann-Pick diseaseclassical infantile form. It is an early-onset lysosomal storagedisorder caused by failure to hydrolyze sphingomyelin to ceramide.It results in the accumulation of sphingomyelin and othermetabolically related lipids in reticuloendothelial and other celltypes throughout the body, leading to cell death. Niemann-Pickdisease type A is a primarily neurodegenerative disordercharacterized by onset within the first year of life, mentalretardation, digestive disorders, failure to thrive, majorhepatosplenomegaly, and severe neurologic symptoms. The severeneurological disorders and pulmonary infections lead to an earlydeath, often around the age of four. Clinical features arevariable. A phenotypic continuum exists between type A (basicneurovisceral) and type B (purely visceral) forms of Niemann-Pickdisease, and the intermediate types encompass a cluster ofvariants combining clinical features of both types A and B.

Defects in SMPD1 are the cause of Niemann-Pick diseasetype B (NPDB) [MIM:607616], also known as Niemann-Pick diseasevisceral form. It is a late-onset lysosomal storage disordercaused by failure to hydrolyze sphingomyelin to ceramide. Itresults in the accumulation of sphingomyelin and othermetabolically related lipids in reticuloendothelial and other celltypes throughout the body, leading to cell death. Clinical signsinvolve only visceral organs. The most constant sign ishepatosplenomegaly which can be associated with pulmonarysymptoms. Patients remain free of neurologic manifestations.However, a phenotypic continuum exists between type A (basicneurovisceral) and type B (purely visceral) forms of Niemann-Pickdisease, and the intermediate types encompass a cluster ofvariants combining clinical features of both types A and B. InNiemann-Pick disease type B, onset of the first symptoms occurs inearly childhood and patients can survive into adulthood.

Note=A chromosomal aberration involving ASPSCR1 is foundin patients with alveolar soft part sarcoma. Translocationt(X,17)(p11,q25) with TFE3 forms a ASPSCR1-TFE3 fusion protein.

Note=A chromosomal aberration involving ASPSCR1 has beenfound in two patients with of papillary renal cell carcinoma.Translocation t(X,17)(p11.2,q25).

Defects in AGA are the cause of aspartylglucosaminuria(AGU) [MIM:208400]. AGU is an inborn lysosomal storage disease.Clinical features of AGU include mild to severe mental retardationmanifesting from the age of 2, coarse facial features and mildconnective tissue abnormalities. This recessively inheriteddisease is overrepresented in the Finnish population.

Defects in ASPM are the cause of microcephaly primarytype 5 (MCPH5) [MIM:608716], also known as true microcephaly ormicrocephaly vera. Microcephaly is defined as a head circumferencemore than 3 standard deviations below the age-related mean. Brainweight is markedly reduced and the cerebral cortex isdisproportionately small. Despite this marked reduction in size,the gyral pattern is relatively well preserved, with no majorabnormality in cortical architecture. Primary microcephaly isfurther defined by the absence of other syndromic features orsignificant neurological deficits. This entity is inherited asautosomal recessive trait.

Defects in ASS1 are the cause of citrullinemia type 1(CTLN1) [MIM:215700]. Citrullinemia belongs to the urea cycledisorders. It is an autosomal recessive disease characterizedprimarily by elevated serum and urine citrulline levels. Ammoniaintoxication is another manifestation. CTLN1 usually manifests inthe first few days of life. Affected infants appear normal atbirth, but as ammonia builds up in the body they present symptomssuch as lethargy, poor feeding, vomiting, seizures and loss ofconsciousness. Less commonly, a milder CTLN1 form can developlater in childhood or adulthood.

Note=A chromosomal aberration involving ASXL2 is a causeof therapy-related myelodysplastic syndrome. Translocationt(2,8)(p23,p11.2) with MYST3 generates a MYST3-ASXL2 fusionprotein.

Defects in ATP10A are a cause of Angelman syndrome (AS)[MIM:105830], also known as 'happy puppet syndrome'. AS ischaracterized by features of severe motor and intellectualretardation, microcephaly, ataxia, frequent jerky limb movementsand flapping of the arms and hands, hypotonia, hyperactivity,hypopigmentation, seizures, absence of speech, frequent smilingand episodes of paroxysmal laughter, and an unusual faciescharacterized by macrostomia, a large mandible and open-mouthedexpression, a great propensity for protruding the tongue ('tonguethrusting'), and an occipital groove.

Defects in ATP13A2 are the cause of Kufor-Rakeb syndrome(KRS) [MIM:606693], also known as Parkinson disease type 9(PARK9). KRS is a rare hereditary disease with juvenile onset. Inaddition to typical signs of Parkinson disease, affectedindividuals show symptoms of more widespread neurodegeneration,including dementia.

Note=A chromosomal aberration involving ATP13A4 is foundin 2 patients with specific language impairment (SLI) disorders.Paracentric inversion inv(3)(q25,q29). The inversion produces adisruption of the protein.

Defects in ATP1A2 are the cause of migraine familialhemiplegic type 2 (FHM2) [MIM:602481]. FHM2 is a rare, severe,autosomal dominant subtype of migraine characterized by aura andsome hemiparesis.

Defects in ATP1A2 are a cause of alternating hemiplegiaof childhood (AHC) [MIM:104290]. AHC is typically distinguishedfrom familial hemiplegic migraine by infantile onset of thesymptoms and high prevalence of associated neurological deficitsthat become increasingly obvious with age.

Defects in ATP1A3 are the cause of dystonia type 12(DYT12) [MIM:128235], also known as rapid-onset dystoniaparkinsonism (RDP). DYT12 is an autosomal dominant dystonia-parkinsonism disorder. Dystonia is defined by the presence ofsustained involuntary muscle contractions, often leading toabnormal postures. DYT12 patients develop dystonia andparkinsonism between 15 and 45 years of age. The disease ischaracterized by an unusually rapid evolution of signs andsymptoms. The sudden onset of symptoms over hours to a few weeks,often associated with physical or emotional stress, suggests atrigger initiating a nervous system insult resulting in permanentneurologic disability.

Defects in ATP2A1 are the cause of Brody myopathy (BRM)[MIM:601003]. An autosomal recessive myopathy characterized byincreasing impairment of relaxation of fast twist skeletal muscleduring exercise.

Defects in ATP2A2 are a cause of acrokeratosisverruciformis (AKV) [MIM:101900], also known as Hopf disease. AKVis a localized disorder of keratinization, which is inherited asan autosomal dominant trait. Its onset is early in life withmultiple flat-topped, flesh-colored papules on the hands and feet,punctate keratoses on the palms and soles, with varying degrees ofnail involvement. The histopathology shows a distinctive patternof epidermal features with hyperkeratosis, hypergranulosis, andacanthosis together with papillomatosis. These changes arefrequently associated with circumscribed elevations of theepidermis that are said to resemble church spires. There are nofeatures of dyskeratosis or acantholysis, the typical findings inlesions of Darier disease.

Defects in ATP2A2 are the cause of Darier disease (DD)[MIM:124200], also known as Darier-White disease (DAR). DD is anautosomal dominantly inherited skin disorder characterized by lossof adhesion between epidermal cells (acantholysis) and abnormalkeratinization. Patients with mild disease may have no more than afew scattered keratotic papules or subtle nail changes, whereasthose with severe disease are handicapped by widespread malodorouskeratotic plaques. In a few families, neuropsychiatricabnormalities such as mild mental retardation, schizophrenia,bipolar disorder and epilepsy have been reported. Stress, UVexposure, heat, sweat, friction, and oral contraception exacerbatedisease symptoms. Prevalence has been estimated at 1 in 50000.Clinical variants of DD include hypertrophic, vesicobullous,hypopigmented, cornifying, zosteriform or linear, acute andcomedonal subtypes. Comedonal Darier disease (CDD) ischaracterized by the coexistence of acne-like comedonal lesionswith typical Darier hyperkeratotic papules on light-exposed areas.At histopathologic level, CDD differs from classic DD in theprominent follicular involvement and the presence of greatlyelongated dermal villi.

Defects in ATP2C1 are the cause of Hailey-Hailey disease(HHD) [MIM:169600], also known as benign familial pemphigus. HHDis an autosomal dominant disorder characterized by persistentblisters and suprabasal cell separation (acantholysis) of theepidermis, due to impaired keratinocyte adhesion. Patients lackingall isoforms except isoform 2 have HHD.

Defects in ATP8B1 are the cause of progressive familialintrahepatic cholestasis type 1 (PFIC1) [MIM:211600], also knownas Byler disease. PFIC1 is an autosomal recessive disorder,characterized by early infancy cholestasis, that may be initiallyepisodic but progresses to malnutrition, growth retardation andend-stage liver disease before adulthood.

Defects in ATP8B1 are the cause of benign recurrentintrahepatic cholestasis type 1 (BRIC1) [MIM:243300], also knownas Summerskill syndrome. BRIC is characterized by intermittentepisodes of cholestasis without progression to liver failure.There is initial elevation of serum bile acids, followed bycholestatic jaundice which generally spontaneously resolves afterperiods of weeks to months. The cholestatic attacks vary inseverity and duration. Patients are asymptomatic between episodes,both clinically and biochemically.

Defects in ATP8B1 can be associated with intrahepaticcholestasis of pregnancy (ICP) [MIM:147480], also known aspregnancy-related cholestasis. ICP is a multifactorial liverdisorder of pregnancy. It presents during the second or, morecommonly, the third trimestre of pregnancy with intense prurituswhich becomes more severe with advancing gestation andcholestasis. Cholestasis results from abnormal biliary transportfrom the liver into the small intestine. ICP causes fetaldistress, spontaneous premature delivery and intrauterine death.ICP patients have spontaneous and progressive disappearance ofcholestasis after delivery.

Defects in ATCAY are the cause of cerebellar ataxia,cayman type (ATCAY) [MIM:601238]. ATCAY is found in a populationisolate on Grand Cayman Island and causes a marked psychomotorretardation and prominent nonprogressive cerebellar dysfunctionincluding nystagmus, intention tremor, dysarthria, and wide-basedataxic gait. Hypotonia is present from early childhood.

Defects in ATF1 may be a cause of angiomatoid fibroushistiocytoma (AFH) [MIM:612160]. A distinct variant of malignantfibrous histiocytoma that typically occurs in children andadolescents and is manifest by nodular subcutaneous growth.Characteristic microscopic features include lobulated sheets ofhistiocyte-like cells intimately associated with areas ofhemorrhage and cystic pseudovascular spaces, as well as a strikingcuffing of inflammatory cells, mimicking a lymph node metastasis.Note=Chromosomal aberrations involving ATF1 are found in patientswith angiomatoid fibrous histiocytoma. Translocationt(12,16)(q13,p11.2) with FUS generates a chimeric ATF1/FUSprotein. Translocation t(12,22)(q13,q12) with EWSR1 generates achimeric ATF1/EWSR1 protein.

Defects in ADAMTSL2 are the cause of geleophysicdysplasia (GLPD) [MIM:231050]. Geleophysic dysplasia is anautosomal recessive disorder characterized by short stature,brachydactyly, thick skin and cardiac valvular anomalies oftenresponsible for an early death.

Defects in ADAMTSL4 are a cause of autosomal recessiveisolated ectopia lentis (ARI-EL) [MIM:225100]. ARI-EL is a rarecondition characterized by partial or complete displacement of thelens from its space resulting from defective zonule formation.

Defects in ATL1 are the cause of spastic paraplegiaautosomal dominant type 3 (SPG3) [MIM:182600], also known asStrumpell-Lorrain syndrome. Spastic paraplegia is a degenerativespinal cord disorder characterized by a slow, gradual, progressiveweakness and spasticity of the lower limbs.

Defects in ATM are the cause of ataxia telangiectasia(AT) [MIM:208900], also known as Louis-Bar syndrome, whichincludes four complementation groups: A, C, D and E. This rarerecessive disorder is characterized by progressive cerebellarataxia, dilation of the blood vessels in the conjunctiva andeyeballs, immunodeficiency, growth retardation and sexualimmaturity. AT patients have a strong predisposition to cancer,about 30% of patients develop tumors, particularly lymphomas andleukemias. Cells from affected individuals are highly sensitive todamage by ionizing radiation and resistant to inhibition of DNAsynthesis following irradiation.

Note=Defects in ATM contribute to T-cell acutelymphoblastic leukemia (TALL) and T-prolymphocytic leukemia(TPLL). TPLL is characterized by a high white blood cell count,with a predominance of prolymphocytes, marked splenomegaly,lymphadenopathy, skin lesions and serous effusion. The clinicalcourse is highly aggressive, with poor response to chemotherapyand short survival time. TPLL occurs both in adults as a sporadicdisease and in younger AT patients.

Note=Defects in ATM contribute to B-cell non-Hodgkinlymphomas (BNHL), including mantle cell lymphoma (MCL).

Note=Defects in ATM contribute to B-cell chroniclymphocytic leukemia (BCLL). BCLL is the commonest form ofleukemia in the elderly. It is characterized by the accumulationof mature CD5+ B lymphocytes, lymphadenopathy, immunodeficiencyand bone marrow failure.

Defects in FXYD2 are the cause of hypomagnesemia type 2(HOMG2) [MIM:154020], also known as dominant renal hypomagnesemiaor hypomagnesemia with hypocalciuria. HOMG2 is a disorder due toprimary renal wasting of magnesium. Plasma levels of otherelectrolytes are normal. The only abnormality found, in additionto low magnesium levels, is lowered renal excretion of calciumresulting in hypocalciuria.

Defects in MT-ATP6 are the cause of neurogenic muscleweakness, ataxia, and retinitis pigmentosa (NARP) [MIM:551500].

Defects in MT-ATP6 are a cause of Leber hereditary opticneuropathy (LHON) [MIM:535000]. LHON is a maternally inheriteddisease resulting in acute or subacute loss of central vision, dueto optic nerve dysfunction. Cardiac conduction defects andneurological defects have also been described in some patients.LHON results from primary mitochondrial DNA mutations affectingthe respiratory chain complexes.

Defects in MT-ATP6 are a cause of Leigh syndrome (LS)[MIM:256000]. LS is a severe neurological disorder characterizedby bilaterally symmetrical necrotic lesions in subcortical brainregions.

Defects in MT-ATP6 are a cause of mitochondrial infantilebilateral striatal necrosis (MIBSN) [MIM:500003]. Bilateralstriatal necrosis is a neurological disorder resembling Leighsyndrome.

Defects in ATP7A are the cause of Menkes disease (MNKD)[MIM:309400], also known as kinky hair disease. MNKD is an X-linked recessive disorder of copper metabolism characterized bygeneralized copper deficiency. MNKD results in progressiveneurodegeneration and connective-tissue disturbances: focalcerebral and cerebellar degeneration, early growth retardation,peculiar hair, hypopigmentation, cutis laxa, vascularcomplications and death in early childhood. The clinical featuresresult from the dysfunction of several copper-dependent enzymes.

Defects in ATP7A are the cause of occipital horn syndrome(OHS) [MIM:304150], also known as X-linked cutis laxa. OHS is anX-linked recessive disorder of copper metabolism. Common featuresare unusual facial appearance, skeletal abnormalities, chronicdiarrhea and genitourinary defects. The skeletal abnormalitiesincluded occipital horns, short, broad clavicles, deformed radii,ulnae and humeri, narrowing of the rib cage, undercalcified longbones with thin cortical walls and coxa valga.

Defects in ATP7A are a cause of distal spinal muscularatrophy X-linked type 3 (DSMAX3) [MIM:300489]. DSMAX3 is aneuromuscular disorder. Distal spinal muscular atrophy, also knownas distal hereditary motor neuronopathy, represents aheterogeneous group of neuromuscular disorders caused by selectivedegeneration of motor neurons in the anterior horn of the spinalcord, without sensory deficit in the posterior horn. The overallclinical picture consists of a classical distal muscular atrophysyndrome in the legs without clinical sensory loss. The diseasestarts with weakness and wasting of distal muscles of the anteriortibial and peroneal compartments of the legs. Later on, weaknessand atrophy may expand to the proximal muscles of the lower limbsand/or to the distal upper limbs.

Defects in ATP7B are the cause of Wilson disease (WD)[MIM:277900]. WD is an autosomal recessive disorder of coppermetabolism in which copper cannot be incorporated intoceruloplasmin in liver, and cannot be excreted from the liver intothe bile. Copper accumulates in the liver and subsequently in thebrain and kidney. The disease is characterized by neurologicmanifestations and signs of cirrhosis.

Defects in ATPAF2 are a cause of mitochondrialencephalocardiomyopathy neonatal due to ATP synthase deficiency(MT-ATPSD) [MIM:604273], also known as ATPase deficiency. Amitochondrial disorder with heterogeneous clinical manifestationsincluding dysmorphic features, psychomotor retardation, hypotonia,growth retardation, cardiomyopathy, enlarged liver, hypoplastickidneys and elevated lactate levels in urine, plasma andcerebrospinal fluid.

Defects in ATRX are the cause of alpha-thalassemia mentalretardation syndrome X-linked non-deletion type (ATRX)[MIM:301040]. ATR-X is an X-linked disorder comprising severepsychomotor retardation, facial dysmorphism, urogenitalabnormalities, and alpha-thalassemia. An essential phenotypictrait are hemoglobin H erythrocyte inclusions.

Defects in ATRX are the cause of mental retardationsyndromic X-linked with hypotonic facies syndrome type 1 (MRXSHF1)[MIM:309580], also called Carpenter-Waziri syndrome (CWS), Juberg-Marsidi syndrome (JMS), Smith-Fineman-Myers syndrome type 1(SFM1). Clinical features include severe mental retardation,dysmorphic facies, and a highly skewed X-inactivation pattern incarrier women. Other more variable features include hypogonadism,deafness, renal anomalies, and mild skeletal defects.

Defects in ATRX are a cause of alpha-thalassemiamyelodysplasia syndrome (ATMDS) [MIM:300448]. In this disorder,alpha-thalassemia occurs as an acquired abnormality in associationwith a multilineage myelodysplasia.

Defects in ATR are a cause of Seckel syndrome type 1(SCKL1) [MIM:210600]. SCKL1 is a rare autosomal recessive disordercharacterized by growth retardation, microcephaly with mentalretardation, and a characteristic 'bird-headed' facial appearance.

Defects in ADAMTS10 are the cause of Weill-Marchesanisyndrome autosomal recessive (ARWMS) [MIM:277600]. ARWMS is a rareconnective tissue disorder characterized by short stature,brachydactyly, joint stiffness, and eye abnormalities includingmicrospherophakia, ectopia lentis, severe myopia and glaucoma.

Defects in ADAMTS13 are the cause of thromboticthrombocytopenic purpura congenital (TTP) [MIM:274150], also knownas Upshaw-Schulman syndrome (USS). A hematologic diseasecharacterized by hemolytic anemia with fragmentation oferythrocytes, thrombocytopenia, diffuse and non-focal neurologicfindings, decreased renal function and fever.

Defects in ADAMTS17 are the cause of Weill-Marchesani-like syndrome (WMLS) [MIM:613195]. It is a disorder characterizedby many of the key features of Weill-Marchesani syndrome,including lenticular myopia, ectopia lentis, glaucoma,spherophakia and short stature. However, the characteristicbrachydactyly or decreased joint flexibility of Weill-Marchesanisyndrome are absent.

Defects in ADAMTS2 are the cause of Ehlers-Danlossyndrome type 7C (EDS7C) [MIM:225410]. EDS is a connective tissuedisorder characterized by hyperextensible skin, atrophic cutaneousscars due to tissue fragility and joint hyperlaxity. EDS7C ismarked by extremely fragile tissues, hyperextensible skin and easybruising. Facial skin contains numerous folds, as in the cutislaxa syndrome.

Defects in TAT are the cause of tyrosinemia type 2(TYRO2) [MIM:276600], also known as Richner-Hanhart syndrome.TYRO2 is an inborn error of metabolism characterized by elevationsof tyrosine in the blood and urine, and oculocutaneousmanifestations. Typical features include palmoplantar keratosis,painful corneal ulcers, and mental retardation.

Defects in ATXN1 are the cause of spinocerebellar ataxiatype 1 (SCA1) [MIM:164400], also known as olivopontocerebellaratrophy I (OPCA I or OPCA1). Spinocerebellar ataxia is aclinically and genetically heterogeneous group of cerebellardisorders. Patients show progressive incoordination of gait andoften poor coordination of hands, speech and eye movements, due tocerebellum degeneration with variable involvement of the brainstemand spinal cord. SCA1 belongs to the autosomal dominant cerebellarataxias type I (ADCA I) which are characterized by cerebellarataxia in combination with additional clinical features like opticatrophy, ophthalmoplegia, bulbar and extrapyramidal signs,peripheral neuropathy and dementia. SCA1 is caused by expansion ofa CAG repeat in the coding region of ATXN1. Longer expansionsresult in earlier onset and more severe clinical manifestations ofthe disease.

Defects in ATXN2 are the cause of spinocerebellar ataxiatype 2 (SCA2) [MIM:183090], also known as olivopontocerebellaratrophy II (OPCA II or OPCA2). Spinocerebellar ataxia is aclinically and genetically heterogeneous group of cerebellardisorders. Patients show progressive incoordination of gait andoften poor coordination of hands, speech and eye movements, due tocerebellum degeneration with variable involvement of the brainstemand spinal cord. SCA2 belongs to the autosomal dominant cerebellarataxias type I (ADCA I) which are characterized by cerebellarataxia in combination with additional clinical features like opticatrophy, ophthalmoplegia, bulbar and extrapyramidal signs,peripheral neuropathy and dementia. SCA2 is characterized byhyporeflexia, myoclonus and action tremor and dopamine-responsiveparkinsonism. Note=SCA2 is caused by expansion of a CAG repeatresulting in about 36 to 52 repeats in some patients. Longerexpansions result in earlier the expansion, onset of the disease.

Defects in ATXN2 are a cause of susceptibility toamyotrophic lateral sclerosis type 13 (ALS13) [MIM:183090]. It isa neurodegenerative disorder affecting upper motor neurons in thebrain and lower motor neurons in the brain stem and spinal cord,resulting in fatal paralysis. Sensory abnormalities are absent.Death usually occurs within 2 to 5 years. The etiology ofamyotrophic lateral sclerosis is likely to be multifactorial,involving both genetic and environmental factors. The disease isinherited in 5-10% of the cases. Note=An increased risk fordeveloping amyotrophic lateral sclerosis is seems to be conferredby CAG repeat intermediate expansions greater than 23 but belowthe threshold for developing spinocerebellar ataxia.

Defects in ATXN3 are the cause of spinocerebellar ataxiatype 3 (SCA3) [MIM:109150], also known as Machado-Joseph disease(MJD). Spinocerebellar ataxia is a clinically and geneticallyheterogeneous group of cerebellar disorders. Patients showprogressive incoordination of gait and often poor coordination ofhands, speech and eye movements, due to degeneration of thecerebellum with variable involvement of the brainstem and spinalcord. SCA3 belongs to the autosomal dominant cerebellar ataxiastype I (ADCA I) which are characterized by cerebellar ataxia incombination with additional clinical features like optic atrophy,ophthalmoplegia, bulbar and extrapyramidal signs, peripheralneuropathy and dementia. The molecular defect in SCA3 is the a CAGrepeat expansion in ATXN3 coding region. Longer expansions resultin earlier onset and more severe clinical manifestations of thedisease.

Defects in ATXN7 are the cause of spinocerebellar ataxiatype 7 (SCA7) [MIM:164500], also known as olivopontocerebellaratrophy III (OPCA III or OPCA3) or olivopontocerebellar atrophywith retinal degeneration. Spinocerebellar ataxia is a clinicallyand genetically heterogeneous group of cerebellar disorders.Patients show progressive incoordination of gait and often poorcoordination of hands, speech and eye movements, due todegeneration of the cerebellum with variable involvement of thebrainstem and spinal cord. SCA7 belongs to the autosomal dominantcerebellar ataxias type II (ADCA II) which are characterized bycerebellar ataxia with retinal degeneration and pigmentary maculardystrophy.

Defects in AUH are the cause of 3-methylglutaconicaciduria type 1 (MGA1) [MIM:250950]. MGA1 is an inborn error ofleucine metabolism. It leads to an autosomal recessive syndromewith variable clinical phenotype, ranging from delayed speechdevelopment to severe psychomotor retardation, coma, failure tothrive, metabolic acidosis and dystonia. MGA1 can be distinguishedfrom other forms of MGA by the pattern of metabolite excretion: 3-methylglutaconic acid levels are higher than those detected inother forms, whereas methylglutaric acid levels are usually onlyslightly elevated, and there is a high level of 3-hydroxyisovaleric acid excretion (not present in other MGA forms).

Note=Disruptive regulation of expression is a possibilemechanism of the perturbation of chromosomal integrity in cancercells through its dominant-negative effect on cytokinesis.

Defects in AURKC are the cause of male infertility withlarge-headed multiflagellar polyploid spermatozoa (MIMPS)[MIM:243060], also known as infertility associated with multi-tailed spermatozoa and excessive DNA.

Defects in ACVR2B are the cause of visceral heterotaxyautosomal type 4 (HTX4) [MIM:613751]. A form of visceralheterotaxy, a complex disorder due to disruption of the normalleft-right asymmetry of the thoracoabdominal organs. It results inan abnormal arrangement of visceral organs, and a wide variety ofcongenital defects. Clinical features of visceral heterotaxy type4 include dextrocardia, right aortic arch and a right-sidedspleen, anomalies of the inferior and the superior vena cava,atrial ventricular canal defect with dextro-transposed greatarteries, pulmonary stenosis, polysplenia and midline liver.

Defects in AXIN1 are involved in hepatocellular carcinoma(HCC) [MIM:114550].

Defects in AXIN1 are a cause of caudal duplicationanomaly (CADUA) [MIM:607864]. Caudal duplication anomaly ischaracterized by the occurrence of duplications of differentorgans in the caudal region. Note=Caudal duplication anomaly isassociated with hypermethylation of the AXIN1 promoter.

Defects in AXIN2 are involved in colorectal cancer (CRC)[MIM:114500]. They appear to be specifically associated withdefective mismatch repair.

Defects in AXIN2 are the cause of oligodontia-colorectalcancer syndrome (ODCRCS) [MIM:608615]. Affected individualsmanifest severe tooth agenesis and colorectal cancer orprecancerous lesions of variable types.

Defects in B2M are the cause of hypercatabolichypoproteinemia (HYCATHYP) [MIM:241600]. Affected individuals showmarked reduction in serum concentrations of immunoglobulin andalbumin, probably due to rapid degradation.

Note=Beta-2-microglobulin may adopt the fibrillarconfiguration of amyloid in certain pathologic states. Thecapacity to assemble into amyloid fibrils is concentrationdependent. Persistently high beta(2)-microglobulin serum levelslead to amyloidosis in patients on long-term hemodialysis.

Defects in SLC4A1 are the cause of elliptocytosis type 4(EL4) [MIM:109270]. EL4 is a Rhesus-unlinked form of hereditaryelliptocytosis, a genetically heterogeneous, autosomal dominanthematologic disorder. It is characterized by variable hemolyticanemia and elliptical or oval red cell shape.

Defects in SLC4A1 are the cause of spherocytosis type 4(SPH4) [MIM:612653], also known as hereditary spherocytosis type 4(HS4). Spherocytosis is a hematologic disorder leading to chronichemolytic anemia and characterized by numerous abnormally shapederythrocytes which are generally spheroidal.

Defects in SLC4A1 are the cause of autosomal dominantdistal renal tubular acidosis (AD-dRTA) [MIM:179800]. This diseaseis characterized by reduced ability to acidify urine, variablehyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis,and nephrolithiasis.

Defects in SLC4A1 are the cause of autosomal recessivedistal renal tubular acidosis (AR-dRTA) [MIM:611590].

Defects in B3GALTL are the cause of Peters-plus syndrome(PpS) [MIM:261540]. PpS is an autosomal recessive disordercharacterized by anterior eye-chamber abnormalities,disproportionate short stature, developmental delay,characteristic craniofacial features, cleft lip and/or palate.

Defects in B4GALT1 are the cause of congenital disorderof glycosylation type 2D (CDG2D) [MIM:607091]. CDGs are a familyof severe inherited diseases caused by a defect in protein N-glycosylation. They are characterized by under-glycosylated serumproteins. These multisystem disorders present with a wide varietyof clinical features, such as disorders of the nervous systemdevelopment, psychomotor retardation, dysmorphic features,hypotonia, coagulation disorders, and immunodeficiency. The broadspectrum of features reflects the critical role of N-glycoproteinsduring embryonic development, differentiation, and maintenance ofcell functions.

Defects in B4GALT7 are the cause of Ehlers-Danlossyndrome progeroid type (EDSP) [MIM:130070]. EDSP is a variantform of Ehlers-Danlos syndrome characterized by progeroid facies,mild mental retardation, short stature, skin hyperextensibility,moderate skin fragility, joint hypermobility principally indigits.

Defects in BAAT are involved in familial hypercholanemia(FHCA) [MIM:607748]. FHCA is a disorder characterized by elevatedserum bile acid concentrations, itching, and fat malabsorption.

Note=A functional variant in the transcriptionalregulatory region of in ACOT7L cosegregates with disease phenotypein family affected by nasopharyngeal carcinoma. The variantcreates an AP1-binding site that significantly enhances binding ofAP1 to the promoter, resulting in up-regulation.

Defects in BAG3 are the cause of myopathy myofibrillarBAG3-related (MFM-BAG3) [MIM:612954]. A neuromuscular disorderthat results in early-onset, severe, progressive, diffuse muscleweakness associated with cardiomyopathy, severe respiratoryinsufficiency during adolescence, and a rigid spine in somepatients. At ultrastructural level, muscle fibers displaystructural alterations consisting of replacement of the normalmyofibrillar markings by small, dense granules, or larger hyalinemasses, or amorphous material.

Genetic variations in BANK1 influence susceptibility tosystemic lupus erythematosus (SLE) [MIM:152700]. SLE is a chronic,inflammatory and often febrile multisystemic disorder ofconnective tissue. It affects principally the skin, joints,kidneys and serosal membranes. It is thought to represent afailure of the regulatory mechanisms of the autoimmune system.

Note=BCAP31 is deleted in the chromosome Xq28 deletionsyndrome which involves BCAP31 and the and the promoter region ofABCD1.

Defects in SLC7A9 are a cause of non-type I cystinuria(CSNU) [MIM:220100]. CSNU arises from impaired transport ofcystine and dibasic amino acids through the epithelial cells ofthe renal tubule and gastrointestinal tract. Three types ofcystinuria have been described: type I (fully recessive orsilent), type II (high excretor), type III (moderate excretor).Defects in SLC7A9 are associated with type II and type IIIcystinuria. They also might account for some non-classic type Icystinuria cases.

Note=BAZ1B is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.Haploinsufficiency of BAZ1B may be the cause of certaincardiovascular and musculo-skeletal abnormalities observed in thedisease.

Defects in BBS10 are the cause of Bardet-Biedl syndrometype 10 (BBS10) [MIM:209900]. Bardet-Biedl syndrome (BBS) is agenetically heterogeneous, autosomal recessive disordercharacterized by usually severe pigmentary retinopathy, earlyonset obesity, polydactyly, hypogenitalism, renal malformation andmental retardation.

Defects in BBS12 are the cause of Bardet-Biedl syndrometype 12 (BBS12) [MIM:209900]. Bardet-Biedl syndrome (BBS) is agenetically heterogeneous, autosomal recessive disordercharacterized by usually severe pigmentary retinopathy, earlyonset obesity, polydactyly, hypogenitalism, renal malformation andmental retardation. Secondary features include diabetes mellitus,hypertension and congenital heart disease. A relatively highincidence of BBS is found in the mixed Arab populations of Kuwaitand in Bedouin tribes throughout the Middle East, most likely dueto the high rate of consaguinity in these populations and afounder effect. BBS12 seems to be rarely involved in oligogenicinheritance.

Defects in BBS1 are a cause of Bardet-Biedl syndrome type1 (BBS1) [MIM:209900]. Bardet-Biedl syndrome (BBS) is agenetically heterogeneous disorder characterized by usually severepigmentary retinopathy, early onset obesity, polydactyly,hypogenitalism, renal malformation and mental retardation.Secondary features include diabetes mellitus, hypertension andcongenital heart disease. A relatively high incidence of BBS isfound in the mixed Arab populations of Kuwait and in Bedouintribes throughout the Middle East, most likely due to the highrate of consaguinity in these populations and a founder effect.Inheritance is autosomal recessive, but three mutated alleles (twoat one locus, and a third at a second locus) may be required fordisease manifestation in some cases (triallelic inheritance).

Defects in BBS2 are the cause of Bardet-Biedl syndrometype 2 (BBS2) [MIM:209900]. Bardet-Biedl syndrome (BBS) is agenetically heterogeneous, autosomal recessive disordercharacterized by usually severe pigmentary retinopathy, earlyonset obesity, polydactyly, hypogenitalism, renal malformation andmental retardation. Secondary features include diabetes mellitus,hypertension and congenital heart disease. A relatively highincidence of BBS is found in the mixed Arab populations of Kuwaitand in Bedouin tribes throughout the Middle East, most likely dueto the high rate of consaguinity in these populations and afounder effect.

Defects in BBS4 are the cause of Bardet-Biedl syndrometype 4 (BBS4) [MIM:209900]. Bardet-Biedl syndrome (BBS) is agenetically heterogeneous, autosomal recessive disordercharacterized by usually severe pigmentary retinopathy, earlyonset obesity, polydactyly, hypogenitalism, renal malformation andmental retardation. Secondary features include diabetes mellitus,hypertension and congenital heart disease. A relatively highincidence of BBS is found in the mixed Arab populations of Kuwaitand in Bedouin tribes throughout the Middle East, most likely dueto the high rate of consaguinity in these populations and afounder effect.

Defects in BBS5 are a cause of Bardet-Biedl syndrome type5 (BBS5) [MIM:209900]. Bardet-Biedl syndrome (BBS) is agenetically heterogeneous disorder characterized by usually severepigmentary retinopathy, early onset obesity, polydactyly,hypogenitalism, renal malformation and mental retardation.Secondary features include diabetes mellitus, hypertension andcongenital heart disease. A relatively high incidence of BBS isfound in the mixed Arab populations of Kuwait and in Bedouintribes throughout the Middle East, most likely due to the highrate of consaguinity in these populations and a founder effect.

Defects in BBS7 are a cause of Bardet-Biedl syndrome type7 (BBS7) [MIM:209900]. Bardet-Biedl syndrome (BBS) is agenetically heterogeneous disorder characterized by usually severepigmentary retinopathy, early onset obesity, polydactyly,hypogenitalism, renal malformation and mental retardation.Secondary features include diabetes mellitus, hypertension andcongenital heart disease. A relatively high incidence of BBS isfound in the mixed Arab populations of Kuwait and in Bedouintribes throughout the Middle East, most likely due to the highrate of consaguinity in these populations and a founder effect.Inheritance is autosomal recessive, but three mutated alleles (twoat one locus, and a third at a second locus) may be required fordisease manifestation in some cases (triallelic inheritance).

Note=Chromosomal aberrations involving BCL11A may be acause of lymphoid malignancies. Translocation t(2,14)(p13,q32.3)causes BCL11A deregulation and amplification.

Note=A chromosomal aberration involving BCAS3 has beenfound in some breast carcinoma cell lines. Translocationt(17,20)(q23,q13) with BCAS4.

Note=A chromosomal aberration involving BCAS4 has beenfound in some breast carcinoma cell lines. Translocationt(17,20)(q23,q13) with BCAS3.

Defects in BCMO1 are the cause of autosomal dominanthypercarotenemia and vitamin A deficiency (ADHVAD) [MIM:115300].Vitamin A is essential for normal embryonic development as well asnormal physiological functions in children and adults.Hypercarotenemia is characterized by an excess carotene in theserum, but unlike excess vitamin A, carotene is non-toxic. So far,only a few cases of excess vitamin A have been reported.Individuals were thought to be vitamin A deficient due to animpairment in the conversion of carotenoids to retinal in theintestine.

Note=A chromosomal aberration involving BCL10 isrecurrent in low-grade mucosa-associated lymphoid tissue (MALTlymphoma). Translocation t(1,14)(p22,q32). Although the BCL10/IgHtranslocation leaves the coding region of BCL10 intact, frequentBCL10 mutations could be attributed to the Ig somatichypermutation mechanism resulting in nucleotide transitions.

Note=Defects in BCL10 are involved in various types ofcancer.

Note=A chromosomal aberration involving BCL2 has beenfound in chronic lymphatic leukemia. Translocationt(14,18)(q32,q21) with immunoglobulin gene regions. BCL2 mutationsfound in non-Hodgkin lymphomas carrying the chromosomaltranslocation could be attributed to the Ig somatic hypermutationmechanism resulting in nucleotide transitions.

Note=A chromosomal aberration involving BCL3 may be acause of B-cell chronic lymphocytic leukemia (B-CLL).Translocation t(14,19)(q32,q13.1) with immunoglobulin generegions.

Note=Chromosomal aberrations involving BCL6 may be acause of B-cell non-Hodgkin lymphoma. Translocationt(3,14)(q27,q32), translocation t(3,22)(q27,q11) withimmunoglobulin gene regions.

Note=A chromosomal aberration involving BCL6 may be acause of a form of B-cell leukemia. Translocation t(3,11)(q27,q23)with POU2AF1/OBF1.

Note=A chromosomal aberration involving BCL6 may be acause of lymphoma. Translocation t(3,4)(q27,p11) with ARHH/TTF.

Note=Chromosomal aberrations involving BCL7A may be acause of B-cell non-Hodgkin lymphoma. Three-way translocationt(8,14,12)(q24.1,q32.3,q24.1) with MYC and with immunoglobulingene regions.

Note=BCL7B is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.Haploinsufficiency of BCL7B may be the cause of certaincardiovascular and musculo-skeletal abnormalities observed in thedisease.

Note=A chromosomal aberration involving BCL8 has beenobserved in diffuse large cell lymphoma (DLCL). Translocationt(14,15)(q32,q11-q13). The BCL8/IgH translocation leaves thecoding region of BCL8 intact, but may have pathogenic effects dueto alterations in the expression level of BCL8.

Note=A chromosomal aberration involving BCL9 is found ina patient with precusor B-cell acute lymphoblastic leukemia (ALL).Translocation t(1,14)(q21,q32). This translocation leaves thecoding region intact, but may have pathogenic effects due toalterations in the expression level of BCL9. Several cases oftranslocations within the 3'-UTR of BCL9 have been found in B-cellmalignancies.

Defects in BCOR are the cause of microphthalmia syndromictype 2 (MCOPS2) [MIM:300166]. Microphthalmia is a clinicallyheterogeneous disorder of eye formation, ranging from small sizeof a single eye to complete bilateral absence of ocular tissues(anophthalmia). In many cases, microphthalmia/anophthalmia occursin association with syndromes that include non-ocularabnormalities. MCOPS2 is a very rare multiple congenital anomalysyndrome characterized by eye anomalies (congenital cataract,microphthalmia, or secondary glaucoma), facial abnormalities (longnarrow face, high nasal bridge, pointed nose with cartilagesseparated at the tip, cleft palate, or submucous cleft palate),cardiac anomalies (atrial septal defect, ventricular septaldefect, or floppy mitral valve) and dental abnormalities (canineradiculomegaly, delayed dentition, oligodontia, persistent primaryteeth, or variable root length).

Note=A chromosomal aberration involving BCR is a cause ofchronic myeloid leukemia. Translocation t(9,22)(q34,q11) withABL1. The translocation produces a BCR-ABL found also in acutemyeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

Defects in BCS1L are the cause of GRACILE syndrome(GRACILE) [MIM:603358]. GRACILE stands for 'growth retardation,aminoaciduria, cholestasis, iron overload, lactic acidosis, andearly death'. It is a recessively inherited lethal diseasecharacterized by fetal growth retardation, lactic acidosis,aminoaciduria, cholestasis, and abnormalities in iron metabolism.

Defects in BCS1L are a cause of mitochondrial complex IIIdeficiency (MT-C3D) [MIM:124000]. A disorder of the mitochondrialrespiratory chain resulting in a highly variable phenotypedepending on which tissues are affected. Clinical features includemitochondrial encephalopathy, psychomotor retardation, ataxia,severe failure to thrive, liver dysfunction, renal tubulopathy,muscle weakness and exercise intolerance.

Defects in BCS1L are the cause of Bjoernstad syndrome(BJS) [MIM:262000]. BJS is an autosomal recessive conditioncharacterized by sensorineural hearing loss and pili torti. Thehearing loss in BJS is congenital and of variable severity. Pilitorti (twisted hairs), a condition in which the hair shafts areflattened at irregular intervals and twisted 180 degrees from thenormal axis, making the hair extremely brittle, is usuallyrecognized early in childhood.

Defects in BDNF are a cause of congenital centralhypoventilation syndrome (CCHS) [MIM:209880], also known ascongenital failure of autonomic control or Ondine curse. CCHS is arare disorder characterized by abnormal control of respiration inthe absence of neuromuscular or lung disease, or an identifiablebrain stem lesion. A deficiency in autonomic control ofrespiration results in inadequate or negligible ventilatory andarousal responses to hypercapnia and hypoxemia. CCHS is frequentlycomplicated with neurocristopathies such as Hirschsprung diseasethat occurs in about 16% of CCHS cases.

Defects in BEAN1 are the cause of spinocerebellar ataxiatype 31 (SCA31) [MIM:117210], also known as spinocerebellar ataxia16q22-linked. A form of spinocerebellar ataxia, a clinically andgenetically heterogeneous group of cerebellar disorders. Patientsshow progressive incoordination of gait and often poorcoordination of hands, speech and eye movements, due todegeneration of the cerebellum with variable involvement of thebrainstem and spinal cord. SCA31 belongs to the autosomal dominantcerebellar ataxias type III (ADCA III) which are characterized bypure cerebellar ataxia without additional signs.

Defects in BEST1 are the cause of vitelliform maculardystrophy type 2 (VMD2) [MIM:153700], also known as Best maculardystrophy (BMD). VMD2 is an autosomal dominant form of maculardegeneration that usually begins in childhood or adolescence. VMD2is characterized by typical 'egg-yolk' macular lesions due toabnormal accumulation of lipofuscin within and beneath the retinalpigment epithelium cells. Progression of the disease leads todestruction of the retinal pigment epithelium and vision loss.

Defects in BEST1 are the cause of retinitis pigmentosatype 50 (RP50) [MIM:613194]. A retinal dystrophy belonging to thegroup of pigmentary retinopathies. RP is characterized by retinalpigment deposits visible on fundus examination and primary loss ofrod photoreceptor cells followed by secondary loss of conephotoreceptors. Patients typically have night vision blindness andloss of midperipheral visual field. As their condition progresses,they lose their far peripheral visual field and eventually centralvision as well.

Defects in BEST1 are a cause of adult-onset vitelliformmacular dystrophy (AVMD) [MIM:608161]. AVMD is a rare autosomaldominant disorder with incomplete penetrance and highly variableexpression. Patients usually become symptomatic in the fourth orfifth decade of life with a protracted disease of decreased visualacuity.

Defects in BEST1 are the cause of bestrophinopathyautosomal recessive (ARB) [MIM:611809]. A retinopathycharacterized by central visual loss, an absent electro-oculogramlight rise, and a reduced electroretinogram.

Defects in BEST1 are the cause ofvitreoretinochoroidopathy autosomal dominant (ADVIRC)[MIM:193220]. A disorder characterized by vitreoretinochoroidaldystrophy. The clinical presentation is variable and may beassociated with cataract, nanophthalmos, microcornea, shallowanterior chamber, and glaucoma.

Defects in BFSP1 are the cause of cataract corticaljuvenile-onset (CCJO) [MIM:611391]. A juvenile-onset cataract withopacities restricted to the cortex of the lens, not involving thenucleus.

Defects in BFSP2 are the cause of cataract autosomaldominant BFSP2-related (ADC-BFSP2) [MIM:611597], also known ascataract autosomal dominant multiple types 1. Cataract is anopacification of the crystalline lens of the eye that frequentlyresults in visual impairment or blindness. Opacities vary inmorphology, are often confined to a portion of the lens, and maybe static or progressive. In general, the more posteriorly locatedand dense an opacity, the greater the impact on visual function.Cataract autosomal dominant BFSP2-related is characterized by avariable phenotype that may or may not be consistent within afamily. The opacities can be nuclear, sutural, stellate cortical,lamellar, cortical, nuclear embryonic, Y-sutural, punctatecortical, congenital or with juvenile- and adult-onset.

Defects in GLB1 are the cause of GM1-gangliosidosis type1 (GM1G1) [MIM:230500], also known as infantile GM1-gangliosidosis. GM1-gangliosidosis is an autosomal recessivelysosomal storage disease marked by the accumulation of GM1gangliosides, glycoproteins and keratan sulfate primarily inneurons of the central nervous system. GM1G1 is characterized byonset within the first three months of life, central nervoussystem degeneration, coarse facial features, hepatosplenomegaly,skeletal dysmorphology reminiscent of Hurler syndrome, and rapidlyprogressive psychomotor deterioration. Urinary oligosaccharidelevels are high. It leads to death usually between the first andsecond year of life.

Defects in GLB1 are the cause of GM1-gangliosidosis type2 (GM1G2) [MIM:230600], also known as late infantile/juvenile GM1-gangliosidosis. GM1G2 is characterized by onset between ages 1 and5. The main symptom is locomotor ataxia, ultimately leading to astate of decerebration with epileptic seizures. Patients do notdisplay the skeletal changes associated with the infantile form,but they nonetheless excrete elevated amounts of beta-linkedgalactose-terminal oligosaccharides. Inheritance is autosomalrecessive.

Defects in GLB1 are the cause of GM1-gangliosidosis type3 (GM1G3) [MIM:230650], also known as adult or chronic GM1-gangliosidosis. GM1G3 is characterized by a variable phenotype.Patients show mild skeletal abnormalities, dysarthria, gaitdisturbance, dystonia and visual impairment. Visceromegaly isabsent. Intellectual deficit can initially be mild or absent butprogresses over time. Inheritance is autosomal recessive.

Defects in GLB1 are the cause of mucopolysaccharidosistype 4B (MPS4B) [MIM:253010], also known as Morquio syndrome B.MPS4B is a form of mucopolysaccharidosis type 4, an autosomalrecessive lysosomal storage disease characterized by intracellularaccumulation of keratan sulfate and chondroitin-6-sulfate. Keyclinical features include short stature, skeletal dysplasia,dental anomalies, and corneal clouding. Intelligence is normal andthere is no direct central nervous system involvement, althoughthe skeletal changes may result in neurologic complications. Thereis variable severity, but patients with the severe phenotypeusually do not survive past the second or third decade of life.

Defects in TGFBI are the cause of epithelial basementmembrane corneal dystrophy (EBMD) [MIM:121820], also known asCogan corneal dystrophy or map-dot-fingerprint type cornealdystrophy. EBMD is a bilateral anterior corneal dystrophycharacterized by grayish epithelial fingerprint lines, geographicmap-like lines, and dots (or microcysts) on slit-lamp examination.Pathologic studies show abnormal, redundant basement membrane andintraepithelial lacunae filled with cellular debris. Although thisdisorder usually is not considered to be inherited, families withautosomal dominant inheritance have been identified.

Defects in TGFBI are the cause of corneal dystrophyGroenouw type 1 (CDGG1) [MIM:121900], also known as cornealdystrophy granular type. Inheritance is autosomal dominant.Corneal dystrophies show progressive opacification of the cornealeading to severe visual handicap.

Defects in TGFBI are the cause of corneal dystrophylattice type 1 (CDL1) [MIM:122200]. Inheritance is autosomaldominant.

Defects in TGFBI are a cause of corneal dystrophy Thiel-Behnke type (CDTB) [MIM:602082], also known as corneal dystrophyof Bowman layer type 2 (CDB2).

Defects in TGFBI are the cause of Reis-Buecklers cornealdystrophy (CDRB) [MIM:608470], also known as corneal dystrophy ofBowman layer type 1 (CDB1).

Defects in TGFBI are the cause of lattice cornealdystrophy type 3A (CDL3A) [MIM:608471]. CDL3A clinically resemblesto lattice corneal dystrophy type 3, but differs in that its ageof onset is 70 to 90 years. It has an autosomal dominantinheritance pattern.

Defects in TGFBI are the cause of Avellino cornealdystrophy (ACD) [MIM:607541]. ACD could be considered a variant ofgranular dystrophy with a significant amyloidogenic tendency.Inheritance is autosomal dominant.

Defects in GUSB are the cause of mucopolysaccharidosistype 7 (MPS7) [MIM:253220], also known as Sly syndrome. MPS7 is anautosomal recessive lysosomal storage disease characterized byinability to degrade glucuronic acid-containingglycosaminoglycans. The phenotype is highly variable, ranging fromsevere lethal hydrops fetalis to mild forms with survival intoadulthood. Most patients with the intermediate phenotype showhepatomegaly, skeletal anomalies, coarse facies, and variabledegrees of mental impairment.

Note=Mucopolysaccharidosis type 7 is associated with non-immune hydrops fetalis, a generalized edema of the fetus withfluid accumulation in the body cavities due to non-immune causes.Non-immune hydrops fetalis is not a diagnosis in itself but asymptom, a feature of many genetic disorders, and the end-stage ofa wide variety of disorders.

Defects in ARFGEF2 are the cause of autosomal recessiveperiventricular nodular heterotopia type 2 (PVNH2) [MIM:608097],also known as periventricular heterotopia with microcephalyautosomal recessive. PVNH is a developmental disordercharacterized by the presence of periventricular nodules ofcerebral gray matter, resulting from a failure of neurons tomigrate normally from the lateral ventricular proliferative zone,where they are formed, to the cerebral cortex. PVNH2 is anautosomal recessive form characterized by microcephaly (smallbrain), severe developmental delay and recurrent infections. Noanomalies extrinsic to the central nervous system, such asdysmorphic features or grossly abnormal endocrine or otherconditions, are associated with PVNH2.

Defects in BIN1 are the cause of centronuclear myopathyautosomal recessive (ARCNM) [MIM:255200], also known as autosomalrecessive myotubular myopathy. Centronuclear myopathies arecongenital muscle disorders characterized by progressive muscularweakness and wasting involving mainly limb girdle, trunk, and neckmuscles. It may also affect distal muscles. Weakness may bepresent during childhood or adolescence or may not become evidentuntil the third decade of life. Ptosis is a frequent clinicalfeature. The most prominent histopathologic features include highfrequency of centrally located nuclei in muscle fibers notsecondary to regeneration, radial arrangement of sarcoplasmicstrands around the central nuclei, and predominance and hypotrophyof type 1 fibers.

Note=A chromosomal aberration involving BIRC3 isrecurrent in low-grade mucosa-associated lymphoid tissue (MALTlymphoma). Translocation t(11,18)(q21,q21) with MALT1. Thistranslocation is found in approximately 50% of cytogeneticallyabnormal low-grade MALT lymphoma.

Defects in BLOC1S3 are the cause of Hermansky-Pudlaksyndrome type 8 (HPS8) [MIM:203300]. Hermansky-Pudlak syndrome(HPS) is a genetically heterogeneous, rare, autosomal recessivedisorder characterized by oculocutaneous albinism, bleeding due toplatelet storage pool deficiency, and lysosomal storage defects.This syndrome results from defects of diverse cytoplasmicorganelles including melanosomes, platelet dense granules andlysosomes. Ceroid storage in the lungs is associated withpulmonary fibrosis, a common cause of premature death inindividuals with HPS.

Defects in BLK are a cause of maturity-onset diabetes ofthe young type 11 (MODY11) [MIM:613375]. MODY11 is a form ofdiabetes that is characterized by an autosomal dominant mode ofinheritance, onset in childhood or early adulthood (usually before25 years of age), a primary defect in insulin secretion andfrequent insulin-independence at the beginning of the disease.

Defects in BLM are the cause of Bloom syndrome (BLM)[MIM:210900]. BLM is an autosomal recessive disorder characterizedby proportionate pre- and postnatal growth deficiency, sun-sensitive telangiectatic hypo- and hyperpigmented skin,predisposition to malignancy, and chromosomal instability.

Defects in BLNK are the cause of agammaglobulinemia type4 (AGM4) [MIM:613502]. It is a primary immunodeficiencycharacterized by profoundly low or absent serum antibodies and lowor absent circulating B cells due to an early block of B-celldevelopment. Affected individuals develop severe infections in thefirst years of life.

Defects in BMP15 are the cause of ovarian dysgenesis type2 (ODG2) [MIM:300510], also known as X-linked hypergonadotropicovarian dysgenesis or hypergonadotropic ovarian failure due toovarian dysgenesis. Ovarian dysgenesis leads to ovarian failureand accounts for about half of the cases of primary amenorrhea.

Defects in BMP15 are the cause of premature ovarianfailure type 4 (POF4) [MIM:300510]. An ovarian disorder defined asthe cessation of ovarian function under the age of 40 years. It ischaracterized by oligomenorrhea or amenorrhea, in the presence ofelevated levels of serum gonadotropins and low estradiol.

Defects in BMP4 are the cause of microphthalmia syndromictype 6 (MCOPS6) [MIM:607932], also known as microphthalmia andpituitary anomalies or microphthalmia with brain and digitdevelopmental anomalies. Microphthalmia is a clinicallyheterogeneous disorder of eye formation, ranging from small sizeof a single eye to complete bilateral absence of ocular tissues(anophthalmia). In many cases, microphthalmia/anophthalmia occursin association with syndromes that include non-ocularabnormalities. MCOPS6 is characterized bymicrophthalmia/anophthalmia associated with facial, genital,skeletal, neurologic and endocrine anomalies.

Defects in BMP4 are the cause of non-syndromic orofacialcleft type 11 (OFC11) [MIM:600625]. Non-syndromic orofacial cleftis a common birth defect consisting of cleft lips with or withoutcleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides andrange in severity from a simple notch in the upper lip to acomplete opening in the lip extending into the floor of thenostril and involving the upper gum. OFC11 is an unusual anomalyconsisting of a paramedian scar of the upper lip with anappearance suggesting that a typical cleft lip was corrected inutero.

Defects in BMPR2 are the cause of primary pulmonaryhypertension (PPH1) [MIM:178600]. PPH1 is a rare autosomaldominant disorder characterized by plexiform lesions ofproliferating endothelial cells in pulmonary arterioles. Thelesions lead to elevated pulmonary arterial pression, rightventricular failure, and death. The disease can occur from infancythroughout life and it has a mean age at onset of 36 years.Penetrance is reduced. Although familial PPH1 is rare, casessecondary to known etiologies are more common and include thoseassociated with the appetite-suppressant drugs.

Defects in BMPR2 are a cause of pulmonary venoocclusivedisease (PVOD) [MIM:265450]. PVOD is a rare form of pulmonaryhypertension in which the vascular changes originate in the smallpulmonary veins and venules. The pathogenesis is unknown and anylink with PPH1 has been speculative. The finding of PVODassociated with a BMPR2 mutation reveals a possible pathogeneticconnection with PPH1.

Defects in BMPR1A are a cause of juvenile polyposissyndrome (JPS) [MIM:174900], also known as juvenile intestinalpolyposis (JIP). JPS is an autosomal dominant gastrointestinalhamartomatous polyposis syndrome in which patients are at risk fordeveloping gastrointestinal cancers. The lesions are typified by asmooth histological appearance, predominant stroma, cystic spacesand lack of a smooth muscle core. Multiple juvenile polyps usuallyoccur in a number of Mendelian disorders. Sometimes, these polypsoccur without associated features as in JPS, here, polyps tend tooccur in the large bowel and are associated with an increased riskof colon and other gastrointestinal cancers.

Defects in BMPR1A are a cause of Cowden disease (CD)[MIM:158350]. CD is an autosomal dominant cancer syndromecharacterized by multiple hamartomas and by a high risk forbreast, thyroid and endometrial cancers.

Defects in BMPR1A are the cause of hereditary mixedpolyposis syndrome 2 (HMPS2) [MIM:610069]. Hereditary mixedpolyposis syndrome (HMPS) is characterized by atypical juvenilepolyps, colonic adenomas, and colorectal carcinomas.

Note=A microdeletion of chromosome 10q23 involving BMPR1Aand PTEN is a cause of chromosome 10q23 deletion syndrome, whichshows overlapping features of the following three disorders:Bannayan-Zonana syndrome, Cowden disease and juvenile polyposissyndrome.

Defects in BMPR1B are the cause of acromesomelicchondrodysplasia with genital anomalies (AMDGA) [MIM:609441].Acromesomelic chondrodysplasias are rare hereditary skeletaldisorders characterized by short stature, very short limbs, andhand/foot malformations. The severity of limb abnormalitiesincreases from proximal to distal with profoundly affected handsand feet showing brachydactyly and/or rudimentary fingers (knob-like fingers).

Defects in BMPR1B are a cause of brachydactyly type A2(BDA2) [MIM:112600]. Brachydactylies (BDs) are a group ofinherited malformations characterized by shortening of the digitsdue to abnormal development of the phalanges and/or themetacarpals. They have been classified on an anatomic and geneticbasis into five groups, A to E, including three subgroups (A1 toA3) that usually manifest as autosomal dominant traits. BDA2 wasdescribed first in a large Norwegian kindred. BDA2 is caused bymutations in BMPR1B gene and studies demonstrate that thesemutations function as dominant negatives in vitro and in vivo.

Defects in HLCS are the cause of holocarboxylasesynthetase deficiency (HLCS deficiency) [MIM:253270], also knownas biotin-responsive multiple carboxylase deficiency. HLCSdeficiency is a neonatal form of multiple carboxylase deficiency,an autosomal recessive disorder characterized by metabolicketoacidosis, hyperammonemia, excretion of abnormal organic acidmetabolites and dermatitis. Clinical and biochemical symptomsimprove dramatically with administration of biotin.

Genetic variations in T are associated withsusceptibility to neural tube defects (NTD) [MIM:182940]. NTD arecommon congenital malformations. Spina bifida, which results frommalformations in the caudal region of the neural tube, iscompatible with life but associated with significant morbidity,including lower limb paralysis.

T is involved in susceptibility to the development ofchordoma (CHDM) [MIM:215400]. Chordomas are rare, clinicallymalignant tumors derived from notochordal remnants. They occuralong the length of the spinal axis, predominantly in thesphenooccipital, vertebral and sacrococcygeal regions. They arecharacterized by slow growth, local destruction of bone, extensioninto adjacent soft tissues and rarely, distant metastatic spread.Note=Susceptibility to development of chordomas is due to a T geneduplication.

Note=Defects in BRAF are found in a wide range ofcancers.

Defects in BRAF may be a cause of colorectal cancer (CRC)[MIM:114500].

Defects in BRAF are involved in lung cancer (LNCR)[MIM:211980].

Defects in BRAF are involved in non-Hodgkin lymphoma(NHL) [MIM:605027]. NHL is a cancer that starts in cells of thelymph system, which is part of the body's immune system. NHLs canoccur at any age and are often marked by enlarged lymph nodes,fever and weight loss.

Defects in BRAF are a cause of cardiofaciocutaneoussyndrome (CFC syndrome) [MIM:115150], also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctivefacial appearance, heart defects and mental retardation. Heartdefects include pulmonic stenosis, atrial septal defects andhypertrophic cardiomyopathy. Some affected individuals presentwith ectodermal abnormalities such as sparse, friable hair,hyperkeratotic skin lesions and a generalized ichthyosis-likecondition. Typical facial features are similar to Noonan syndrome.They include high forehead with bitemporal constriction,hypoplastic supraorbital ridges, downslanting palpebral fissures,a depressed nasal bridge, and posteriorly angulated ears withprominent helices. The inheritance of CFC syndrome is autosomaldominant.

Defects in BRAF are the cause of Noonan syndrome type 7(NS7) [MIM:613706]. Noonan syndrome is a disorder characterized byfacial dysmorphic features such as hypertelorism, a downwardeyeslant and low-set posteriorly rotated ears. Other features caninclude short stature, a short neck with webbing or redundancy ofskin, cardiac anomalies, deafness, motor delay and variableintellectual deficits.

Defects in BRAF are the cause of LEOPARD syndrome type 3(LEOPARD3) [MIM:613707]. LEOPARD3 is a disorder characterized bylentigines, electrocardiographic conduction abnormalities, ocularhypertelorism, pulmonic stenosis, abnormalities of genitalia,retardation of growth, and sensorineural deafness.

Note=A chromosomal aberration involving BRAF is found inpilocytic astrocytomas. A tandem duplication of 2 Mb at 7q34 leadsto the expression of a KIAA1549-BRAF fusion protein with aconstitutive kinase activity and inducing cell transformation.

Defects in BRCA1 are a cause of susceptibility to breastcancer (BC) [MIM:114480]. A common malignancy originating frombreast epithelial tissue. Breast neoplasms can be distinguished bytheir histologic pattern. Invasive ductal carcinoma is by far themost common type. Breast cancer is etiologically and geneticallyheterogeneous. Important genetic factors have been indicated byfamilial occurrence and bilateral involvement. Mutations at morethan one locus can be involved in different families or even inthe same case. Note=Mutations in BRCA1 are thought to beresponsible for 45% of inherited breast cancer. Moreover, BRCA1carriers have a 4-fold increased risk of colon cancer, whereasmale carriers face a 3-fold increased risk of prostate cancer.Cells lacking BRCA1 show defects in DNA repair by homologousrecombination.

Defects in BRCA1 are a cause of susceptibility to breast-ovarian cancer familial type 1 (BROVCA1) [MIM:604370]. A conditionassociated with familial predisposition to cancer of the breastand ovaries. Characteristic features in affected families are anearly age of onset of breast cancer (often before age 50),increased chance of bilateral cancers (cancer that develop in bothbreasts, or both ovaries, independently), frequent occurrence ofbreast cancer among men, increased incidence of tumors of otherspecific organs, such as the prostate. Note=Mutations in BRCA1 arethought to be responsible for more than 80% of inherited breast-ovarian cancer.

Defects in BRCA1 are a cause of genetic susceptibility toovarian cancer [MIM:113705].

Defects in BRCA2 are a cause of susceptibility to breastcancer (BC) [MIM:114480]. A common malignancy originating frombreast epithelial tissue. Breast neoplasms can be distinguished bytheir histologic pattern. Invasive ductal carcinoma is by far themost common type. Breast cancer is etiologically and geneticallyheterogeneous. Important genetic factors have been indicated byfamilial occurrence and bilateral involvement. Mutations at morethan one locus can be involved in different families or even inthe same case.

Defects in BRCA2 are the cause of pancreatic cancer type2 (PNCA2) [MIM:613347]. It is a malignant neoplasm of thepancreas. Tumors can arise from both the exocrine and endocrineportions of the pancreas, but 95% of them develop from theexocrine portion, including the ductal epithelium, acinar cells,connective tissue, and lymphatic tissue.

Defects in BRCA2 are a cause of susceptibility to breast-ovarian cancer familial type 2 (BROVCA2) [MIM:612555]. A conditionassociated with familial predisposition to cancer of the breastand ovaries. Characteristic features in affected families are anearly age of onset of breast cancer (often before age 50),increased chance of bilateral cancers (cancer that develop in bothbreasts, or both ovaries, independently), frequent occurrence ofbreast cancer among men, increased incidence of tumors of otherspecific organs, such as the prostate.

Defects in BRCA2 are the cause of Fanconi anemiacomplementation group D type 1 (FANCD1) [MIM:605724]. It is adisorder affecting all bone marrow elements and resulting inanemia, leukopenia and thrombopenia. It is associated withcardiac, renal and limb malformations, dermal pigmentary changes,and a predisposition to the development of malignancies. At thecellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosomebreakage) and defective DNA repair.

Defects in BRCA2 are a cause of glioma type 3 (GLM3)[MIM:613029]. Gliomas are benign or malignant central nervoussystem neoplasms derived from glial cells. They compriseastrocytomas and glioblastoma multiforme that are derived fromastrocytes, oligodendrogliomas derived from oligodendrocytes andependymomas derived from ependymocytes.

Note=A chromosomal aberration involving BRCC3 is a causeof pro-lymphocytic T-cell leukemia (T-PLL). Translocationt(X,14)(q28,q11) with TCRA.

Note=A chromosomal aberration involving BRD3 is found ina rare, aggressive, and lethal carcinoma arising in midline organsof young people. Translocation t(15,9)(q14,q34) with NUT whichproduces a BRD3-NUT fusion protein.

Note=A chromosomal aberration involving BRD4 is found ina rare, aggressive, and lethal carcinoma arising in midline organsof young people. Translocation t(15,19)(q14,p13) with NUT whichproduces a BRD4-NUT fusion protein.

Note=A chromosomal aberration involving BRWD3 can befound in patients with B-cell chronic lymphocytic leukemia (B-CLL). Translocation t(X,11)(q21,q23) with ARHGAP20 does not resultin fusion transcripts but disrupts both genes.

Defects in BRWD3 are the cause of mental retardation X-linked type 93 (MRX93) [MIM:300659], also known as mentalretardation X-linked with macrocephaly. Mental retardation ischaracterized by significantly sub-average general intellectualfunctioning associated with impairments in adaptative behavior andmanifested during the developmental period. Mentally retardedindividuals are at least twice as likely to have macrocephaly thanare their intellectually normal peers.

Defects in BSCL2 are the cause of congenital generalizedlipodystrophy type 2 (CGL2) [MIM:269700]. Congenital generalizedlipodystrophy is an autosomal recessive disorder characterized bya near absence of adipose tissue, extreme insulin resistance,hypertriglyceridemia, hepatic steatosis and early onset ofdiabetes.

Defects in BSCL2 are the cause of spastic paraplegia type17 (SPG17) [MIM:270685], also known as Silver spastic paraplegiasyndrome. Spastic paraplegia is a neurodegenerative disordercharacterized by a slow, gradual, progressive weakness andspasticity of the lower limbs. SPG17 is characterized by prominentamyotrophy of the hand muscles, the presence of mild to severepyramidal tract signs, and spastic paraplegia. SPG17 is a motorneuron disease overlapping with distal spinal muscular atrophytype 5.

Defects in BSCL2 are a cause of distal hereditary motorneuropathy type 5 (HMN5) [MIM:600794], also known aS distalhereditary motor neuropathy type V (DSMAV). HMN5 is an autosomaldominant disorder characterized by degeneration of motor nervefibers, predominantly in limb distal regions.

Defects in BSND are the cause of Bartter syndrome type 4A(BS4A) [MIM:602522], also known as infantile Bartter syndrome withsensorineural deafness. BS refers to a group of autosomalrecessive disorders characterized by impaired salt reabsorption inthe thick ascending loop of Henle with pronounced salt wasting,hypokalemic metabolic alkalosis, and varying degrees ofhypercalciuria. BS4A is associated with sensorineural deafness.

Genetic variations in BTBD9 may be associated withsusceptibility to restless legs syndrome type 6 (RLS6)[MIM:611185], also called periodic limb movements in sleep.Restless legs syndrome (RLS) is a neurologic disordercharacterized by an uncontrollable urge to move the legs duringperiods of rest. The majority of patients with RLS also haveperiodic limb movements in sleep, which are characterized byinvoluntary, highly stereotypical, regularly occurring limbmovements that occur during sleep.

Defects in BTD are the cause of biotinidase deficiency(BTD deficiency) [MIM:253260], also called late-onset multiplecarboxylase deficiency. BTD deficiency is a juvenile form ofmultiple carboxylase deficiency, an autosomal recessive disorderof biotin metabolism, characterized by ketoacidosis,hyperammonemia, excretion of abnormal organic acid metabolites,and dermatitis. BTD deficiency is characterized by seizures,hypotonia, skin rash, alopecia, ataxia, hearing loss, and opticatrophy. If untreated, symptoms usually become progressivelyworse, and coma and death may occur.

Note=A chromosomal aberration involving BTG1 may be acause of a form of B-cell chronic lymphocytic leukemia.Translocation t(8,12)(q24,q22) with MYC.

Defects in BTK are the cause of X-linkedagammaglobulinemia (XLA) [MIM:300755], also known as X-linkedagammaglobulinemia type 1 (AGMX1) or immunodeficiency type 1(IMD1). XLA is a humoral immunodeficiency disease which results indevelopmental defects in the maturation pathway of B-cells.Affected boys have normal levels of pre-B-cells in their bonemarrow but virtually no circulating mature B-lymphocytes. Thisresults in a lack of immunoglobulins of all classes and leads torecurrent bacterial infections like otitis, conjunctivitis,dermatitis, sinusitis in the first few years of life, or even somepatients present overwhelming sepsis or meningitis, resulting indeath in a few hours. Treatment in most cases is by infusion ofintravenous immunoglobulin.

Defects in BTK may be the cause of X-linkedhypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD) [MIM:307200], also known as agammaglobulinemia and isolatedgrowth hormone deficiency or Fleisher syndrome or isolated growthhormone deficiency type 3 (IGHD3). In rare cases XLA is inheritedtogether with isolated growth hormone deficiency (IGHD).

Genetic variation in BTNL2 is a cause of susceptibilityto sarcoidosis type 2 (SS2) [MIM:612387]. Sarcoidosis is anidiopathic, systemic, inflammatory disease characterized by theformation of immune granulomas in involved organs. Granulomaspredominantly invade the lungs and the lymphatic system, but alsoskin, liver, spleen, eyes and other organs may be involved. Note=Anucleotide transition affecting a splice donor site results in theuse of an alternative splice site and the production of isoform 3.Individuals expressing isoform 3 have a higher risk forsarcoidosis.

Note=Defects in BUB1B are associated with tumorformation.

Defects in BUB1B are the cause of premature chromatidseparation trait (PCS) [MIM:176430]. PCS consists of separate andsplayed chromatids with discernible centromeres and involves allor most chromosomes of a metaphase. It is found in up to 2% ofmetaphases in cultured lymphocytes from approximately 40% ofnormal individuals. When PCS is present in 5% or more of cells, itis known as the heterozygous PCS trait and has no obviousphenotypic effect, although some have reported decreasedfertility. Inheritance is autosomal dominant.

Defects in BUB1B are the cause of mosaic variegatedaneuploidy syndrome (MVA) [MIM:257300]. MVA is a severe autosomalrecessive developmental disorder characterized by mosaicaneuploidies, predominantly trisomies and monosomies, involvingmultiple different chromosomes and tissues. The proportion ofaneuploid cells varies but is usually more than 25% and issubstantially greater than in normal individuals. Affectedindividuals typically present with severe intrauterine growthretardation and microcephaly. Eye anomalies, mild dysmorphism,variable developmental delay, and a broad spectrum of additionalcongenital abnormalities and medical conditions may also occur.The risk of malignancy is high, with rhabdomyosarcoma, Wilms tumorand leukemia reported in several cases. MVA is caused by biallelicmutations in the BUB1B gene.

Defects in CYP11B1 are the cause of adrenal hyperplasiatype 4 (AH4) [MIM:202010]. AH4 is a form of congenital adrenalhyperplasia, a common recessive disease due to defective synthesisof cortisol. Congenital adrenal hyperplasia is characterized byandrogen excess leading to ambiguous genitalia in affectedfemales, rapid somatic growth during childhood in both sexes withpremature closure of the epiphyses and short adult stature. Fourclinical types: "salt wasting" (SW, the most severe type), "simplevirilizing" (SV, less severely affected patients), with normalaldosterone biosynthesis, "non-classic form" or late onset (NC orLOAH), and "cryptic" (asymptomatic). AH4 patients usually havehypertension.

Defects in CYP11B1 are a cause of hyperaldosteronismfamilial type 1 (FH1) [MIM:103900]. It is a disorder characterizedby hypertension, variable hyperaldosteronism, and abnormal adrenalsteroid production, including 18-oxocortisol and 18-hydroxycortisol. There is significant phenotypic heterogeneity,and some individuals never develop hypertension. Note=Themolecular defect causing hyperaldosteronism familial type 1 is ananti-Lepore-type fusion of the CYP11B1 and CYP11B2 genes. Thehybrid gene has the promoting part of CYP11B1, ACTH-sensitive, andthe coding part of CYP11B2.

Defects in CYP11B2 are the cause of corticosteronemethyloxidase type 1 deficiency (CMO-1 deficiency) [MIM:203400],also known as aldosterone deficiency due to defect in 18-hydroxylase or aldosterone deficiency I. CMO-1 deficiency is anautosomal recessive disorder of aldosterone biosynthesis. Thereare two biochemically different forms of selective aldosteronedeficiency be termed corticosterone methyloxidase (CMO) deficiencytype 1 and type 2. In CMO-1 deficiency, aldosterone isundetectable in plasma, while its immediate precursor, 18-hydroxycorticosterone, is low or normal.

Defects in CYP11B2 are the cause of corticosteronemethyloxidase type 2 deficiency (CMO-2 deficiency) [MIM:610600].CMO-2 is an autosomal recessive disorder of aldosteronebiosynthesis. In CMO-2 deficiency, aldosterone can be low ornormal, but at the expense of increased secretion of 18-hydroxycorticosterone. Consequently, patients have a greatlyincreased ratio of 18-hydroxycorticosterone to aldosterone and alow ratio of corticosterone to 18-hydroxycorticosterone in serum.

Defects in CYP11B2 are a cause of hyperaldosteronismfamilial type 1 (FH1) [MIM:103900]. It is a disorder characterizedby hypertension, variable hyperaldosteronism, and abnormal adrenalsteroid production, including 18-oxocortisol and 18-hydroxycortisol. There is significant phenotypic heterogeneity,and some individuals never develop hypertension. Note=Themolecular defect causing hyperaldosteronism familial type 1 is ananti-Lepore-type fusion of the CYP11B1 and CYP11B2 genes. Thehybrid gene has the promoting part of CYP11B1, ACTH-sensitive, andthe coding part of CYP11B2.

Defects in C1GALT1C1 are the cause of Tn syndrome (TNSYN)[MIM:300622]. Tn syndrome is a rare autoimmune disease caused bysomatic mutation in the C1GALT1C1 gene in which subpopulations ofblood cells of all lineages carry an incompletely glycosylatedmembrane glycoprotein, i.e., the Tn antigen. Since leukocytes andplatelets are affected as well as red cells, anemia, leukopeniaand thrombocytopenia are features. Tn-polyagglutinability issometimes associated with leukemia or is a preleukemic state.

Defects in C1QA are a cause of complement component C1qdeficiency (C1QD) [MIM:613652]. A rare defect resulting in C1deficiency and impaired activation of the complement classicalpathway. C1 deficiency generally leads to severe immune complexdisease with features of systemic lupus erythematosus andglomerulonephritis.

Defects in C1QB are a cause of complement component C1qdeficiency (C1QD) [MIM:613652]. A rare defect resulting in C1deficiency and impaired activation of the complement classicalpathway. C1 deficiency generally leads to severe immune complexdisease with features of systemic lupus erythematosus andglomerulonephritis.

Defects in C1QC are a cause of complement component C1qdeficiency (C1QD) [MIM:613652]. A rare defect resulting in C1deficiency and impaired activation of the complement classicalpathway. C1 deficiency generally leads to severe immune complexdisease with features of systemic lupus erythematosus andglomerulonephritis.

Defects in C1QTNF5 are a cause of late-onset retinaldegeneration (LORD) [MIM:605670]. LORD is an autosomal dominantdisorder characterized by onset in the fifth to sixth decade withnight blindness and punctate yellow-white deposits in the retinalfundus, progressing to severe central and peripheral degeneration,with choroidal neovascularization and chorioretinal atrophy.

Defects in C1S are the cause of complement component C1sdeficiency (C1SD) [MIM:120580]. A rare defect resulting in C1deficiency and impaired activation of the complement classicalpathway. C1 deficiency generally leads to severe immune complexdisease with features of systemic lupus erythematosus andglomerulonephritis.

Defects in MTHFD1 may be a cause of susceptibility tofolate-sensitive neural tube defects (folate-sensitive NTD)[MIM:601634]. The most common NTDs are open spina bifida(myelomeningocele) and anencephaly. Genetic defects in MTHFD1 mayaffect the risk of spina bifida via the maternal rather than theembryonic genotype.

Genetic variation in MTHFD1 could be associated withsusceptibility to colorectal cancer (CRC) [MIM:114500].

Defects in CC2D1A are the cause of mental retardationautosomal recessive type 3 (MRT3) [MIM:608443]. Patients displaysevere mental retardation and psychomotor development delay inearly childhood. Non-syndromic mental retardation patients do notmanifest other clinical signs.

Defects in CC2D2A are the cause of Meckel syndrome type 6(MKS6) [MIM:612284]. MKS is an autosomal recessive disordercharacterized by a combination of renal cysts and variablyassociated features including developmental anomalies of thecentral nervous system (typically encephalocele), hepatic ductaldysplasia and cysts, and polydactyly.

Defects in CC2D2A are the cause of Joubert syndrome type9 (JBTS9) [MIM:612285]. JBTS is an autosomal recessive disorderpresenting with cerebellar ataxia, oculomotor apraxia, hypotonia,neonatal breathing abnormalities and psychomotor delay.Neuroradiologically, it is characterized by cerebellar vermianhypoplasia/aplasia, thickened and reoriented superior cerebellarpeduncles, and an abnormally large interpeduncular fossa, givingthe appearance of a molar tooth on transaxial slices (molar toothsign). Additional variable features include retinal dystrophy andrenal disease.

Defects in CC2D2A are a cause of COACH syndrome (COACHS)[MIM:216360]. It is a disorder characterized by mentalretardation, ataxia due to cerebellar hypoplasia, and hepaticfibrosis. Patients present the molar tooth sign, a midbrain-hindbrain malformation pathognomonic for Joubert syndrome andrelated disorders. Other features, such as coloboma and renalcysts, may be variable.

Defects in CIITA are a cause of bare lymphocyte syndrometype 2 (BLS2) [MIM:209920], also known as hereditary MHC class IIdeficiency or HLA class II-deficient combined immunodeficiency.BLS2 is a severe combined immunodeficiency disease with earlyonset. It is characterized by a profound defect in constitutiveand interferon-gamma induced MHC II expression, absence ofcellular and humoral T-cell response to antigen challenge,hypogammaglobulinemia and impaired antibody production. Theconsequence include extreme susceptibility to viral, bacterial andfungal infections.

Defects in SDHC are the cause of hereditaryparagangliomas type 3 (PGL3) [MIM:605373], also known as autosomaldominant non-chromaffin paragangliomas type 3. Non-chromaffinparagangliomas are usually benign, neural crest derived tumors ofparasympathetic ganglia.

Defects in SDHC are a cause of paraganglioma and gastricstromal sarcoma (PGGSS) [MIM:606864], also known as Carney-Stratakis syndrome. Gastrointestinal stromal tumors may besporadic or inherited in an autosomal dominant manner, alone or asa component of a syndrome associated with other tumors, such as inthe context of neurofibromatosis type 1 (NF1). Patients have bothgastrointestinal stromal tumors and paragangliomas. Susceptibilityto the tumors was inherited in an apparently autosomal dominantmanner, with incomplete penetrance.

Defects in CACNA2D4 are the cause of retinal conedystrophy 4 (RCD4) [MIM:610478]. RCD4 is characterized by minimalsymptoms except for slowly progressive reduction in visual acuity.

Defects in CABP4 are the cause of congenital stationarynight blindness type 2B (CSNB2B) [MIM:610427]. Congenitalstationary night blindness is a non-progressive retinal disordercharacterized by impaired night vision.

Defects in CACNA1A are the cause of spinocerebellarataxia type 6 (SCA6) [MIM:183086]. Spinocerebellar ataxia is aclinically and genetically heterogeneous group of cerebellardisorders. Patients show progressive incoordination of gait andoften poor coordination of hands, speech and eye movements, due todegeneration of the cerebellum with variable involvement of thebrainstem and spinal cord. SCA6 is mainly caused by expansion of aCAG repeat in the coding region of CACNA1A. There seems to be acorrelation between the repeat number and earlier onset of thedisorder.

Defects in CACNA1A are the cause of migraine familialhemiplegic type 1 (FHM1) [MIM:141500], also known as migrainefamilial hemiplegic 1 (MHP1). FHM1, a rare autosomal dominantsubtype of migraine with aura, is associated with ictalhemiparesis and, in some families, progressive cerebellar atrophy.

Defects in CACNA1A are the cause of episodic ataxia type2 (EA2) [MIM:108500], also known as acetazolamide-responsivehereditary paroxysmal cerebellar ataxia (APCA). EA2 is anautosomal dominant disorder characterized by acetozolamide-responsive attacks of ataxia, migraine-like symptoms, interictalnystagmus, and cerebellar atrophy.

Defects in CACNA1C are the cause of Timothy syndrome (TS)[MIM:601005]. TS is a disorder characterized by multiorgandysfunction including lethal arrhythmias, webbing of fingers andtoes, congenital heart disease, immune deficiency, intermittenthypoglycemia, cognitive abnormalities and autism.

Defects in CACNA1C are the cause of Brugada syndrome type3 (BRS3) [MIM:611875]. BRS3 is a heart disease characterized bythe association of Brugada syndrome with shortened QT intervals.Brugada syndrome is a tachyarrhythmia characterized by rightbundle branch block and ST segment elevation on anelectrocardiogram (ECG). It can cause the ventricles to beat sofast that the blood is prevented from circulating efficiently inthe body. When this situation occurs (called ventricularfibrillation), the individual will faint and may die in a fewminutes if the heart is not reset.

Defects in CACNA1F are the cause of congenital stationarynight blindness type 2A (CSNB2A) [MIM:300071]. Congenitalstationary night blindness is a non-progressive retinal disordercharacterized by impaired night vision.

Defects in CACNA1F are the cause of cone-rod dystrophy X-linked type 3 (CORDX3) [MIM:300476]. CORDs are inherited retinaldystrophies belonging to the group of pigmentary retinopathies.CORDs are characterized by retinal pigment deposits visible onfundus examination, predominantly in the macular region, andinitial loss of cone photoreceptors followed by rod degeneration.This leads to decreased visual acuity and sensitivity in thecentral visual field, followed by loss of peripheral vision.Severe loss of vision occurs earlier than in retinitis pigmentosa.

Defects in CACNA1F are the cause of Aaland island eyedisease (AIED) [MIM:300600], also known as Forsius-Eriksson typeocular albinism. On the Aaland island in the Baltic Sea, AIED isan X-linked recessive retinal disease characterized by acombination of fundus hypopigmentation, decreased visual acuitydue to foveal hypoplasia, nystagmus, astigmatism, protan colorvision defect, myopia, and defective dark adaptation. Except forprogression of axial myopia, the disease can be considered to be astationary condition. Electroretinography reveals abnormalities inboth photopic and scotopic functions.

Defects in CACNA1H are a cause of susceptibility toidiopathic generalized epilepsy type 6 (IGE6) [MIM:611942]. IGE ischaracterized by recurring generalized seizures in the absence ofdetectable brain lesions and/or metabolic abnormalities.Generalized seizures arise diffusely and simultaneously from bothhemispheres of the brain. IGE6 is a polygenic and multifactorialdisease.

Defects in CACNA1S are the cause of periodic paralysishypokalemic type 1 (HOKPP1) [MIM:170400], also designated HYPOPP.HOKPP1 is an autosomal dominant disorder manifested by episodicflaccid generalized muscle weakness associated with falls of serumpotassium levels.

Defects in CACNA1S are the cause of malignanthyperthermia susceptibility type 5 (MHS5) [MIM:601887], anautosomal dominant disorder that is potentially lethal insusceptible individuals on exposure to commonly used inhalationalanesthetics and depolarizing muscle relaxants.

Defects in CACNA1S are the cause of susceptibility tothyrotoxic periodic paralysis type 1 (TTPP1) [MIM:188580]. Asporadic muscular disorder characterized by episodic weakness andhypokalemia during a thyrotoxic state. It is clinically similar tohereditary hypokalemic periodic paralysis, except for the factthat hyperthyroidism is an absolute requirement for diseasemanifestation. The disease presents with recurrent episodes ofacute muscular weakness of the four extremities that vary inseverity from paresis to complete paralysis. Attacks are triggeredby ingestion of a high carbohydrate load or strenuous physicalactivity followed by a period of rest. Thyrotoxic periodicparalysis can occur in association with any cause ofhyperthyroidism, but is most commonly associated with Gravesdisease.

Defects in CACNB2 are the cause of Brugada syndrome type4 (BRS4) [MIM:611876]. BRS4 is a heart disease characterized bythe association of Brugada syndrome with shortened QT intervals.Brugada syndrome is a tachyarrhythmia characterized by rightbundle branch block and ST segment elevation on anelectrocardiogram (ECG). It can cause the ventricles to beat sofast that the blood is prevented from circulating efficiently inthe body. When this situation occurs (called ventricularfibrillation), the individual will faint and may die in a fewminutes if the heart is not reset.

Genetic variations in CACNB4 are the cause ofsusceptibility to idiopathic generalized epilepsy type 9 (IGE9)[MIM:607682]. IGE9 is characterized by recurring generalizedseizures in the absence of detectable brain lesions and/ormetabolic abnormalities. Generalized seizures arise diffusely andsimultaneously from both hemispheres of the brain.

Genetic variations in CACNB4 are the cause ofsusceptibility to juvenile myoclonic epilepsy type 6 (EJM6)[MIM:607682]. EJM6 is a subtype of idiopathic generalizedepilepsy. Patients have afebrile seizures only, with onset inadolescence (rather than in childhood) and myoclonic jerks whichusually occur after awakening and are triggered by sleepdeprivation and fatigue.

Note=A chromosomal aberration involving CDH11 is a commongenetic feature of aneurysmal bone cyst, a benign osseousneoplasm. Translocation t(16,17)(q22,p13) with USP6. Thetranslocation generates a fusion gene in which the strong CDH11promoter is fused to the entire USP6 coding sequence, resulting inUSP6 transcriptional up-regulation.

Note=A chromosomal aberration involving CDH15 and KIRREL3is found in a patient with severe mental retardation anddysmorphic facial features. Translocation t(11,16)(q24.2,q24).

Defects in CDH15 are the cause of mental retardationautosomal dominant type 3 (MRD3) [MIM:612580]. Mental retardationis characterized by significantly sub-average general intellectualfunctioning associated with impairments in adaptative behavior andmanifested during the developmental period.

Defects in CDH23 are the cause of Usher syndrome type 1D(USH1D) [MIM:601067]. USH is a genetically heterogeneous conditioncharacterized by the association of retinitis pigmentosa andsensorineural deafness. Age at onset and differences in auditoryand vestibular function distinguish Usher syndrome type 1 (USH1),Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3).USH1 is characterized by profound congenital sensorineuraldeafness, absent vestibular function and prepubertal onset ofprogressive retinitis pigmentosa leading to blindness.

Defects in CDH23 are a cause of Usher syndrome type 1D/F(USH1DF) [MIM:601067]. USH1DF patients are heterozygous formutations in CDH23 and PCDH15, indicating a digenic inheritancepattern.

Defects in CDH23 are the cause of deafness autosomalrecessive type 12 (DFNB12) [MIM:601386]. DFNB12 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in CDH1 are the cause of hereditary diffusegastric cancer (HDGC) [MIM:137215]. An autosomal dominant cancerpredisposition syndrome with increased susceptibility to diffusegastric cancer. Diffuse gastric cancer is a malignant diseasecharacterized by poorly differentiated infiltrating lesionsresulting in thickening of the stomach. Malignant tumors start inthe stomach, can spread to the esophagus or the small intestine,and can extend through the stomach wall to nearby lymph nodes andorgans. It also can metastasize to other parts of the body.Note=Heterozygous germline mutations CDH1 are responsible forfamilial cases of diffuse gastric cancer. Somatic mutations in thehas also been found in patients with sporadic diffuse gastriccancer and lobular breast cancer.

Defects in CDH1 are a cause of susceptibility toendometrial cancer (ENDMC) [MIM:608089].

Defects in CDH1 are a cause of susceptibility to ovariancancer (OC) [MIM:167000]. Ovarian cancer common malignancyoriginating from ovarian tissue. Although many histologic types ofovarian neoplasms have been described, epithelial ovariancarcinoma is the most common form. Ovarian cancers are oftenasymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients arediagnosed with advanced disease.

Defects in CDH3 are the cause of hypotrichosis withjuvenile macular dystrophy (HJMD) [MIM:601553]. HJMD is a rareautosomal recessive disorder characterized by early hair lossheralding severe degenerative changes of the retinal macula andculminating in blindness during the second to third decade oflife.

Defects in CDH3 are the cause of ectodermal dysplasiawith ectrodactyly and macular dystrophy (EEM) [MIM:225280], alsoknown as EEM syndrome, Albrectsen-Svendsen syndrome or Ohdo-Hirayama-Terawaki syndrome. Ectodermal dysplasia defines aheterogeneous group of disorders due to abnormal development oftwo or more ectodermal structures. EEM is an autosomal recessivecondition characterized by features of ectodermal dysplasia suchas sparse eyebrows and scalp hair, and selective tooth agenesisassociated with macular dystrophy and ectrodactyly.

Defects in CA2 are the cause of osteopetrosis autosomalrecessive type 3 (OPTB3) [MIM:259730], also known as osteopetrosiswith renal tubular acidosis, carbonic anhydrase II deficiencysyndrome, Guibaud-Vainsel syndrome or marble brain disease.Osteopetrosis is a rare genetic disease characterized byabnormally dense bone, due to defective resorption of immaturebone. The disorder occurs in two forms: a severe autosomalrecessive form occurring in utero, infancy, or childhood, and abenign autosomal dominant form occurring in adolescence oradulthood. Autosomal recessive osteopetrosis is usually associatedwith normal or elevated amount of non-functional osteoclasts.OPTB3 is associated with renal tubular acidosis, cerebralcalcification (marble brain disease) and in some cases with mentalretardation.

Defects in CA4 are the cause of retinitis pigmentosa type17 (RP17) [MIM:600852]. RP leads to degeneration of retinalphotoreceptor cells. Patients typically have night visionblindness and loss of midperipheral visual field. As theircondition progresses, they lose their far peripheral visual fieldand eventually central vision as well. RP17 inheritance isautosomal dominant. Note=Defective acid overload removal fromretina and retinal epithelium, due to mutant CA4, is responsiblefor photoreceptor degeneration, indicating that impaired pHhomeostasis is the most likely cause underlying the RP17phenotype.

Defects in CA8 are the cause of cerebellar ataxia mentalretardation and dysequilibrium syndrome type 3 (CMARQ3)[MIM:613227]. CMARQ3 is a congenital cerebellar ataxia associatedwith dysarthia, quadrupedal gait and mild mental retardation.

Defects in CAPN10 are a cause of susceptibility todiabetes mellitus non-insulin-dependent type 1 (NIDDM1)[MIM:601283]. It is a multifactorial disorder of glucosehomeostasis caused by a lack of sensitivity to the body's owninsulin. Affected individuals usually have an obese body habitusand manifestations of a metabolic syndrome characterized bydiabetes, insulin resistance, hypertension andhypertriglyceridemia. The disease results in long-termcomplications that affect the eyes, kidneys, nerves, and bloodvessels.

Defects in CAPN3 are the cause of limb-girdle musculardystrophy type 2A (LGMD2A) [MIM:253600]. LGMD2A is an autosomalrecessive degenerative myopathy characterized by progressivesymmetrical atrophy and weakness of the proximal limb muscles andelevated serum creatine kinase. The symptoms usually begin duringthe first two decades of life, and the disease gradually worsens,often resulting in loss of walking ability 10 or 20 years afteronset.

Defects in CANT1 are the cause of Desbuquois dysplasia(DBQD) [MIM:251450]. A chondrodysplasia characterized by severeprenatal and postnatal growth retardation (less than -5 SD), jointlaxity, short extremities, progressive scoliosis, round face,midface hypoplasia, prominent bulging eyes. The main radiologicfeatures are short long bones with metaphyseal splay, a 'Swedishkey' appearance of the proximal femur (exaggerated trochanter),and advance carpal and tarsal bone age. Two forms of Desbuquoisdysplasia are distinguished on the basis of the presence (type 1)or absence (type 2) of characteristic hand anomalies: an extraossification center distal to the second metacarpal, deltaphalanx, bifid distal thumb phalanx, and phalangeal dislocations.

Defects in CARD9 are the cause of familial candidiasistype 2 (CANDF2) [MIM:212050]. Chronic mucocutaneous candidiasis ischaracterized by impaired clearance of fungal infections andresults in colonization and infections of the mucosa or skin,predominantly with Candida albicans. CANDF2 is an autosomalrecessive chronic mucocutaneous candidiasis.

Note=A chromosomal aberration involving CASC5 isassociated with acute myeloblastic leukemia (AML). Translocationt(11,15)(q23,q14) with MLL/HRX. May give rise to a MLL-CASC5fusion protein.

Defects in CASP8 are the cause of caspase-8 deficiency(CASP8D) [MIM:607271]. CASP8D is a disorder resembling autoimmunelymphoproliferative syndrome (ALPS). It is characterized bylymphadenopathy, splenomegaly, and defective CD95-inducedapoptosis of peripheral blood lymphocytes (PBLs). It leads todefects in activation of T-lymphocytes, B-lymphocytes, and naturalkiller cells leading to immunodeficiency characterized byrecurrent sinopulmonary and herpes simplex virus infections andpoor responses to immunization.

Defects in CASP10 are the cause of autoimmunelymphoproliferative syndrome type 2A (ALPS2A) [MIM:603909]. ALPS2is characterized by abnormal lymphocyte and dendritic cellhomeostasis and immune regulatory defects.

Defects in CASP10 are a cause of familial non-Hodgkinlymphoma (NHL) [MIM:605027]. NHL is a cancer that starts in cellsof the lymph system, which is part of the body's immune system.NHLs can occur at any age and are often marked by enlarged lymphnodes, fever and weight loss.

Defects in CASP10 are a cause of gastric cancer (GASC)[MIM:613659]. A malignant disease which starts in the stomach, canspread to the esophagus or the small intestine, and can extendthrough the stomach wall to nearby lymph nodes and organs. It alsocan metastasize to other parts of the body. The term gastriccancer or gastric carcinoma refers to adenocarcinoma of thestomach that accounts for most of all gastric malignant tumors.Two main histologic types are recognized, diffuse type andintestinal type carcinomas. Diffuse tumors are poorlydifferentiated infiltrating lesions resulting in thickening of thestomach. In contrast, intestinal tumors are usually exophytic,often ulcerating, and associated with intestinal metaplasia of thestomach, most often observed in sporadic disease.

Defects in CASQ2 are the cause of catecholaminergicpolymorphic ventricular tachycardia type 2 (CPVT2) [MIM:611938],also known as stress-induced polymorphic ventricular tachycardia(VTSIP). CPVT2 is an autosomal recessive form of arrhythmogenicdisorder characterized by stress-induced, bidirectionalventricular tachycardia that may degenerate into cardiac arrestand cause sudden death.

Defects in CASR are the cause of familial hypocalciurichypercalcemia type 1 (FHH) [MIM:145980]. FHH is characterized byaltered calcium homeostasis. Affected individuals exhibit mild ormodest hypercalcemia, relative hypocalciuria, and inappropriatelynormal PTH levels.

Defects in CASR are the cause of neonatal severe primaryhyperparathyroidism (NSHPT) [MIM:239200]. NSHPT is a rareautosomal recessive life-threatening disorder characterized byvery high serum calcium concentrations, skeletal demineralization,and parathyroid hyperplasia. In some instances NSHPT has beendemonstrated to be the homozygous form of FHH.

Defects in CASR are a cause of familial isolatedhypoparathyroidism (FIH) [MIM:146200], also called autosomaldominant hypoparathyroidism or autosomal dominant hypocalcemia.FIH is characterized by hypocalcemia and hyperphosphatemia due toinadequate secretion of parathyroid hormone. Symptoms areseizures, tetany and cramps. An autosomal recessive form of FIHalso exists.

Defects in CASR are the cause of idiopathic generalizedepilepsy type 8 (IGE8) [MIM:612899], also known as EIG8. Adisorder characterized by recurring generalized seizures in theabsence of detectable brain lesions and/or metabolicabnormalities. Seizure types are variable, but include myoclonicseizures, absence seizures, febrile seizures, complex partialseizures, and generalized tonic-clonic seizures.

Note=Homozygous defects in CASR can be a cause of primaryhyperparathyroidism in adulthood. Patients suffer fromosteoporosis and renal calculi, have marked hypercalcemia andincreased serum PTH concentrations.

Defects in CAT are the cause of acatalasia (ACATLAS)[MIM:115500], also known as acatalasemia. This disease ischaracterized by absence of catalase activity in red cells and isoften associated with ulcerating oral lesions.

Defects in CTSC are a cause of Papillon-Lefevre syndrome(PLS) [MIM:245000], also known as keratosis palmoplantaris withperiodontopathia. PLS is an autosomal recessive disordercharacterized by palmoplantar keratosis and severe periodontitisaffecting deciduous and permanent dentitions and resulting inpremature tooth loss. The palmoplantar keratotic phenotype varyfrom mild psoriasiform scaly skin to overt hyperkeratosis.Keratosis also affects other sites such as elbows and knees.

Defects in CTSC are a cause of Haim-Munk syndrome (HMS)[MIM:245010], also known as keratosis palmoplantaris withperiodontopathia and onychogryposis or Cochin Jewish disorder. HMSis an autosomal recessive disorder characterized by palmoplantarkeratosis, onychogryphosis and periodontitis. Additional featuresare pes planus, arachnodactyly, and acroosteolysis.

Defects in CTSC are a cause of aggressive periodontititistype 1 (AP1) [MIM:170650], also known as juvenile periodontitis(JPD) and prepubertal periodontitis (PPP). AP1 is characterized bysevere and protracted gingival infections, leading to tooth loss.AP1 inheritance is autosomal dominant.

Defects in CTSD are the cause of neuronal ceroidlipofuscinosis type 10 (CLN10) [MIM:610127], also known asneuronal ceroid lipofuscinosis due to cathepsin D deficiency. Aform of neuronal ceroid lipofuscinosis with onset at birth orearly childhood. Neuronal ceroid lipofuscinoses are progressiveneurodegenerative, lysosomal storage diseases characterized byintracellular accumulation of autofluorescent liposomal material,and clinically by seizures, dementia, visual loss, and/or cerebralatrophy.

Defects in CTSK are the cause of pycnodysostosis (PKND)[MIM:265800]. PKND is an autosomal recessive osteochondrodysplasiacharacterized by osteosclerosis and short stature.

Defects in CAV1 are the cause of congenital generalizedlipodystrophy type 3 (CGL3) [MIM:612526], also calledBerardinelli-Seip congenital lipodystrophy type 3 (BSCL3).Congenital generalized lipodystrophies are autosomal recessivedisorders characterized by a near absence of adipose tissue,extreme insulin resistance, hypertriglyceridemia, hepaticsteatosis and early onset of diabetes.

Defects in CAV3 are the cause of limb-girdle musculardystrophy type 1C (LGMD1C) [MIM:607801]. LGMD1C is a myopathycharacterized by calf hypertrophy and mild to moderate proximalmuscle weakness. LGMD1C inheritance can be autosomal dominant orrecessive.

Defects in CAV3 are a cause of hyperCKmia (HYPCK)[MIM:123320]. It is a disease characterized by persistent elevatedlevels of serum creatine kinase without muscle weakness.

Defects in CAV3 are a cause of rippling muscle disease(RMD) [MIM:606072]. RMD is a rare disorder characterized bymechanically triggered contractions of skeletal muscle. In RMD,mechanical stimulation leads to electrically silent musclecontractions that spread to neighboring fibers that cause visibleripples to move over the muscle.

Defects in CAV3 are a cause of cardiomyopathy familialhypertrophic (CMH) [MIM:192600], also designated FHC or HCM.Familial hypertrophic cardiomyopathy is a hereditary heartdisorder characterized by ventricular hypertrophy, which isusually asymmetric and often involves the interventricular septum.The symptoms include dyspnea, syncope, collapse, palpitations, andchest pain. They can be readily provoked by exercise. The disorderhas inter- and intrafamilial variability ranging from benign tomalignant forms with high risk of cardiac failure and suddencardiac death.

Defects in CAV3 are the cause of long QT syndrome type 9(LQT9) [MIM:611818]. Long QT syndromes are heart disorderscharacterized by a prolonged QT interval on the ECG andpolymorphic ventricular arrhythmias. They cause syncope and suddendeath in response to excercise or emotional stress. They canpresent with a sentinel event of sudden cardiac death in infancy.

Defects in CAV3 can be a cause of sudden infant deathsyndrome (SIDS) [MIM:272120]. SIDS is the sudden death of aninfant younger than 1 year that remains unexplained after athorough case investigation, including performance of a completeautopsy, examination of the death scene, and review of clinicalhistory. Pathophysiologic mechanisms for SIDS may includerespiratory dysfunction, cardiac dysrhythmias, cardiorespiratoryinstability, and inborn errors of metabolism, but definitivepathogenic mechanisms precipitating an infant sudden death remainelusive. Long QT syndromes-associated mutations can be responsiblefor some SIDS cases.

Defects in C2orf71 are the cause of retinitis pigmentosatype 54 (RP54) [MIM:613428]. A retinal dystrophy belonging to thegroup of pigmentary retinopathies. RP is characterized by retinalpigment deposits visible on fundus examination and primary loss ofrod photoreceptor cells followed by secondary loss of conephotoreceptors. Patients typically have night vision blindness andloss of midperipheral visual field. As their condition progresses,they lose their far peripheral visual field and eventually centralvision as well.

Defects in SERPINA6 are a cause of corticosteroid-bindingglobulin deficiency (CBG deficiency) [MIM:611489]. CBG deficiencyis an extremely rare hereditary disorder characterized by reducedcorticosteroid-binding capacity with normal or low plasmacorticosteroid-binding globulin concentration, and normal or lowbasal cortisol levels associated with hypo/hypertension and musclefatigue.

Defects in CBL are the cause of Noonan syndrome-likedisorder (NSL) [MIM:613563]. NSL is a syndrome characterized by aphenotype reminiscent of Noonan syndrome. Clinical features arehighly variable, including facial dysmorphism, short neck,developmental delay, hyperextensible joints and thoraxabnormalities with widely spaced nipples. The facial featuresconsist of triangular face with hypertelorism, large low-set ears,ptosis, and flat nasal bridge. Some patients manifest cardiacdefects.

Note=A chromosomal aberration involving CPA6 was found ina patient with Duane retraction syndrome. Translocationt(6,8)(q26,q13).

Defects in CPN1 are the cause of carboxypeptidase Ndeficiency (CPN deficiency) [MIM:212070]. Patients affectedpresent some combination of angioedema or chronic urticaria, aswell as hay fever or astma, and have also slightly depressed serumcarboxy peptidase N, suggestive of autosomal recessive inheritanceof this disorder.

Note=Chromosomal aberrations involving CREBBP may be acause of acute myeloid leukemias. Translocation t(8,16)(p11,p13)with MYST3/MOZ, translocation t(11,16)(q23,p13.3) with MLL/HRX,translocation t(10,16)(q22,p13) with MYST4/MORF. MYST3-CREBBP mayinduce leukemia by inhibiting RUNX1-mediated transcription.

Defects in CREBBP are a cause of Rubinstein-Taybisyndrome type 1 (RSTS1) [MIM:180849]. RSTS1 is an autosomaldominant disorder characterized by craniofacial abnormalities,broad thumbs, broad big toes, mental retardation and a propensityfor development of malignancies.

Defects in CBS are the cause of cystathionine beta-synthase deficiency (CBSD) [MIM:236200]. CBSD is an enzymaticdeficiency resulting in altered sulfur metabolism andhomocystinuria. The clinical features of untreated homocystinuriadue to CBS deficiency include myopia, ectopia lentis, mentalretardation, skeletal anomalies resembling Marfan syndrome, andthromboembolic events. Light skin and hair can also be present.Biochemical features include increased urinary homocystine andmethionine.

Defects in CBX2 are the cause of gonadal dysgenesis XYcomplete CBX2-related (GDXYC-CBX2) [MIM:613080]. It is a disorderof sex development. Affected individuals have a 46,XY karyotypebut present as phenotypically normal females.

Defects in CCBE1 are the cause of Hennekamlymphangiectasia-lymphedema syndrome (HLYLMP) [MIM:235510]. HLYLMPis a generalized lymph-vessels dysplasia characterized byintestinal lymphangiectasia with severe lymphedema of the limbs,genitalia and face. In addition, affected individuals have unusualfacies and severe mental retardation.

Note=A chromosomal aberration involving CCDC34 is foundin a patient with hamartoma of the retinal pigment epithelium andretina. Translocation t(11,18) (p13,p11.2).

Note=Defects in CCDC39 are a cause of a primary ciliarydyskinesia. CILD is an autosomal recessive disorder characterizedby axonemal abnormalities of motile cilia. Respiratory infectionsleading to chronic inflammation and bronchiectasis are recurrent,due to defects in the respiratory cilia, reduced fertility isoften observed in male patients due to abnormalities of spermtails. Half of the patients exhibit situs inversus, due todysfunction of monocilia at the embryonic node and randomizationof left-right body asymmetry. Primary ciliary dyskinesiaassociated with situs inversus is referred to as Kartagenersyndrome.

Note=Defects in CCDC40 are a cause of a primary ciliarydyskinesia. CILD is an autosomal recessive disorder characterizedby axonemal abnormalities of motile cilia. Respiratory infectionsleading to chronic inflammation and bronchiectasis are recurrent,due to defects in the respiratory cilia, reduced fertility isoften observed in male patients due to abnormalities of spermtails. Half of the patients exhibit situs inversus, due todysfunction of monocilia at the embryonic node and randomizationof left-right body asymmetry. Primary ciliary dyskinesiaassociated with situs inversus is referred to as Kartagenersyndrome.

Defects in CCDC50 are the cause of deafness autosomaldominant type 44 (DFNA44) [MIM:607453]. A form of non-syndromichearing loss. It is initially moderate and affects mainly low tomid frequencies. Later, it progresses to involve all thefrequencies and leads to a profound hearing loss by the 6thdecade. The onset of the hearing loss occurs in the first decadeof life.

Defects in CCDC6 are a cause of thyroid papillarycarcinoma (TPC) [MIM:188550]. TPC is a common tumor of the thyroidthat typically arises as an irregular, solid or cystic mass fromotherwise normal thyroid tissue. Papillary carcinomas aremalignant neoplasm characterized by the formation of numerous,irregular, finger-like projections of fibrous stroma that iscovered with a surface layer of neoplastic epithelial cells.Note=A chromosomal aberration involving CCDC6 is found in thyroidpapillary carcinomas. Inversion inv(10)(q11.2,q21) generates theRET/CCDC6 (PTC1) oncogene.

Defects in HCCS are a cause of microphthalmia syndromictype 7 (MCOPS7) [MIM:309801], also known as microphthalmia withlinear skin defects (MLS) or MIDAS syndrome. Microphthalmia is aclinically heterogeneous disorder of eye formation, ranging fromsmall size of a single eye TO complete bilateral absence of oculartissues (anophthalmia). In many cases, microphthalmia/anophthalmiaoccurs in association with syndromes that include non-ocularabnormalities. MCOPS7 is a disorder characterized by unilateral orbilateral microphthalmia, linear skin defects in affected females,and in utero lethality for males. Skin defects are limited to theface and neck, consisting of areas of aplastic skin that heal withage to form hyperpigmented areas. Additional features in femalepatients include agenesis of the corpus callosum, sclerocornea,chorioretinal abnormalities, infantile seizures, congenital heartdefect, mental retardation, and diaphragmatic hernia.

Defects in CCM2 are the cause of cerebral cavernousmalformations type 2 (CCM2) [MIM:603284]. Cerebral cavernousmalformations (CCMs) are congenital vascular anomalies of thecentral nervous system that can result in hemorrhagic stroke,seizures, recurrent headaches, and focal neurologic deficits. CCMshave an incidence of 0.1%-0.5% in the general population and areusually present clinically during the 3rd to 5th decades of life.The lesions are characterized by grossly enlarged blood vesselsconsisting of a single layer of endothelium and without anyintervening neural tissue, ranging in diameter from a fewmillimeters to several centimeters.

Note=A chromosomal aberration involving CCND1 may be acause of B-lymphocytic malignancy, particularly mantle-celllymphoma (MCL). Translocation t(11,14)(q13,q32) withimmunoglobulin gene regions. Activation of CCND1 may be oncogenicby directly altering progression through the cell cycle.

Note=A chromosomal aberration involving CCND1 may be acause of parathyroid adenomas. Translocation t(11,11)(q13,p15)with the parathyroid hormone (PTH) enhancer.

Defects in CCND1 are a cause of multiple myeloma (MM)[MIM:254500]. MM is a malignant tumor of plasma cells usuallyarising in the bone marrow and characterized by diffuseinvolvement of the skeletal system, hyperglobulinemia, Bence-Jonesproteinuria and anemia. Complications of multiple myeloma are bonepain, hypercalcemia, renal failure and spinal cord compression.The aberrant antibodies that are produced lead to impaired humoralimmunity and patients have a high prevalence of infection.Amyloidosis may develop in some patients. Multiple myeloma is partof a spectrum of diseases ranging from monoclonal gammopathy ofunknown significance (MGUS) to plasma cell leukemia. Note=Achromosomal aberration involving CCND1 is found in multiplemyeloma. Translocation t(11,14)(q13,q32) with the IgH locus.

Genetic variation in CCR5 is associated withsuseptibility to diabetes mellitus insulin-dependent type 22(IDDM22) [MIM:612522]. A multifactorial disorder of glucosehomeostasis that is characterized by susceptibility toketoacidosis in the absence of insulin therapy. Clinical fetauresare polydipsia, polyphagia and polyuria which result fromhyperglycemia-induced osmotic diuresis and secondary thirst. Thesederangements result in long-term complications that affect theeyes, kidneys, nerves, and blood vessels.

Defects in CD151 are the cause of nephropathy withpretibial epidermolysis bullosa and deafness (NPEBD) [MIM:609057].NPEBD is characterized by the association of hereditary nephritis,epidermolysis bullosa, deafness, and beta-thalassemia minor.

Defects in CD19 are the cause of immunodeficiency commonvariable type 3 (CVID3) [MIM:613493], also called antibodydeficiency due to CD19 defect. CVID3 is a primary immunodeficiencycharacterized by antibody deficiency, hypogammaglobulinemia,recurrent bacterial infections and an inability to mount anantibody response to antigen. The defect results from a failure ofB-cell differentiation and impaired secretion of immunoglobulins,the numbers of circulating B cells is usually in the normal range,but can be low.

Defects in MS4A1 are the cause of immunodeficiency commonvariable type 5 (CVID5) [MIM:613495], also called antibodydeficiency due to CD20 defect. CVID5 is a primary immunodeficiencycharacterized by antibody deficiency, hypogammaglobulinemia,recurrent bacterial infections and an inability to mount anantibody response to antigen. The defect results from a failure ofB-cell differentiation and impaired secretion of immunoglobulins,the numbers of circulating B cells is usually in the normal range,but can be low.

Genetic variations in CD24 are associated withsusceptibility to multiple sclerosis (MS) [MIM:126200]. Amultifactorial, inflammatory, demyelinating disease of the centralnervous system. Sclerotic lesions are characterized byperivascular infiltration of monocytes and lymphocytes and appearas indurated areas in pathologic specimens (sclerosis in plaques).The pathological mechanism is regarded as an autoimmune attack ofthe myelin sheat, mediated by both cellular and humoral immunity.Clinical manifestations include visual loss, extra-ocular movementdisorders, paresthesias, loss of sensation, weakness, dysarthria,spasticity, ataxia and bladder dysfunction. Genetic andenvironmental factors influence susceptibility to the disease.Note=Polymorphisms in CD24 may act as a genetic modifier forsusceptibility and progression of MS in some populations, perhapsby affecting the efficiency of CD24 expression on the cellsurface.

Note=The association between cutaneous and uvealmelanomas in some families suggests that mutations in CDKN2A mayaccount for a proportion of uveal melanomas. However CDKN2Amutations are rarely found in uveal melanoma patients.

Defects in CDKN2A are the cause of cutaneous malignantmelanoma type 2 (CMM2) [MIM:155601]. Malignant melanoma is amalignant neoplasm of melanocytes, arising de novo or from a pre-existing benign nevus, which occurs most often in the skin butalso may involve other sites.

Defects in CDKN2A are the cause of familial atypicalmultiple mole melanoma-pancreatic carcinoma syndrome (FAMMMPC)[MIM:606719].

Defects in CDKN2A are a cause of Li-Fraumeni syndrome(LFS) [MIM:151623]. LFS is a highly penetrant familial cancerphenotype usually associated with inherited mutations in TP53.

Defects in CDKN2A are the cause of melanoma-astrocytomasyndrome (MASTS) [MIM:155755]. The melanoma-astrocytoma syndromeis characterized by a dual predisposition to melanoma and neuralsystem tumors, commonly astrocytoma.

Defects in CD2AP are the cause of susceptibility to focalsegmental glomerulosclerosis type 3 (FSGS3) [MIM:607832]. A renalpathology defined by the presence of segmental sclerosis inglomeruli and resulting in proteinuria, reduced glomerularfiltration rate and edema. Renal insufficiency often progresses toend-stage renal disease, a highly morbid state requiring eitherdialysis therapy or kidney transplantation.

Defects in CD320 are the cause of methylmalonic aciduriatype TCblR (MMATC) [MIM:613646], also called methylmalonicaciduria due to transcobalamin receptor defect. MMATC is ametabolic disorder characterized by increased blood C3-acylcarnitine levels, elevated methylmalonate and homocysteine,and low uptake of transcobalamin-bound cobalamin, but normalconversion to adenosylcobalamin and methylcobalamin. Plasmavitamin B12 and total homocysteine are normal.

Defects in CD36 are the cause of platelet glycoprotein IVdeficiency (PG4D)[MIM:608404], also known as CD36 deficiency.Platelet glycoprotein IV deficiency can be divided into 2subgroups. The type I phenotype is characterized by platelets andmonocytes/macrophages exhibiting complete CD36 deficiency. Thetype II phenotype lacks the surface expression of CD36 inplatelets, but expression in monocytes/macrophages is near normal.

Genetic variations in CD36 are associated withsusceptibility to coronary heart disease type 7 (CHDS7)[MIM:610938].

Defects in CD3D are a cause of severe combinedimmunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-positive (T(-)/B(+)/NK(+) SCID) [MIM:608971]. Aform of severe combined immunodeficiency (SCID), a genetically andclinically heterogeneous group of rare congenital disorderscharacterized by impairment of both humoral and cell-mediatedimmunity, leukopenia, and low or absent antibody levels. Patientspresent in infancy recurrent, persistent infections byopportunistic organisms. The common characteristic of all types ofSCID is absence of T-cell-mediated cellular immunity due to adefect in T-cell development.

Defects in CD247 are the cause of immunodeficiency due todefect in CD3-zeta (CD3ZID) [MIM:610163]. An immunologicaldeficiency characterized by T-cells impaired immune response toalloantigens, tetanus toxoid and mitogens.

Defects in CD40LG are the cause of X-linkedimmunodeficiency with hyper-IgM type 1 (HIGM1) [MIM:308230], alsoknown as X-linked hyper IgM syndrome (XHIM). HIGM1 is animmunoglobulin isotype switch defect characterized by elevatedconcentrations of serum IgM and decreased amounts of all otherisotypes. Affected males present at an early age (usually withinthe first year of life) recurrent bacterial and opportunisticinfections, including Pneumocystis carinii pneumonia andintractable diarrhea due to cryptosporidium infection. Despitesubstitution treatment with intravenous immunoglobulin, theoverall prognosis is rather poor, with a death rate of about 10%before adolescence.

Defects in CD59 are the cause of CD59 deficiency (CD59D)[MIM:612300].

Defects in CD79A are the cause of agammaglobulinemia type3 (AGM3) [MIM:613501]. It is a primary immunodeficiencycharacterized by profoundly low or absent serum antibodies and lowor absent circulating B cells due to an early block of B-celldevelopment. Affected individuals develop severe infections in thefirst years of life. Note=Two different mutations, one at thesplice donor site of intron 2 and the other at the splice acceptorsite for exon 3, have been identified. Both mutations give rise toa truncated protein.

Defects in CD79B are the cause of agammaglobulinemia type6 (AGM6) [MIM:612692]. It is a primary immunodeficiencycharacterized by profoundly low or absent serum antibodies and lowor absent circulating B cells due to an early block of B-celldevelopment. Affected individuals develop severe infections in thefirst years of life.

Defects in CD81 are the cause of immunodeficiency commonvariable type 6 (CVID6) [MIM:613496], also called antibodydeficiency due to CD81 defect. CVID6 is a primary immunodeficiencycharacterized by antibody deficiency, hypogammaglobulinemia,recurrent bacterial infections and an inability to mount anantibody response to antigen. The defect results from a failure ofB-cell differentiation and impaired secretion of immunoglobulins,the numbers of circulating B cells is usually in the normal range,but can be low.

Defects in CD8A are a cause of familial CD8 deficiency(CD8 deficiency) [MIM:608957]. Familial CD8 deficiency is a novelautosomal recessive immunologic defect characterized by absence ofCD8+ cells, leading to recurrent bacterial infections.

Defects in CDAN1 are the cause of congenitaldyserythropoietic anemia type 1 (CDA1) [MIM:224120]. An autosomalrecessive blood disorder characterized by morphologicalabnormalities of erythroblasts, ineffective erythropoiesis,macrocytic anemia and secondary hemochromatosis. It isoccasionally associated with bone abnormalities, especially of thehands and feet (acrodysostosis), nail hypoplasia, and scoliosis.Ultrastructural features include internuclear chromatin bridgesconnecting some nearly completely separated erythroblasts and anabnormal appearance (spongy or Swiss-cheese appearance) of theheterochromatin in a high proportion of the erythroblasts.

Note=A chromosomal aberration involving CDC5L is found inmulticystic renal dysplasia. Translocation t(6,19)(p21,q13.1) withUSF2.

Defects in CDC73 are a cause of familial isolatedhyperparathyroidism (FIHP) [MIM:145000], also known ashyperparathyroidism type 1 (HRPT1). FIHP is an autosomal dominantdisorder characterized by hypercalcemia, elevated parathyroidhormone (PTH) levels, and uniglandular or multiglandularparathyroid tumors.

Defects in CDC73 are the cause of hyperparathyroidism-jawtumor syndrome (HPT-JT) [MIM:145001], also known ashyperparathyroidism type 2 (HRPT2) or familial primaryhyperparathyroidism with multiple ossifying jaw fibromas. HPT-JTis an autosomal dominant, multiple neoplasia syndrome primarilycharacterized by hyperparathyroidism due to parathyroid tumors.Thirty percent of individuals with HPT-JT may also developossifying fibromas, primarily of the mandible and maxilla, whichare distinc from the brown tumors associated with severehyperparathyroidism. Kidney lesions may also occur in HPT-JT asbilateral cysts, renal hamartomas or Wilms tumors.

Defects in CDC73 are a cause of parathyroid carcinoma(PRTC) [MIM:608266]. These cancers characteristically result inmore profound clinical manifestations of hyperparathyroidism thando parathyroid adenomas, the most frequent cause of primaryhyperparathyroidism. Early en bloc resection of the primary tumoris the only curative treatment.

Defects in CDHR1 are the cause of cone-rod dystrophy type15 (CORD15) [MIM:613660]. CORD15 is an inherited retinal dystrophycharacterized by retinal pigment deposits visible on fundusexamination, predominantly in the macular region, and initial lossof cone photoreceptors followed by rod degeneration. This leads todecreased visual acuity and sensitivity in the central visualfield, followed by loss of peripheral vision. Severe loss ofvision occurs earlier than in retinitis pigmentosa.

Note=Chromosomal aberrations involving CDK12 may be acause gastric cancer. Deletions within 17q12 region producingfusion transcripts with ERBB2, leading to CDK12-ERBB2 fusionleading to trunctated CDK12 protein not in-frame with ERBB2.

Defects in CDK4 are a cause of susceptibility tocutaneous malignant melanoma type 3 (CMM3) [MIM:609048]. Malignantmelanoma is a malignant neoplasm of melanocytes, arising de novoor from a pre-existing benign nevus, which occurs most often inthe skin but also may involve other sites.

Note=Chromosomal aberrations involving CDKL5 are found inpatients manifesting early-onset seizures and spams andpsychomotor impairment. Translocation t(X,6)(p22.3,q14),translocation t(X,7)(p22.3,p15).

Defects in CDKL5 are a cause of epileptic encephalopathyearly infantile type 2 (EIEE2) [MIM:300672], also known asatypical CDKL5-related Rett syndrome. EIEE2 is a severe form ofepilepsy characterized by seizures or spasms beginning in infancy.Patients manifest features resembling Rett syndrome such asmicrocephaly, lack of speech development, stereotypic handmovements.

Defects in CDKN3 are found in patients withhepatocellular carcinoma (HCC) [MIM:114550].

Defects in CDKN1B are the cause of multiple endocrineneoplasia type 4 (MEN4) [MIM:610755]. Multiple endocrine neoplasia(MEN) syndromes are inherited cancer syndromes of the thyroid.MEN4 is a MEN-like syndrome with a phenotypic overlap of both MEN1and MEN2.

Defects in CDKN1C are a cause of Beckwith-Wiedemannsyndrome (BWS) [MIM:130650]. BWS is a genetically heterogeneousdisorder characterized by anterior abdominal wall defectsincluding exomphalos (omphalocele), pre- and postnatal overgrowth,and macroglossia. Additional less frequent complications includespecific developmental defects and a predisposition to embryonaltumors.

Note=Defects in CDKN1C are involved in tumor formation.

Defects in CDSN are a cause of hypotrichosis simplex ofthe scalp (HTSS) [MIM:146520], also known as hypotrichosis Spanishtype. HTSS is an autosomal dominant form of isolated alopecia.Affected individuals have normal hair in early childhood butexperience progressive loss of scalp hair beginning in the middleof the first decade and almost complete baldness by the thirddecade.

Note=A chromosomal aberration involving CEP110 may be acause of stem cell myeloproliferative disorder (MPD).Translocation t(8,9)(p12,q33) with FGFR1. MPD is characterized bymyeloid hyperplasia, eosinophilia and T-cell or B-celllymphoblastic lymphoma. In general it progresses to acute myeloidleukemia. The fusion protein CEP110-FGFR1 is found in thecytoplasm, exhibits constitutive kinase activity and may beresponsible for the transforming activity.

Defects in CEP152 are the cause of microcephaly primarytype 4 (MCPH4) [MIM:604321]. A disease defined as a headcircumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebralcortex is disproportionately small. Despite this marked reductionin size, the gyral pattern is relatively well preserved, with nomajor abnormality in cortical architecture. Affected individualsare mentally retarded. Primary microcephaly is further defined bythe absence of other syndromic features or significantneurological deficits due to degenerative brain disorder.

Defects in CEP290 are a cause of Joubert syndrome type 5(JBTS5) [MIM:610188]. Joubert syndrome is an autosomal recessivedisease characterized by cerebellar vermis hypoplasia withprominent superior cerebellar peduncles (the 'molar tooth sign' onaxial magnetic resonance imaging), psychomotor delay, hypotonia,ataxia, oculomotor apraxia and neonatal breathing abnormalities.JBTS5 shares the neurologic and neuroradiologic features ofJoubert syndrome together with severe retinal dystrophy and/orprogressive renal failure characterized by nephronophthisis.

Defects in CEP290 are a cause of Senior-Loken syndrometype 6 (SLSN6) [MIM:610189]. Senior-Loken syndrome is also knownas juvenile nephronophthisis with Leber amaurosis. It is anautosomal recessive renal-retinal disorder, characterized byprogressive wasting of the filtering unit of the kidney, with orwithout medullary cystic renal disease, and progressive eyedisease.

Defects in CEP290 are the cause of Leber congenitalamaurosis type 10 (LCA10) [MIM:611755]. LCA designates aclinically and genetically heterogeneous group of childhoodretinal degenerations, generally inherited in an autosomalrecessive manner. Affected infants have little or no retinalphotoreceptor function as tested by electroretinography. LCArepresents the most common genetic cause of congenital visualimpairment in infants and children.

Defects in CEP290 are the cause of Meckel syndrome type 4(MKS4) [MIM:611134]. MKS4 is an autosomal recessive disordercharacterized by a combination of renal cysts and variablyassociated features including developmental anomalies of thecentral nervous system (typically encephalocele), hepatic ductaldysplasia and cysts, and polydactyly.

Note=Antibodies against CEP290 are present in sera frompatients with cutaneous T-cell lymphomas, but not in the healthycontrol population.

Defects in CEP290 are the cause of Bardet-Biedl syndrometype 14 (BBS14) [MIM:209900]. A syndrome characterized by usuallysevere pigmentary retinopathy, early-onset obesity, polydactyly,hypogenitalism, renal malformation and mental retardation.Secondary features include diabetes mellitus, hypertension andcongenital heart disease. Inheritance is autosomal recessive, butthree mutated alleles (two at one locus, and a third at a secondlocus) may be required for disease manifestation in some cases(triallelic inheritance).

Defects in CEL are a cause of maturity-onset diabetes ofthe young type 8 with exocrine dysfunction (MODY8) [MIM:609812],also known as diabetes and pancreatic exocrine dysfunction (DPED).MODY is a form of diabetes that is characterized by an autosomaldominant mode of inheritance, onset in childhood or earlyadulthood (usually before 25 years of age), a primary defect ininsulin secretion and frequent insulin-independence at thebeginning of the disease.

Defects in CENPJ are the cause of microcephaly primarytype 6 (MCPH6) [MIM:608393]. A disorder defined as a headcircumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebralcortex is disproportionately small. Despite this marked reductionin size, the gyral pattern is relatively well preserved, with nomajor abnormality in cortical architecture. Primary microcephalyis further defined by the absence of other syndromic features orsignificant neurological deficits.

Defects in CENPJ are the cause of Seckel syndrome type 4(SCKL4) [MIM:613676]. SCKL4 is a rare autosomal recessive disordercharacterized by proportionate dwarfism of prenatal onsetassociated with low birth weight, growth retardation, severemicrocephaly with a bird-headed like appearance, and mentalretardation.

Note=Chromosomal aberrations involving CENPK are a causeof acute leukemias. Translocation t(5,11)(q12,q23) with MLL.

Defects in CERKL are the cause of retinitis pigmentosatype 26 (RP26) [MIM:608380]. RP leads to degeneration of retinalphotoreceptor cells. Patients typically have night visionblindness and loss of midperipheral visual field. As theircondition progresses, they lose their far peripheral visual fieldand eventually central vision as well. RP26 inheritance isautosomal recessive.

Defects in CP are the cause of aceruloplasminemia(ACERULOP) [MIM:604290]. It is an autosomal recessive disorder ofiron metabolism characterized by iron accumulation in the brain aswell as visceral organs. Clinical features consist of the triad ofretinal degeneration, diabetes mellitus and neurologicaldisturbances.

Note=Ceruloplasmin levels are decreased in Wilsondisease, in which copper cannot be incorporated into ceruloplasminin liver because of defects in the copper-transporting ATPase 2.

Defects in CETP are a cause of hyperalphalipoproteinemia(HYPALIP) [MIM:143470]. Affected individuals show high levels ofalpha-lipoprotein (high density lipoprotein/HDL).

Defects in CETP are the cause of cholesteryl estertransfer protein deficiency (CETP deficiency) [MIM:607322]. Thisis an autosomal dominant condition associated with increased HDLcholesterol levels.

Defects in CFB are a cause of susceptibility to hemolyticuremic syndrome atypical type 4 (AHUS4) [MIM:612924]. An atypicalform of hemolytic uremic syndrome. It is a complex genetic diseasecharacterized by microangiopathic hemolytic anemia,thrombocytopenia, renal failure and absence of episodes ofenterocolitis and diarrhea. In contrast to typical hemolyticuremic syndrome, atypical forms have a poorer prognosis, withhigher death rates and frequent progression to end-stage renaldisease. Note=Susceptibility to the development of atypicalhemolytic uremic syndrome can be conferred by mutations in variouscomponents of or regulatory factors in the complement cascadesystem. Other genes may play a role in modifying the phenotype.

Genetic variations in CFH are associated with basallaminar drusen (BLD) [MIM:126700], also known as drusen of Bruchmembrane or cuticular drusen or grouped early adult-onset drusen.Drusen are extracellular deposits that accumulate below theretinal pigment epithelium on Bruch membrane. Basal laminar drusenrefers to an early adult-onset drusen phenotype that shows apattern of uniform small, slightly raised yellow subretinalnodules randomly scattered in the macula. In later stages, thesedrusen often become more numerous, with clustered groups of drusenscattered throughout the retina. In time these small basal laminardrusen may expand and ultimately lead to a serous pigmentepithelial detachment of the macula that may result in visionloss.

Defects in CFH are the cause of complement factor Hdeficiency (CFH deficiency) [MIM:609814]. CFH deficiencydetermines uncontrolled activation of the alternative complementpathway with consumption of C3 and often other terminal complementcomponents. It is associated with a number of renal diseases withvariable clinical presentation and progression, includingmembranoproliferative glomerulonephritis and atypical hemolyticuremic syndrome. CFH deficiency patients may show increasedsusceptibility to meningococcal infections.

Defects in CFH are a cause of susceptibility to hemolyticuremic syndrome atypical type 1 (AHUS1) [MIM:235400]. An atypicalform of hemolytic uremic syndrome. It is a complex genetic diseasecharacterized by microangiopathic hemolytic anemia,thrombocytopenia, renal failure and absence of episodes ofenterocolitis and diarrhea. In contrast to typical hemolyticuremic syndrome, atypical forms have a poorer prognosis, withhigher death rates and frequent progression to end-stage renaldisease. Note=Susceptibility to the development of atypicalhemolytic uremic syndrome can be conferred by mutations in variouscomponents of or regulatory factors in the complement cascadesystem. Other genes may play a role in modifying the phenotype.

Genetic variation in CFH is associated with age-relatedmacular degeneration type 4 (ARMD4) [MIM:610698]. ARMD is amultifactorial eye disease and the most common cause ofirreversible vision loss in the developed world. In most patients,the disease is manifest as ophthalmoscopically visible yellowishaccumulations of protein and lipid (known as drusen) that liebeneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.

Defects in CFI are a cause of susceptibility to hemolyticuremic syndrome atypical type 3 (AHUS3) [MIM:612923]. An atypicalform of hemolytic uremic syndrome. It is a complex genetic diseasecharacterized by microangiopathic hemolytic anemia,thrombocytopenia, renal failure and absence of episodes ofenterocolitis and diarrhea. In contrast to typical hemolyticuremic syndrome, atypical forms have a poorer prognosis, withhigher death rates and frequent progression to end-stage renaldisease. Note=Susceptibility to the development of atypicalhemolytic uremic syndrome can be conferred by mutations in variouscomponents of or regulatory factors in the complement cascadesystem. Other genes may play a role in modifying the phenotype.

Defects in CFI are the cause of complement factor Ideficiency (CFI deficiency) [MIM:610984]. CFI deficiency is anautosomal recessive condition associated with a propensity topyogenic infections.

Defects in CFC1 are the cause of visceral heterotaxyautosomal type 2 (HTX2) [MIM:605376]. A form of visceralheterotaxy, a complex disorder due to disruption of the normalleft-right asymmetry of the thoracoabdominal organs. It results inan abnormal arrangement of visceral organs, and a wide variety ofcongenital defects including cardiac malformations and situsinversus or situs ambiguus.

Defects in CFC1 are a cause of transposition of the greatarteries, dextro-looped (DTGA) [MIM:608808]. The more common formof DTGA, consists of complete inversion of the great vessels, sothat the aorta incorrectly arises from the right ventricle and thepulmonary artery incorrectly arises from the left ventricle. Thiscreates completely separate pulmonary and systemic circulatorysystems, an arrangement that is incompatible with life. Patientsoften have atrial and/or ventricular septal defects or other typesof shunting that allow some mixing between the circulations inorder to support life minimally, but surgical intervention isalways required.

Defects in CFC1 are a cause of conotruncal heartmalformations (CTHM) [MIM:217095]. CTHM consist of cardiac outflowtract defects, such as tetralogy of Fallot, pulmonary atresia,double-outlet right ventricle, truncus arteriosus communis, andaortic arch anomalies.

Defects in CFTR are the cause of cystic fibrosis (CF)[MIM:219700], also known as mucoviscidosis. CF is the most commongenetic disease in the Caucasian population, with a prevalence ofabout 1 in 2'000 live births. Inheritance is autosomal recessive.CF is a common generalized disorder of exocrine gland functionwhich impairs clearance of secretions in a variety of organs. Itis characterized by the triad of chronic bronchopulmonary disease(with recurrent respiratory infections), pancreatic insufficiency(which leads to malabsorption and growth retardation) and elevatedsweat electrolytes.

Defects in CFTR are the cause of congenital bilateralabsence of the vas deferens (CBAVD) [MIM:277180]. CBAVD is animportant cause of sterility in men and could represent anincomplete form of cystic fibrosis, as the majority of mensuffering from cystic fibrosis lack the vas deferens.

Defects in C7orf10 are the cause of glutaric aciduriatype 3 (GA3) [MIM:231690]. GA3 is a metabolic disorder due toperoxisomal glutaryl-CoA oxidase deficiency and characterized bythe excretion of abnormal quantities of glutaric acid but low 3-hydroxyglutaric acid.

Defects in CTH are the cause of cystathioninuria (CSTNU)[MIM:219500]. It is an autosomal recessive phenotype characterizedby abnormal accumulation of plasma cystathionine, leading toincreased urinary excretion.

A chromosomal aberration involving CGNL1 is a cause ofaromatase excess syndrome [MIM:139300]. This is characterized byan estrogen excess due to an increased aromatase activity. Aninversion on inv(15)(q21.2,q21.3) moves the promoter of the CGNL1gene into a 5-prime position in relation to the aromatase codingregion.

Defects in C8orf38 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinical disorders,from lethal neonatal disease to adult-onset neurodegenerativedisorders. Phenotypes include macrocephaly with progressiveleukodystrophy, non-specific encephalopathy, cardiomyopathy,myopathy, liver disease, Leigh syndrome, Leber hereditary opticneuropathy, and some forms of Parkinson disease.

A genetic variation in CHI3L1 is associated withsusceptibility to asthma-related traits type 7 (ASRT7)[MIM:611960]. Asthma-related traits include clinical symptoms ofasthma, such as coughing, wheezing and dyspnea, bronchialhyperresponsiveness (BHR) as assessed by methacholine challengetest, serum IgE levels, atopy, and atopic dermatitis.

Defects in HSPD1 are a cause of spastic paraplegiaautosomal dominant type 13 (SPG13) [MIM:605280]. Spasticparaplegia is a degenerative spinal cord disorder characterized bya slow, gradual, progressive weakness and spasticity of the lowerlimbs.

Defects in HSPD1 are the cause of leukodystrophyhypomyelinating type 4 (HLD4) [MIM:612233], also calledmitochondrial HSP60 chaperonopathy or MitCHAP-60 disease. HLD4 isa severe autosomal recessive hypomyelinating leukodystrophy.Clinically characterized by infantile-onset rotary nystagmus,progressive spastic paraplegia, neurologic regression, motorimpairment, profound mental retardation. Death usually occurrswithin the first two decades of life.

Note=A chromosomal aberration involving CHCHD7 is foundin salivary gland pleiomorphic adenomas, the most common benignepithelial tumors of the salivary gland. Translocationt(6,8)(p21.3-22,q13) with PLAG1.

Defects in CHD7 are a cause of CHARGE syndrome (CHARGES)[MIM:214800]. This syndrome, which is a common cause of congenitalanomalies, is characterized by a non-random pattern of congenitalanomalies including choanal atresia and malformations of theheart, inner ear, and retina.

Genetic variations in CHD7 are associated withsusceptibility to idiopathic scoliosis type 3 (IS3) [MIM:608765].Idiopathic scoliosis (IS) is the most common spinal deformity inchildren.

Defects in CHD7 are the cause of Kallmann syndrome type 5(KAL5) [MIM:612370]. Kallmann syndrome is a disorder thatassociates hypogonadotropic hypogonadism and anosmia. Anosmia orhyposmia is related to the absence or hypoplasia of the olfactorybulbs and tracts. Hypogonadism is due to deficiency ingonadotropin-releasing hormone and probably results from a failureof embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In some patients other developmentalanomalies can be present, which include renal agenesis, cleft lipand/or palate, selective tooth agenesis, and bimanual synkinesis.In some cases anosmia may be absent or inconspicuous.

Defects in CHD7 are a cause of idiopathichypogonadotropic hypogonadism (IHH) [MIM:146110]. IHH is definedas a deficiency of the pituitary secretion of follicle-stimulatinghormone and luteinizing hormone, which results in the impairmentof pubertal maturation and of reproductive function.

Note=A chromosomal aberration involving CHIC2 is found ina form of acute myeloid leukemia (AML). Translocationt(4,12)(q12,p13) with ETV6.

Defects in CHN1 are the cause of Duane retractionsyndrome type 2 (DURS2) [MIM:604356]. Duane retraction syndrome isa congenital eye movement disorder characterized by a failure ofcranial nerve VI (the abducens nerve) to develop normally,resulting in restriction or absence of abduction, adduction, orboth, and narrowing of the palpebral fissure and retraction of theglobe on attempted adduction. Undiagnosed in children, it can leadto amblyopia, a permanent uncorrectable loss of vision.

Defects in CHEK2 are associated with Li-Fraumeni syndrome2 (LFS2) [MIM:609265], a highly penetrant familial cancerphenotype usually associated with inherited mutations in p53/TP53.

Defects in CHEK2 may be a cause of susceptibility toprostate cancer (PC) [MIM:176807]. It is a malignancy originatingin tissues of the prostate. Most prostate cancers areadenocarcinomas that develop in the acini of the prostatic ducts.Other rare histopathologic types of prostate cancer that occur inapproximately 5% of patients include small cell carcinoma,mucinous carcinoma, prostatic ductal carcinoma, transitional cellcarcinoma, squamous cell carcinoma, basal cell carcinoma, adenoidcystic carcinoma (basaloid), signet-ring cell carcinoma andneuroendocrine carcinoma.

Defects in CHEK2 are found in some patients withosteogenic sarcoma (OSRC) [MIM:259500].

Defects in CHMP2B are the cause of frontotemporaldementia, chromosome 3-linked (FTD3) [MIM:600795]. FTD3 ischaracterized by an onset of dementia in the late 50's initiallycharacterized by behavioral and personality changes includingapathy, restlessness, disinhibition and hyperorality, progressingto stereotyped behaviors, non-fluent aphasia, mutism and dystonia,with a marked lack of insight. The brains of individuals with FTD3have no distinctive neuropathological features. They show globalcortical and central atrophy, but no beta-amyloid deposits.

Defects in CHMP4B are the cause of cataract posteriorpolar type 3 (CTPP3) [MIM:605387]. A subcapsular opacity, usuallydisk-shaped, located at the back of the lens. It can have a markedeffect on visual acuity.

Defects in CHST3 are a cause of spondyloepiphysealdysplasia with congenital joint dislocations (SEDCJD)[MIM:143095]. A bone dysplasia clinically characterized bydislocation of the knees and/or hips at birth, clubfoot, elbowjoint dysplasia with subluxation and limited extension, shortstature, and progressive kyphosis developing in late childhood.The disorder is usually evident at birth, with short stature andmultiple joint dislocations or subluxations that dominate theneonatal clinical and radiographic picture. During childhood, thedislocations improve, both spontaneously and with surgicaltreatment, and features of spondyloepiphyseal dysplasia becomeapparent, leading to arthritis of the hips and spine withintervertebral disk degeneration, rigid kyphoscoliosis, and trunkshortening by late childhood.

Defects in CHST6 are the cause of macular cornealdystrophy (MCD) [MIM:217800]. MCD is an autosomal recessivedisease characterized by corneal opacities. Onset occurs in thefirst decade, usually between ages 5 and 9. The disorder isprogressive. Minute, gray, punctate opacities develop. Cornealsensitivity is usually reduced. Painful attacks with photophobia,foreign body sensations, and recurrent erosions occur in mostpatients. There are different types of MCD: MCD type I, in whichthere is a virtual absence of sulfated keratan sulfate (KS) in theserum and cornea, as determined by KS-specific antibodies, and MCDtype II, in which the normal sulfated KS-antibody response ispresent in cornea and serum. MCD type I patients usually have ahomozygous missense mutation, while MCD type II patients show alarge deletion and replacement in the upstream region of CHST6.The only missense mutation for type II is Cys-50, which isheterozygous with a replacement in the upstream region on theother allele of CHST6.

Note=A chromosomal aberration involving CHST11 is foundin B-cell chronic lymphocytic leukemias. Translocationt(12,14)(q23,q32) with IgH.

Defects in CHST14 are the cause of Ehlers-Danlos syndromemusculocontractural type (EDSMC) [MIM:601776]. It is a form ofEhlers-Danlos syndrome characterized by distinctive craniofacialdysmorphism, congenital contractures of thumbs and fingers,clubfeet, severe kyphoscoliosis, muscular hypotonia,hyperextensible thin skin with easy bruisability and atrophicscarring, wrinkled palms, joint hypermobility, and ocularinvolvement.

Defects in CIRH1A are the cause of North American Indianchildhood cirrhosis (NAIC) [MIM:604901]. NAIC is a severeautosomal recessive intrahepatic cholestasis, originally describedin Ojibway-Cree children from northwestern Quebec. NAIC typicallypresents with transient neonatal jaundice, in a child who isotherwise healthy, and progresses to biliary cirrhosis and portalhypertension. Biochemical and histopathological features suggestinvolvement of the bile ducts rather than of the bile canaliculi.They include elevated gamma glutamyltransferase and alkalinephosphatase levels, and, typically, marked fibrosis around bileducts. Clinically, NAIC is distinct from other nonsyndromicfamilial cholestases because of its marked cholangiopathicfeatures and severe degree of fibrosis on liver histology.

Defects in CISD2 are the cause of Wolfram syndrome 2(WFS2) [MIM:604928]. WFS2 is a rare autosomal recessive disordercharacterized by characterized by optic atrophy and diabetesmellitus. Other symptoms include the presence of profound uppergastrointestinal ulceration, significant bleeding tendency,defective platelet aggregation with collagen and variousneurological symptoms.

Defects in CDK5RAP2 are the cause of microcephaly primarytype 3 (MCPH3) [MIM:604804]. A disorder defined as a headcircumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebralcortex is disproportionately small. Despite this marked reductionin size, the gyral pattern is relatively well preserved, with nomajor abnormality in cortical architecture. Primary microcephalyis further defined by the absence of other syndromic features orsignificant neurological deficits.

Defects in C12orf65 are the cause of combined oxidativephosphorylation deficiency type 7 (COXPD7) [MIM:613559]. Amitochondrial disease resulting in encephalomyopathy. Clinicalmanifestations include psychomotor delay and regression, ataxia,optic atrophy, nystagmus and muscle atrophy and weakness.

Note=Insulin-dependent diabetes mellitus is significantlyassociated with variation within a 233-kb linkage disequilibriumblock on chromosome 16p13 that includes KIAA0350. Three commonnon-coding variants of KIAA0350 in strong linkage disequilibriumreach genome-wide significance for association with the disease(PubMed:17632545).

Defects in CHAT are the cause of congenital myasthenicsyndrome with episodic apnea (CMSEA) [MIM:254210], formerly knownas familial infantile myasthenia gravis 2 (FIMG2). CMSEA is anautosomal recessive congenital myasthenic syndrome. Patients havemyasthenic symptoms since birth or early infancy, negative testsfor anti-AChR antibodies, and abrupt episodic crises withincreased weakness, bulbar paralysis, and apnea precipitated byundue exertion, fever, or excitement.

Defects in CD207 are the cause of Birbeck granuledeficiency (BIRGD) [MIM:613393]. It is a condition characterizedby the absence of Birbeck granules in epidermal Langerhans cells.Despite the lack of Birbeck granules Langerhans cells are presentin normal numbers and have normal morphologic characteristics andantigen-presenting capacity.

Defects in CLEC7A may be a cause of candidiasis familialtype 4 (CANDF4) [MIM:613108]. It is a rare disorder with alteredimmune responses and impaired clearance of fungal infections,selective against Candida. It is characterized by persistentand/or recurrent infections of the skin, nails and mucousmembranes caused by organisms of the genus Candida, mainly Candidaalbicans.

Defects in CLCF1 are the cause of cold-induced sweatingsyndrome type 2 (CISS2) [MIM:610313]. Cold-induced sweatingsyndrome (CISS) is an autosomal recessive disorder characterizedby profuse sweating induced by cool surroundings (temperatures of7 to 18 degrees Celsius). Additional abnormalities include a high-arched palate, nasal voice, depressed nasal bridge, inability tofully extend the elbows and kyphoscoliosis.

Defects in CLCNKA are a cause of Bartter syndrome type 4B(BS4B) [MIM:613090]. A digenic, recessive disorder characterizedby impaired salt reabsorption in the thick ascending loop of Henlewith pronounced salt wasting, hypokalemic metabolic alkalosis, andvarying degrees of hypercalciuria. Bartter syndrome type 4B isassociated with sensorineural deafness.

Defects in CLCNKB are the cause of Bartter syndrome type3 (BS3) [MIM:607364], also known as classic Bartter syndrome. Itis an autosomal recessive form of often severe intravascularvolume depletion due to renal salt-wasting associated with lowblood pressure, hypokalemic alkalosis, hypercalciuria, and normalserum magnesium levels.

Defects in CLCNKB are a cause of Bartter syndrome type 4B(BS4B) [MIM:613090]. A digenic, recessive disorder characterizedby impaired salt reabsorption in the thick ascending loop of Henlewith pronounced salt wasting, hypokalemic metabolic alkalosis, andvarying degrees of hypercalciuria. Bartter syndrome type 4B isassociated with sensorineural deafness.

Defects in CLCN1 are the cause of Thomsen disease (THD)[MIM:160800], also known as autosomal dominant myotonia congenita(MCD). THD is characterized by skeletal muscle stiffness (delayedrelaxation), due to membrane hyperexcitability. A variant form ofThomsen disease is myotonia levior that is characterized by mildersymptoms, later onset and absence of muscle hypo- and hypertrophy.

Defects in CLCN1 are the cause of autosomal recessivemyotonia congenita (MCR) [MIM:255700], also known as Beckerdisease.

Defects in CLCN2 are associated with susceptibility toidiopathic generalized epilepsy type 11 (IGE11) [MIM:607628]. Adisorder characterized by recurring generalized seizures in theabsence of detectable brain lesions and/or metabolicabnormalities. Generalized seizures arise diffusely andsimultaneously from both hemispheres of the brain.

Defects in CLCN2 are the cause of childhood absenceepilepsy type 3 (ECA3) [MIM:607682]. ECA3 is a subtype ofidiopathic generalized epilepsy (IGE) characterized by onset atage 6-7 years, frequent absence seizures (several per day) andbilateral, synchronous, symmetric 3 Hz spike waves on EEG. Duringadolescence, tonic-clonic and myoclonic seizures develop.

Defects in CLCN2 are associated with juvenile absenceepilepsy type 2 (JAE2) [MIM:607628]. JAE is a subtype ofidiopathic generalized epilepsy (IGE) characterized by onsetoccurring around puberty, absence seizures, generalized tonic-clonic seizures (GTCS), GTCS on awakening and myoclonic seizures.

Defects in CLCN2 are associated with juvenile myoclonicepilepsy type 8 (EJM8) [MIM:607628]. A subtype of idiopathicgeneralized epilepsy. Patients have afebrile seizures only, withonset in adolescence (rather than in childhood) and myoclonicjerks which usually occur after awakening and are triggered bysleep deprivation and fatigue.

Defects in CLCN5 are a cause of hypophosphatemic ricketsX-linked recessive (XLRH) [MIM:300554]. XLRH is a renal diseasebelonging to the 'Dent disease complex', a group of disorderscharacterized by proximal renal tubular defect, hypercalciuria,nephrocalcinosis, and renal insufficiency. The spectrum ofphenotypic features is remarkably similar in the variousdisorders, except for differences in the severity of bonedeformities and renal impairment. XLRH patients present withrickets or osteomalacia, hypophosphatemia due to decreased renaltubular phosphate reabsorption, hypercalciuria, and low molecularweight proteinuria. Patients develop nephrocalcinosis withprogressive renal failure in adulthood. Female carriers may haveasymptomatic hypercalciuria or hypophosphatemia only.

Defects in CLCN5 are the cause of nephrolithiasis type 2(NPHL2) [MIM:300009], also known as Dent disease 1. NPHL2 is an X-linked recessive renal disease belonging to the 'Dent diseasecomplex'. NPHL2 patients manifest hypercalciuria,hypophosphatemia, aminoaciduria, nephrocalcinosis andnephrolithiasis, renal insufficiency leading to renal failure inadulthood, rickets (33% of patients) and osteomalacia.

Defects in CLCN5 are the cause of nephrolithiasis type 1(NPHL1) [MIM:310468], also designated XRN. NPHL1 is an X-linkedrecessive renal disease belonging to the 'Dent disease complex'.NPHL1 presents with hypercalciuria, nephrocalcinosis, renal stonesand renal insufficiency. Patients lack urinary acidificationdefects, rickets, and osteomalacia.

Defects in CLCN5 are the cause of low molecular weightproteinuria with hypercalciuria and nephrocalcinosis (LMWPHN)[MIM:308990]. LMWPHN is an X-linked renal disease belonging to the'Dent disease complex'. Patients tend to have hypercalciuricnephrocalcinosis without rickets or renal failure.

Defects in CLDN14 are the cause of deafness autosomalrecessive type 29 (DFNB29) [MIM:605608]. DFNB29 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in CLDN16 are the cause of hypomagnesemia type 3(HOMG3) [MIM:248250], also known as familial hypomagnesemia withhypercalciuria and nephrocalcinosis (FHHNC). HOMG3 is aprogressive renal disease characterized by primary renal magnesiumwasting with hypomagnesemia, hypercalciuria and nephrocalcinosis.Recurrent urinary tract infections and kidney stones are oftenobserved. In spite of hypercalciuria, patients do not showhypocalcemia.

Defects in CLDN19 are the cause of hypomagnesemia renalwith ocular involvement (HOMGO) [MIM:248190]. HOMGO is aprogressive renal disease characterized by primary renal magnesiumwasting with hypomagnesemia, hypercalciuria and nephrocalcinosisassociated with severe ocular abnormalities such as bilateralchorioretinal scars, macular colobomata, significant myopia andnystagmus. The renal phenotype is virtually undistinguishable fromthat of patients with HOMG3 with proven CLDN16 mutations.

Defects in CLDN1 are the cause of ichthyosis-sclerosingcholangitis neonatal syndrome (NISCH) [MIM:607626], also calledichthyosis with leukocyte vacuoles alopecia and sclerosingcholangitis (ILVASC). NISCH is a rare autosomal recessive complexichthyosis syndrome characterized by scalp hypotrichosis, scarringalopecia, vulgar type ichthyosis, and sclerosing cholangitis.

Note=CLDN3 is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.

Note=CLDN4 is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.

Note=CLIP2 is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.Haploinsufficiency of CLIP2 may be the cause of certaincardiovascular and musculo-skeletal abnormalities observed in thedisease.

Defects in CLN3 are the cause of neuronal ceroidlipofuscinosis type 3 (CLN3) [MIM:204200], also known as Battendisease. A form of neuronal ceroid lipofuscinosis. Neuronal ceroidlipofuscinoses are progressive neurodegenerative, lysosomalstorage diseases characterized by intracellular accumulation ofautofluorescent liposomal material, and clinically by seizures,dementia, visual loss, and/or cerebral atrophy. The hallmark ofCLN3 is the ultrastructural pattern of lipopigment with afingerprint profile, which can have 3 different appearances: purewithin a lysosomal residual body, in conjunction with curvilinearor rectilinear profiles, and as a small component within largemembrane-bound lysosomal vacuoles. The combination of fingerprintprofiles within lysosomal vacuoles is a regular feature of bloodlymphocytes from patients with CLN3.

Defects in CLN5 are the cause of neuronal ceroidlipofuscinosis type 5 (CLN5) [MIM:256731], also known as Finnishvariant late-infantile neuronal ceroid lipofuscinosis (vLINCL). Aform of neuronal ceroid lipofuscinosis. Neuronal ceroidlipofuscinoses are progressive neurodegenerative, lysosomalstorage diseases characterized by intracellular accumulation ofautofluorescent liposomal material, and clinically by seizures,dementia, visual loss, and/or cerebral atrophy. The lipopigmentpatterns observed most often in neuronal ceroid lipofuscinosistype 5 comprise mixed combinations of granular, curvilinear, andfingerprint profiles.

Defects in CLN6 are the cause of neuronal ceroidlipofuscinosis type 6 (CLN6) [MIM:601780]. A form of neuronalceroid lipofuscinosis. Neuronal ceroid lipofuscinoses areprogressive neurodegenerative, lysosomal storage diseasescharacterized by intracellular accumulation of autofluorescentliposomal material, and clinically by seizures, dementia, visualloss, and/or cerebral atrophy. The lipopigment patterns observedmost often in neuronal ceroid lipofuscinosis type 6 comprise mixedcombinations of granular, curvilinear, and fingerprint profiles.

Defects in CLN8 are the cause of neuronal ceroidlipofuscinosis type 8 (CLN8) [MIM:600143]. A form of neuronalceroid lipofuscinosis with onset in childhood. Neuronal ceroidlipofuscinoses are progressive neurodegenerative, lysosomalstorage diseases characterized by intracellular accumulation ofautofluorescent liposomal material, and clinically by seizures,dementia, visual loss, and/or cerebral atrophy. The lipopigmentpatterns observed most often in neuronal ceroid lipofuscinosistype 8 comprise mixed combinations of granular, curvilinear, andfingerprint profiles.

Defects in CLN8 are the cause of neuronal ceroidlipofuscinosis type 8 Northern epilepsy variant (CLN8NE)[MIM:610003]. A form of neuronal ceroid lipofuscinosis clinicallycharacterized by epilepsy that presents between 5 and 10 years ofage with frequent tonic-clonic seizures followed by progressivemental retardation. Visual loss is not a prominent feature.Intracellular accumulation of autofluorescent material results incurvilinear and granular profiles on ultrastructural analysis.

Defects in CLRN1 are the cause of Usher syndrome type 3(USH3) [MIM:276902]. USH is a genetically heterogeneous conditioncharacterized by the association of retinitis pigmentosa andsensorineural deafness. Age at onset and differences in auditoryand vestibular function distinguish Usher syndrome type 1 (USH1),Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3).USH3 is characterized by postlingual progressive deafness andonset of retinitis pigmentosa in the second decade of life.

Defects in SLC25A12 are the cause of aspartate-glutamatecarrier 1 deficiency (AGC1D) [MIM:612949], also called globalcerebral hypomyelination. This syndrome consists of a child severepsychomotor retardation, hypotonia and hypomyelination of thecentral nervous system.

Defects in SLC25A13 are the cause of citrullinemia type 2(CTLN2) [MIM:603471]. Citrullinemia belongs to the urea cycledisorders. It is an autosomal recessive disease characterizedprimarily by elevated serum and urine citrulline levels. Ammoniaintoxication is another manifestation. CTLN2 is characterized byneuropsychiatric symptoms including abnormal behaviors, loss ofmemory, seizures and coma. Death can result from brain edema.Onset is sudden and usually between the ages of 20 and 50 years.

Defects in SLC25A13 are the cause of neonatalintrahepatic cholestasis due to citrin deficiency (NICCD)[MIM:605814]. NICCD is a form of citrullinemia type 2 withneonatal onset. NICCD is characterized by suppression of the bileflow, hepatic fibrosis, low birth weight, growth retardation,hypoproteinemia, variable liver dysfunction. NICCD is generallynot severe and symptoms disappear by one year of age with anappropriate diet. Years or even decades later, however, someindividuals develop the characteristic features of citrullinemiatype 2 with neuropsychiatric symptoms.

Defects in CNBP are the cause of dystrophia myotonicatype 2 (DM2) [MIM:602668], also known as proximal myotonicmyopathy (PROMM). A multisystem disease characterized by theassociation of proximal muscle weakness with myotonia, cardiacmanifestations and cataract. Additional features can includehyperhidrosis, testicular atrophy, insulin resistance and diabetesand central nervous system anomalies in rare cases. Note=Thecausative mutation is a CCTG expansion (mean approximately 5000repeats) located in intron 1 of the CNBP gene.

Defects in PDE6H are the cause of cone dystrophy retinaltype 3A (RCD3A) [MIM:610024], also known as cone dystrophy withnight blindness and supernormal rod responses. RCD3A is a rareform of cone dystrophy associated with supernormal rod responses.The disorder is characterized by reduced visual acuity,photoaversion, night blindness, and abnormal color vision. At anearly age, the retina shows subtle depigmentation at the maculaand, later, more obvious areas of atrophy.

Defects in CNGA1 are the cause of retinitis pigmentosatype 49 (RP49) [MIM:613756]. RP leads to degeneration of retinalphotoreceptor cells. Patients typically have night visionblindness and loss of midperipheral visual field. As theircondition progresses, they lose their far peripheral visual fieldand eventually central vision as well.

Defects in CNGA3 are the cause of achromatopsia type 2(ACHM2) [MIM:216900], also known as total colorblindness or rodmonochromacy (RMCH2). ACHM2 is an autosomal recessive conditioncharacterized by day blindness and photophobia. In ACHM2 patientsthe cones are defective and the subjects see better at night.

Defects in CNGB1 are the cause of retinitis pigmentosatype 45 (RP45) [MIM:600724]. RP leads to degeneration of retinalphotoreceptor cells. Patients typically have night visionblindness and loss of midperipheral visual field. As theircondition progresses, they lose their far peripheral visual fieldand eventually central vision as well.

Defects in CNGB3 are the cause of Stargardt disease type1 (STGD1) [MIM:248200]. STGD is one of the most frequent causes ofmacular degeneration in childhood. It is characterized by maculardystrophy with juvenile-onset, rapidly progressive course,alterations of the peripheral retina, and subretinal deposition oflipofuscin-like material. STGD1 inheritance is autosomalrecessive.

Defects in CNGB3 are the cause of achromatopsia type 3(ACHM3) [MIM:262300], also known as Pingelapese blindness. ACHM3is a congenital complete achromatopsia and is distinct from totalcolorblindness mainly because of the consistent concurrence ofsevere myopia.

Defects in CNNM4 are the cause of Jalili syndrome (JALIS)[MIM:217080]. A syndrome characterized by the association of cone-rod dystrophy and amelogenesis imperfecta.

Defects in PDE6G are the cause of retinitis pigmentosatype 57 (RP57) [MIM:613582]. RP57 is a retinal dystrophy belongingto the group of pigmentary retinopathies. Retinitis pigmentosa ischaracterized by retinal pigment deposits visible on fundusexamination and primary loss of rod photoreceptor cells followedby secondary loss of cone photoreceptors. Patients typically havenight vision blindness and loss of midperipheral visual field. Astheir condition progresses, they lose their far peripheral visualfield and eventually central vision as well.

Defects in CNTN1 are the cause of Compton-Northcongenital myopathy (CNCM) [MIM:612540]. CNCM is a familial lethalform of congenital onset muscle weakness, inherited in anautosomal-recessive fashion and characterized by a secondary lossof beta2-syntrophin and alpha-dystrobrevin from the musclesarcolemma, central nervous system involvement, and fetalakinesia.

Note=A chromosomal aberration involving CNTN4 has beenfound in a boy with characteristic physical features of 3pdeletion syndrome (3PDS). Translocation t(3,10)(p26,q26). 3PDS isa rare contiguous gene disorder involving the loss of thetelomeric portion of the short arm of chromosome 3 andcharacterized by developmental delay, growth retardation, anddysmorphic features.

Defects in CNTNAP2 are the cause of cortical dysplasia-focal epilepsy syndrome (CDFES) [MIM:610042]. Affected individualsmanifest cortical dysplasia, focal epilepsy, relativemacrocephaly, and diminished deep-tendon reflexes. Intractablefocal seizures begin in early childhood, after which languageregression, hyperactivity, impulsive and aggressive behavior, andmental retardation develop.

Genetic variations in CNTNAP2 influences susceptibilityto autism type 15 (AUTS15) [MIM:612100]. Autism is aneurodevelopmental disorder characterized by disturbance inlanguage, perception and socialization. The disorder isclassically defined by a triad of limited or absent verbalcommunication, a lack of reciprocal social interaction orresponsiveness, and restricted, stereotypical, and ritualizedpatterns of interests and behavior.

Note=A chromosomal aberration involving CNTNAP2 is foundin a patient with autism spectrum disorder. Paracentric inversion46,XY,inv(7)(q11.22,q35). The inversion breakpoints disrupt thegenes AUTS2 and CNTNAP2.

Defects in COL1A1 are the cause of Caffey disease (CAFFD)[MIM:114000], also known as infantile cortical hyperostosis.Caffey disease is characterized by an infantile episode of massivesubperiosteal new bone formation that typically involves thediaphyses of the long bones, mandible, and clavicles. The involvedbones may also appear inflamed, with painful swelling and systemicfever often accompanying the illness. The bone changes usuallybegin before 5 months of age and resolve before 2 years of age.

Defects in COL1A1 are a cause of Ehlers-Danlos syndrometype 1 (EDS1) [MIM:130000], also known as Ehlers-Danlos syndromegravis. EDS is a connective tissue disorder characterized byhyperextensible skin, atrophic cutaneous scars due to tissuefragility and joint hyperlaxity. EDS1 is the severe form ofclassic Ehlers-Danlos syndrome.

Defects in COL1A1 are the cause of Ehlers-Danlos syndrometype 7A (EDS7A) [MIM:130060], also known as autosomal dominantEhlers-Danlos syndrome type VII. EDS is a connective tissuedisorder characterized by hyperextensible skin, atrophic cutaneousscars due to tissue fragility and joint hyperlaxity. EDS7A ismarked by bilateral congenital hip dislocation, hyperlaxity of thejoints, and recurrent partial dislocations.

Defects in COL1A1 are a cause of osteogenesis imperfectatype 1 (OI1) [MIM:166200]. A dominantly inherited connectivetissue disorder characterized by bone fragility and blue sclerae.Osteogenesis imperfecta type 1 is non-deforming with normal heightor mild short stature, and no dentinogenesis imperfecta.

Defects in COL1A1 are a cause of osteogenesis imperfectatype 2A (OI2A) [MIM:166210], also known as osteogenesis imperfectacongenita. A connective tissue disorder characterized by bonefragility, with many perinatal fractures, severe bowing of longbones, undermineralization, and death in the perinatal period dueto respiratory insufficiency.

Defects in COL1A1 are a cause of osteogenesis imperfectatype 3 (OI3) [MIM:259420]. A connective tissue disordercharacterized by progressively deforming bones, very shortstature, a triangular face, severe scoliosis, grayish sclera, anddentinogenesis imperfecta.

Defects in COL1A1 are a cause of osteogenesis imperfectatype 4 (OI4) [MIM:166220], also known as osteogenesis imperfectawith normal sclerae. A connective tissue disorder characterized bymoderately short stature, mild to moderate scoliosis, grayish orwhite sclera and dentinogenesis imperfecta.

Genetic variations in COL1A1 are a cause ofsusceptibility to osteoporosis (OSTEOP) [MIM:166710], also knownas involutional or senile osteoporosis or postmenopausalosteoporosis. Osteoporosis is characterized by reduced bone mass,disruption of bone microarchitecture without alteration in thecomposition of bone. Osteoporotic bones are more at risk offracture.

Note=A chromosomal aberration involving COL1A1 is foundin dermatofibrosarcoma protuberans. Translocationt(17,22)(q22,q13) with PDGF.

Defects in COL1A2 are the cause of Ehlers-Danlos syndrometype 7B (EDS7B) [MIM:130060]. EDS is a connective tissue disordercharacterized by hyperextensible skin, atrophic cutaneous scarsdue to tissue fragility and joint hyperlaxity. EDS7B is marked bybilateral congenital hip dislocation, hyperlaxity of the joints,and recurrent partial dislocations.

Defects in COL1A2 are a cause of osteogenesis imperfectatype 1 (OI1) [MIM:166200]. A dominantly inherited connectivetissue disorder characterized by bone fragility and blue sclerae.Osteogenesis imperfecta type 1 is non-deforming with normal heightor mild short stature, and no dentinogenesis imperfecta.

Defects in COL1A2 are a cause of osteogenesis imperfectatype 2A (OI2A) [MIM:166210], also known as osteogenesis imperfectacongenita (OIC) or lethal perinatal. A connective tissue disordercharacterized by bone fragility, with many perinatal fractures,severe bowing of long bones, undermineralization, and death in theperinatal period due to respiratory insufficiency.

Defects in COL1A2 are the cause of cardiac valvular formof autosomal recessive Ehlers-Danlos syndrome (cardiac valvularEDS) [MIM:225320], also known as arthrochalasis type Ehlers-Danlossyndrome. In addition to joint laxity, skin hyperextensibility andfriability, and abnormal scar formation, individuals with thisform of EDS appear to be at increased risk for cardiac valvulardysfunction.

Defects in COL1A2 are a cause of osteogenesis imperfectatype 3 (OI3) [MIM:259420]. A connective tissue disordercharacterized by progressively deforming bones, very shortstature, a triangular face, severe scoliosis, grayish sclera, anddentinogenesis imperfecta.

Defects in COL1A2 are a cause of osteogenesis imperfectatype 4 (OI4) [MIM:166220], also known as osteogenesis imperfectawith normal sclerae. A connective tissue disorder characterized bymoderately short stature, mild to moderate scoliosis, grayish orwhite sclera and dentinogenesis imperfecta.

Note=A chromosomal aberration involving COL1A2 may be acause of lipoblastomas, which are benign tumors resulting fromtransformation of adipocytes, usually diagnosed in children.Translocation t(7,8)(p22,q13) with PLAG1.

Defects in COL2A1 are the cause of spondyloepiphysealdysplasia congenital type (SEDC) [MIM:183900]. This disorder ischaracterized by disproportionate short stature and pleiotropicinvolvement of the skeletal and ocular systems.

Defects in COL2A1 are the cause of spondyloepimetaphysealdysplasia Strudwick type (SEMD-STR) [MIM:184250]. A bone diseasecharacterized by disproportionate short stature from birth, with avery short trunk and shortened limbs, and skeletal abnormalitiesincluding lordosis, scoliosis, flattened vertebrae, pectuscarinatum, coxa vara, clubfoot, and abnormal epiphyses ormetaphyses. A distinctive radiographic feature is irregularsclerotic changes, described as dappled in the metaphyses of thelong bones.

Defects in COL2A1 are the cause of achondrogenesis type 2(ACG2) [MIM:200610], also known as achondrogenesis-hypochondrogenesis type II. ACG2 is a disease characterized by theabsence of ossification in the vertebral column, sacrum and pubicbones.

Defects in COL2A1 are the cause of Legg-Calve-Perthesdisease (LCPD) [MIM:150600], also known as Legg-Perthes disease orPerthes disease. LCPD is characterized by loss of circulation tothe femoral head, resulting in avascular necrosis in a growingchild. Clinical pictures of the disease vary, depending on thephase of disease progression through ischemia, revascularization,fracture and collapse, and repair and remodeling of the bone.

Defects in COL2A1 are the cause of Kniest dysplasia (KD)[MIM:156550], also known as Kniest syndrome or metatropic dwarfismtype II. KD is a moderately severe chondrodysplasia phenotype thatresults from mutations in the COL2A1 gene. Characteristics of thedisorder include a short trunk and extremities, mid-facehypoplasia, cleft palate, myopia, retinal detachment, and hearingloss.

Defects in COL2A1 are a cause of primary avascularnecrosis of femoral head (ANFH) [MIM:608805], also known asischemic necrosis of the femoral head or osteonecrosis of thefemoral head. ANFH causes disability that often requires surgicalintervention. Most cases are sporadic, but families in which thereis an autosomal dominant inheritance of the disease have beenidentified. It has been estimated that 300,000 to 600,000 peoplein the United States have ANFH. Approximately 15,000 new cases ofthis common and disabling disorder are reported annually. The ageat the onset is earlier than that for osteoarthritis. Thediagnosis is typically made when patients are between the ages of30 and 60 years. The clinical manifestations, such as pain onexertion, a limping gait, and a discrepancy in leg length, causeconsiderable disability. Moreover, nearly 10 percent of the500,000 total-hip arthroplasties performed each year in the UnitedStates involve patients with ANFH. As a result, this diseasecreates a substantial socioeconomic cost as well as a burden forpatients and their families.

Defects in COL2A1 are the cause of osteoarthritis withmild chondrodysplasia (OACD) [MIM:604864]. Osteoarthritis is acommon disease that produces joint pain and stiffness togetherwith radiologic evidence of progressive degeneration of jointcartilage. Some forms of osteoarthritis are secondary to eventssuch as trauma, infections, metabolic disorders, or congenital orheritable conditions that deform the epiphyses or relatedstructures. In most patients, however, there is no readilyidentifiable cause of osteoarthritis. Inheritance in a Mendeliandominant manner has been demonstrated in some families withprimary generalized osteoarthritis. Reports demonstratecoinheritance of primary generalized osteoarthritis with specificalleles of the gene COL2A1, the precursor of the major protein ofcartilage.

Defects in COL2A1 are the cause of platyspondylic lethalskeletal dysplasia Torrance type (PLSD-T) [MIM:151210].Platyspondylic lethal skeletal dysplasias (PLSDs) are aheterogeneous group of chondrodysplasias characterized by severeplatyspondyly and limb shortening. PLSD-T is characterized byvarying platyspondyly, short ribs with anterior cupping,hypoplasia of the lower ilia with broad ischial and pubic bones,and shortening of the tubular bones with splayed and cuppedmetaphyses. Histology of the growth plate typically shows focalhypercellularity with slightly enlarged chondrocytes in theresting cartilage and relatively well-preserved columnar formationand ossification at the chondro-osseous junction. PLSD-T isgenerally a perinatally lethal disease, but a few long-termsurvivors have been reported.

Defects in COL2A1 are the cause of multiple epiphysealdysplasia with myopia and conductive deafness (EDMMD)[MIM:132450]. Multiple epiphyseal dysplasia is a generalizedskeletal dysplasia associated with significant morbidity. Jointpain, joint deformity, waddling gait, and short stature are themain clinical signs and symptoms. EDMMD is an autosomal dominantdisorder characterized by epiphyseal dysplasia associated withprogressive myopia, retinal thinning, crenated cataracts,conductive deafness.

Defects in COL2A1 are the cause of spondyloperipheraldysplasia (SPD) [MIM:271700]. SPD patients manifest short stature,midface hypoplasia, sensorineural hearing loss, spondyloepiphysealdysplasia, platyspondyly and brachydactyly.

Defects in COL2A1 are the cause of Wagner syndrome type 2(WGN2). WGN2 is characterized by early-onset cataracts, latticedegeneration of the retina, and retinal detachment withoutinvolvement of monocular tissues.

Defects in COL2A1 are the cause of Stickler syndrome type1 (STL1) [MIM:108300], also known as vitreous type 1, ormembranous vitreous type. STL1 is an autosomal dominant form ofStickler syndrome, an inherited disorder that associates ocularsigns with more or less complete forms of Pierre Robin sequence,bone disorders and sensorineural deafness. Ocular disorders mayinclude juvenile cataract, myopia, strabismus, vitreoretinal orchorioretinal degeneration, retinal detachment, and chronicuveitis. Robin sequence includes an opening in the roof of themouth (a cleft palate), a large tongue (macroglossia), and a smalllower jaw (micrognathia). Bones are affected by slightplatyspondylisis and large, often defective epiphyses. Juvenilejoint laxity is followed by early signs of arthrosis. The degreeof hearing loss varies among affected individuals and may becomemore severe over time. Syndrome expressivity is variable.

Defects in COL2A1 are the cause of Stickler syndrome type1 non-syndromic ocular (STL1O) [MIM:609508]. STL1O is an autosomaldominant form of Stickler syndrome characterized by the ocularsigns typically seen in STL1 such as cataract, myopia, retinaldetachment. STL1 systemic features of premature osteoarthritis,cleft palate, hearing impairment, and craniofacial abnormalitiesare either absent or very mild in STL1O patients.

Defects in COL2A1 are a cause of rhegmatogenous retinaldetachment autosomal dominant (DRRD) [MIM:609508]. Rhegmatogenousretinal detachment most frequently results from a break or tear inthe retina that allows fluid from the vitreous humor to enter thepotential space beneath the retina. It is often associated withpathologic myopia and in most cases leads to visual impairment orblindness if untreated.

Defects in C2 are the cause of complement component 2deficiency (C2D) [MIM:217000]. A deficiency of the complementclassical pathway associated with the development of autoimmunedisorders, mainly systemic lupus erythematosus. Skin and jointmanifestations are common and renal disease is relatively rare.Patients with complement component 2 deficiency are also reportedto have recurrent or invasive infections.

Defects in COL3A1 are a cause of Ehlers-Danlos syndrometype 3 (EDS3) [MIM:130020], also known as benign hypermobilitysyndrome. EDS is a connective tissue disorder characterized byhyperextensible skin, atrophic cutaneous scars due to tissuefragility and joint hyperlaxity. EDS3 is a form of Ehlers-Danlossyndrome characterized by marked joint hyperextensibility withoutskeletal deformity.

Defects in COL3A1 are the cause of Ehlers-Danlos syndrometype 4 (EDS4) [MIM:130050]. EDS is a connective tissue disordercharacterized by hyperextensible skin, atrophic cutaneous scarsdue to tissue fragility and joint hyperlaxity. EDS4 is the mostsevere form of the disease. It is characterized by the joint anddermal manifestations as in other forms of the syndrome,characteristic facial features (acrogeria) in most patients, andby proneness to spontaneous rupture of bowel and large arteries.The vascular complications may affect all anatomical areas.

Defects in COL3A1 are a cause of susceptibility to aorticaneurysm abdominal (AAA) [MIM:100070]. AAA is a commonmultifactorial disorder characterized by permanent dilation of theabdominal aorta, usually due to degenerative changes in the aorticwall. Histologically, AAA is characterized by signs of chronicinflammation, destructive remodeling of the extracellular matrix,and depletion of vascular smooth muscle cells.

Defects in C3 are the cause of complement component 3deficiency (C3D) [MIM:120700]. A rare defect of the complementclassical pathway. Patients develop recurrent, severe, pyogenicinfections because of ineffective opsonization of pathogens. Somepatients may also develop autoimmune disorders, such as arthralgiaand vasculitic rashes, lupus-like syndrome andmembranoproliferative glomerulonephritis.

Genetic variation in C3 is associated with susceptibilityto age-related macular degeneration type 9 (ARMD9) [MIM:611378].ARMD is a multifactorial eye disease and the most common cause ofirreversible vision loss in the developed world. In most patients,the disease is manifest as ophthalmoscopically visible yellowishaccumulations of protein and lipid that lie beneath the retinalpigment epithelium and within an elastin-containing structureknown as Bruch membrane.

Defects in C3 are a cause of susceptibility to hemolyticuremic syndrome atypical type 5 (AHUS5) [MIM:612925]. An atypicalform of hemolytic uremic syndrome. It is a complex genetic diseasecharacterized by microangiopathic hemolytic anemia,thrombocytopenia, renal failure and absence of episodes ofenterocolitis and diarrhea. In contrast to typical hemolyticuremic syndrome, atypical forms have a poorer prognosis, withhigher death rates and frequent progression to end-stage renaldisease. Note=Susceptibility to the development of atypicalhemolytic uremic syndrome can be conferred by mutations in variouscomponents of or regulatory factors in the complement cascadesystem. Other genes may play a role in modifying the phenotype.

Defects in COL4A1 are a cause of brain small vesseldisease with hemorrhage (BSVDH) [MIM:607595]. Brain small vesseldiseases underlie 20 to 30 percent of ischemic strokes and alarger proportion of intracerebral hemorrhages. Inheritance isautosomal dominant.

Defects in COL4A1 are the cause of hereditary angiopathywith nephropathy aneurysms and muscle cramps (HANAC) [MIM:611773].The clinical renal manifestations include hematuria and bilaterallarge cysts. Histologic analysis revealed complex basementmembrane defects in kidney and skin. The systemic angiopathyappears to affect both small vessels and large arteries.

Defects in COL4A1 are a cause of porencephaly familial(PCEPH) [MIM:175780]. Porencephaly is a term used for anycavitation or cerebrospinal fluid-filled cyst in the brain.Porencephaly type 1 is usually unilateral and results from focaldestructive lesions such as fetal vascular occlusion or birthtrauma. Type 2, or schizencephalic porencephaly, is usuallysymmetric and represents a primary defect or arrest in thedevelopment of the cerebral ventricles.

Note=Autoantibodies against the NC1 domain of alpha 3(IV)are found in Goodpasture syndrome, an autoimmune disease of lungand kidney.

Defects in COL4A3 are a cause of Alport syndromeautosomal recessive (APSAR) [MIM:203780]. APSAR is characterizedby progressive glomerulonephritis, glomerular basement membranedefects, renal failure, sensorineural deafness and specific eyeabnormalities (lenticonous and macular flecks). The disorder showsconsiderable heterogeneity in that families differ in the age ofend-stage renal disease and the occurrence of deafness.

Defects in COL4A3 are a cause of benign familialhematuria (BFH) [MIM:141200], also known as thin basement membranenephropathy. BFH is characterized by persistent hematuria, anelectron microscopically detectable thin glomerular basementmembrane (GBM) and an autosomal dominant mode of inheritance.Renal function remains normal. In children, differentiationbetween BFH and AS can be difficult, because both disorders aremanifested by persistent hematuria and thin GBM at that age.

Defects in COL4A3 are a cause of Alport syndromeautosomal dominant (APSAD) [MIM:104200]. Alport syndrome ischaracterized by progressive glomerulonephritis, glomerularbasement membrane defects, renal failure, sensorineural deafnessand specific eye abnormalities (lenticonous and macular flecks).The disorder shows considerable heterogeneity in that familiesdiffer in the age of end-stage renal disease and the occurrence ofdeafness.

Defects in COL4A4 are a cause of Alport syndromeautosomal recessive (APSAR) [MIM:203780]. APSAR is characterizedby progressive glomerulonephritis, glomerular basement membranedefects, renal failure, sensorineural deafness and specific eyeabnormalities (lenticonous and macular flecks). The disorder showsconsiderable heterogeneity in that families differ in the age ofend-stage renal disease and the occurrence of deafness.

Defects in COL4A4 are a cause of benign familialhematuria (BFH) [MIM:141200], also known as thin basement membranenephropathy. BFH is characterized by persistent hematuria, anelectron microscopically detectable thin glomerular basementmembrane (GBM) and an autosomal dominant mode of inheritance.Renal function remains normal. In children, differentiationbetween BFH and AS can be difficult, because both disorders aremanifested by persistent hematuria and thin GBM at that age.

Defects in COL4A5 are the cause of Alport syndrome X-linked (APSX) [MIM:301050]. APSX is characterized by progressiveglomerulonephritis, renal failure, sensorineural deafness,specific eye abnormalities (lenticonous and macular flecks), andglomerular basement membrane defects. The disorder showsconsiderable heterogeneity in that families differ in the age ofend-stage renal disease and the occurrence of deafness.

Note=Deletions covering the N-terminal regions of COL4A5and COL4A6, which are localized in a head-to-head manner, arefound in the chromosome Xq22.3 centromeric deletion syndrome. Thisresults in a phenotype with features of diffuse leiomyomatosis andAlport syndrome (DL-ATS).

Note=Deletions covering the N-terminal regions of COL4A5and COL4A6, which are localized in a head-to-head manner, arefound in the chromosome Xq22.3 centromeric deletion syndrome. Thisresults in a phenotype with features of diffuse leiomyomatosis andAlport syndrome (DL-ATS).

Defects in C4A are the cause of complement component 4Adeficiency (C4AD) [MIM:120810]. A rare defect of the complementclassical pathway associated with the development of autoimmunedisorders, mainly systemic lupus with or without associatedglomerulonephritis.

Defects in COL5A1 are a cause of Ehlers-Danlos syndrometype 1 (EDS1) [MIM:130000], also known as Ehlers-Danlos syndromegravis or severe classic type Ehlers-Danlos syndrome. EDS is aconnective tissue disorder characterized by hyperextensible skin,atrophic cutaneous scars due to tissue fragility and jointhyperlaxity. EDS1 is the severe form of classic Ehlers-Danlossyndrome.

Defects in COL5A1 are a cause of Ehlers-Danlos syndrometype 2 (EDS2) [MIM:130010], also known as Ehlers-Danlos syndromemitis or mild classic type Ehlers Danlos syndrome.

Defects in COL5A2 are a cause of Ehlers-Danlos syndrometype 1 (EDS1) [MIM:130000], also known as Ehlers-Danlos syndromegravis or severe classic type Ehlers-Danlos syndrome. EDS is aconnective tissue disorder characterized by hyperextensible skin,atrophic cutaneous scars due to tissue fragility and jointhyperlaxity. EDS1 is the severe form of classic Ehlers-Danlossyndrome.

Defects in COL5A2 are a cause of Ehlers-Danlos syndrometype 2 (EDS2) [MIM:130010], also known as Ehlers-Danlos syndromemitis or mild classic type Ehlers Danlos syndrome.

Defects in C5 are the cause of complement component 5deficiency (C5D) [MIM:609536]. A rare defect of the complementclassical pathway associated with susceptibility to severerecurrent infections, predominantly by Neisseria gonorrhoeae orNeisseria meningitidis.

Note=An association study of C5 haplotypes and genotypesin individuals with chronic hepatitis C virus infection shows thatindividuals homozygous for the C5_1 haplotype have a significantlyhigher stage of liver fibrosis than individuals carrying at least1 other allele (PubMed:15995705).

Defects in COL6A1 are a cause of Bethlem myopathy (BM)[MIM:158810]. BM is a rare autosomal dominant proximal myopathycharacterized by early childhood onset (complete penetrance by theage of 5) and joint contractures most frequently affecting theelbows and ankles.

Defects in COL6A1 are a cause of Ullrich congenitalmuscular dystrophy (UCMD) [MIM:254090], also known as Ullrichscleroatonic muscular dystrophy. UCMD is an autosomal recessivecongenital myopathy characterized by muscle weakness and multiplejoint contractures, generally noted at birth or early infancy. Theclinical course is more severe than in Bethlem myopathy.

Defects in COL6A2 are a cause of Bethlem myopathy (BM)[MIM:158810]. BM is a rare autosomal dominant proximal myopathycharacterized by early childhood onset (complete penetrance by theage of 5) and joint contractures most frequently affecting theelbows and ankles.

Defects in COL6A2 are a cause of Ullrich congenitalmuscular dystrophy (UCMD) [MIM:254090], also known as Ullrichscleroatonic muscular dystrophy. UCMD is an autosomal recessivecongenital myopathy characterized by muscle weakness and multiplejoint contractures, generally noted at birth or early infancy. Theclinical course is more severe than in Bethlem myopathy.

Defects in COL6A2 are the cause of myosclerosis autosomalrecessive (MYOSAR) [MIM:255600], also known as myoscleroticmyopathy or congenital myosclerosis of Lowenthal. A conditioncharacterized by chronic inflammation of skeletal muscle withhyperplasia of the interstitial connective tissue. The clinicalpicture includes slender muscles with firm 'woody' consistency andrestriction of movement of many joints because of musclecontractures.

Defects in COL6A3 are a cause of Bethlem myopathy (BM)[MIM:158810]. BM is a rare autosomal dominant proximal myopathycharacterized by early childhood onset (complete penetrance by theage of 5) and joint contractures most frequently affecting theelbows and ankles.

Defects in COL6A3 are a cause of Ullrich congenitalmuscular dystrophy (UCMD) [MIM:254090], also known as Ullrichscleroatonic muscular dystrophy. UCMD is an autosomal recessivecongenital myopathy characterized by muscle weakness and multiplejoint contractures, generally noted at birth or early infancy. Theclinical course is more severe than in Bethlem myopathy.

Note=Patients affected by atopic dermatitis display anabnormal distribution of COL29A1 mRNA and protein in skinsuggesting that COL29A1 may be involved in the pathogenesis of thedisease.

Defects in C6 are the cause of complement component 6deficiency (C6D) [MIM:612446]. A rare defect of the complementclassical pathway associated with susceptibility to severerecurrent infections, predominantly by Neisseria gonorrhoeae orNeisseria meningitidis.

Note=Epidermolysis bullosa acquisita (EBA) is anautoimmune acquired blistering skin disease resulting fromautoantibodies to type VII collagen.

Defects in COL7A1 are the cause of epidermolysis bullosadystrophica (DEB) [MIM:131750, 226600]. DEB defines a group ofblistering skin diseases characterized by tissue separation whichoccurs below the dermal-epidermal basement membrane at the levelof the anchoring fibrils. Inheritance can be autosomal dominant orrecessive. Various clinical types with different severity arerecognized, ranging from severe mutilating forms to mild formswith limited and localized scarring, and less frequentextracutaneous manifestations. Mild forms include epidermolysisbullosa mitis and epidermolysis bullosa localisata.

Defects in COL7A1 are the cause of epidermolysis bullosadystrophica Pasini type (P-DEB) [MIM:131750], also known asalbopapuloid dominant dystrophic epidermolysis bullosa. P-DEB is asevere, dominantly inherited form of dystrophic epidermolysisbullosa characterized by albopapuloid Pasini papule, dorsalextremity blistering, milia formation and red atrophic scarringafter recurrent blisters.

Defects in COL7A1 are the cause of epidermolysis bullosadystrophica Hallopeau-Siemens type (HS-DEB) [MIM:226600]. HS-DEBis the most severe recessive form and manifests with mutilatingscarring, joint contractures, corneal erosions, esophagusstructures, and propensity to formation of cutaneous squamous cellcarcinomas leading to premature demise of the affectedindividuals.

Defects in COL7A1 are the cause of transient bullousdermolysis of the newborn (TBDN) [MIM:131705]. TBDN is a neonatalform of dystrophic epidermolysis bullosa characterized by sub-epidermal blisters, reduced or abnormal anchoring fibrils at thedermo-epidermal junction, and electron-dense inclusions inkeratinocytes. TBDN heals spontaneously or strongly improveswithin the first months and years of life.

Defects in COL7A1 are the cause of epidermolysis bullosadystrophica pretibial type (PR-DEB) [MIM:131850]. PR-DEB ischaracterized by pretibial blisters that develop into prurigo-likehyperkeratotic lesions. It predominantly affects the pretibialareas, sparing the knees and other parts of the skin. Otherclinical features include nail dystrophy, albopapuloid skinlesions, and hypertrophic scars without pretibial predominance.The phenotype shows considerable interindividual variabilityInheritance is autosomal dominant.

Defects in COL7A1 are the cause of epidermolysis bullosadystrophica Bart type (B-DEB) [MIM:132000]. B-DEB is an autosomaldominant form of dystrophic epidermolysis bullosa characterized bycongenital localized absence of skin, skin fragility and deformityof nails.

Defects in COL7A1 are the cause of epidermolysis bullosapruriginosa (EBP) [MIM:604129]. EBP is a distinct clinical subtypeof DEB. It is characterized by skin fragility, blistering, scarformation, intense pruritus and excoriated prurigo nodules. Onsetis in early childhood, but in some cases is delayed until thesecond or third decade of life. Inheritance can be autosomaldominant or recessive.

Defects in COL7A1 are the cause of isolated toenaildystrophy without skin fragility (INDWSF) [MIM:607523].

Defects in COL7A1 are the cause of epidermolysis bullosadystrophica with subcorneal cleavage (EBDSC) [MIM:607600], alsoknown as epidermolysis bullosa simplex superficialis (EBSS). EBDSCis a new variant of epidermolysis bullosa simplex (EBS),characterized by the development of skin cleavage just beneath thelevel of stratum corneum. It appears to be transmitted as anautosomal dominant trait and differs from other autosomal dominantforms of EBS by the common findings of milia and atrophicscarring, as well as involvement of oral and/or ocular surfaces.It is further differentiated by the presence of blisters and theabsence of spontaneous continual exfoliation or peeling.

Defects in C7 are a cause of complement component 7deficiency (C7D) [MIM:610102]. A rare defect of the complementclassical pathway associated with susceptibility to severerecurrent infections, predominantly by Neisseria gonorrhoeae orNeisseria meningitidis.

Defects in COL8A2 are the cause of corneal dystrophyFuchs endothelial type 1 (FECD1) [MIM:136800]. It is an oculardisorder caused by loss of endothelium of the central cornea. Itis characterized by focal wart-like guttata that arise fromDescemet membrane and develop in the central cornea, epithelialblisters, reduced vision and pain. Descemet membrane is thickenedby abnormal collagenous deposition.

Defects in COL8A2 are the cause of posterior polymorphouscorneal dystrophy type 2 (PPCD2) [MIM:609140]. PPCD is a rarebilateral familial disorder of the corneal epithelium, and isinherited in a autosomal dominant pattern. The clinical featuresusually present earlier than FECD, being from birth onwards. Thedisorder is characterized by alterations of Descemet membranepresenting as vesicles, opacities or band-like lesions on slit-lamp examination and specular microscopy. Affected patienttypically are asymptomatic.

Defects in C8A are a cause of complement component 8deficiency type 1 (C8D1) [MIM:613790]. A rare defect of thecomplement classical pathway associated with susceptibility tosevere recurrent infections, predominantly by Neisseriagonorrhoeae or Neisseria meningitidis.

Defects in C8B are a cause of complement component 8deficiency type 2 (C8D2) [MIM:613789]. A rare defect of thecomplement classical pathway associated with susceptibility tosevere recurrent infections, predominantly by Neisseriagonorrhoeae or Neisseria meningitidis.

Defects in COL9A1 are a cause of COL9A1-related multipleepiphyseal dysplasia (COL9A1-MED) [MIM:120210].

Defects in COL9A1 are the cause of Stickler syndromeautosomal recessive COL9A1-related (COL9A1ARSTL) [MIM:120210].COL9A1ARSTL is an autosomal recessive form of Stickler syndrome,an inherited disorder that associates ocular signs with more orless complete forms of Pierre Robin sequence, bone disorders andsensorineural deafness. Ocular disorders may include juvenilecataract, myopia, strabismus, vitreoretinal or chorioretinaldegeneration, retinal detachment, and chronic uveitis. Robinsequence includes an opening in the roof of the mouth (a cleftpalate), a large tongue (macroglossia), and a small lower jaw(micrognathia). Bones are affected by slight platyspondylisis andlarge, often defective epiphyses. Juvenile joint laxity isfollowed by early signs of arthrosis. The degree of hearing lossvaries among affected individuals and may become more severe overtime. Syndrome expressivity is variable.

Defects in COL9A2 are the cause of multiple epiphysealdysplasia type 2 (EDM2) [MIM:600204]. EDM is a generalizedskeletal dysplasia associated with significant morbidity. Jointpain, joint deformity, waddling gait, and short stature are themain clinical signs and symptoms. EDM is broadly categorized intothe more severe Fairbank and the milder Ribbing types. EDM2inheritance is autosomal dominant.

Defects in COL9A2 may be a cause of susceptibility tointervertebral disc disease (IDD) [MIM:603932], also known aslumbar disk herniation (LDH). IDD is one of the most commonmusculo-skeletal disorders and the predominant cause of low-backpain and unilateral leg pain.

Defects in COL9A3 are the cause of multiple epiphysealdysplasia type 3 (EDM3) [MIM:600969], also known as multipleepiphyseal dysplasia with myopathy. EDM is a generalized skeletaldysplasia associated with significant morbidity. Joint pain, jointdeformity, waddling gait, and short stature are the main clinicalsigns and symptoms. EDM is broadly categorized into the moresevere Fairbank and the milder Ribbing types.

Defects in C9 are a cause of complement component 9deficiency (C9D) [MIM:120940]. A rare defect of the complementclassical pathway associated with susceptibility to severerecurrent infections, predominantly by Neisseria gonorrhoeae orNeisseria meningitidis.

Defects in COL10A1 are the cause of Schmid typemetaphyseal chondrodysplasia (SMCD) [MIM:156500]. SMCD is adominantly inherited disorder of the osseous skeleton. Thecardinal features of the phenotype are mild short stature, coxavara and a waddling gait. Radiography usually shows sclerosis ofthe ribs, flaring of the metaphyses, and a wide irregular growthplate, especially of the knees. A variant form of SMCD isspondylometaphyseal dysplasia Japanese type. It is characterizedby spinal involvement comprising mild platyspondyly, vertebralbody abnormalities, and end-plate irregularity.

Defects in COL11A1 are the cause of Stickler syndrometype 2 (STL2) [MIM:604841], also known as Stickler syndromevitreous type 2. STL2 is an autosomal dominant form of Sticklersyndrome, an inherited disorder that associates ocular signs withmore or less complete forms of Pierre Robin sequence, bonedisorders and sensorineural deafness. Ocular disorders may includejuvenile cataract, myopia, strabismus, vitreoretinal orchorioretinal degeneration, retinal detachment, and chronicuveitis. Robin sequence includes an opening in the roof of themouth (a cleft palate), a large tongue (macroglossia), and a smalllower jaw (micrognathia). Bones are affected by slightplatyspondylisis and large, often defective epiphyses. Juvenilejoint laxity is followed by early signs of arthrosis. The degreeof hearing loss varies among affected individuals and may becomemore severe over time. Syndrome expressivity is variable.

Defects in COL11A1 are the cause of Marshall syndrome(MARSHS) [MIM:154780]. It is an autosomal dominant disorder withocular, orofacial, auditory and skeletal manifestations. It sharesseveral features with Stickler syndrome, such as midfacialhypoplasia, high myopia, and sensorineural-hearing deficit.

Defects in COL11A2 are the cause of Stickler syndrometype 3 (STL3) [MIM:184840]. STL3 is an autosomal dominant non-ocular form of Stickler syndrome. Classical Stickler syndromeassociates ocular signs with more or less complete forms of PierreRobin sequence, bone disorders and sensorineural deafness. Ocularsymptoms are absent in STL3. Robin sequence includes an opening inthe roof of the mouth (a cleft palate), a large tongue(macroglossia), and a small lower jaw (micrognathia). Bones areaffected by slight platyspondylisis and large, often defectiveepiphyses. Juvenile joint laxity is followed by early signs ofarthrosis. The degree of hearing loss varies among affectedindividuals and may become more severe over time. Syndromeexpressivity is variable.

Defects in COL11A2 are the cause of autosomal recessiveotospondylomegaepiphyseal dysplasia (OSMED) [MIM:215150]. OSMED isa skeletal dysplasia accompanied by severe hearing loss. Thephenotype overlaps that of autosomal dominant skeletal disorders(Stickler and Marshall syndromes) but can be distinguished bydisproportionately short limbs and lack of ocular involvement.

Defects in COL11A2 are the cause of Weissenbacher-Zweymueller syndrome (WZS) [MIM:277610]. WZS is an autosomaldominant disorder allelic with STL3 and OSMED. WZS is alsoreferred to as heterozygous OSMED.

Defects in COL11A2 are the cause of deafness autosomaldominant type 13 (DFNA13) [MIM:601868]. DFNA13 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in COL11A2 are the cause of deafness autosomalrecessive type 53 (DFNB53) [MIM:609706].

Defects in COCH are the cause of deafness autosomaldominant type 9 (DFNA9) [MIM:601369]. DFNA9 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information. DFNA9 is characterized by onset in the fourthor fifth decade of life and initially involves the highfrequencies. Deafness is progressive and usually complete by thesixth decade. In addition to cochlear involvement, DFNA9 patientsalso exhibit a spectrum of vestibular dysfunctions. Penetrance ofthe vestibular symptoms is often incomplete, and some patients areminimally affected, whereas others suffer from severe balancedisturbances and episodes of vertigo. Affected individuals havemucopolysaccharide depositions in the channels of the cochlear andvestibular nerves. These depositions apparently causestrangulation and degeneration of dendritic fibers.

Defects in CFL2 are the cause of nemaline myopathy type 7(NEM7) [MIM:610687]. A form of nemaline myopathy. Nemalinemyopathies are muscular disorders characterized by muscle weaknessof varying severity and onset, and abnormal thread-or rod-likestructures in muscle fibers on histologic examination. Nemalinemyopathy type 7 presents at birth with hypotonia and generalizedweakness. Major motor milestones are delayed, but independentambulation is achieved.

Defects in COG1 are the cause of congenital disorder ofglycosylation type 2G (CDG2G) [MIM:611209], also known as CDG-IIcaused by COG1 deficiency. CDGs are a family of severe inheriteddiseases caused by a defect in glycoprotein biosynthesis. They arecharacterized by under-glycosylated serum glycoproteins. Thesemultisystem disorders present with a wide variety of clinicalfeatures, such as disorders of the nervous system development,psychomotor retardation, dysmorphic features, hypotonia,coagulation disorders and immunodeficiency. The broad spectrum offeatures reflects the critical role of N-glycoproteins duringembryonic development, differentiation, and maintenance of cellfunctions. Clinical features of CDG2G include failure to thrive,generalized hypotonia, growth retardation and mild psychomotorretardation. CDG2G is biochemically characterized by a defect inO-glycosylation as well as N-glycosylation.

Defects in COG4 are the cause of congenital disorder ofglycosylation type 2J (CDG2J) [MIM:613489]. It is a multisystemdisorder caused by a defect in glycoprotein biosynthesis andcharacterized by under-glycosylated serum glycoproteins.Congenital disorders of glycosylation result in a wide variety ofclinical features, such as defects in the nervous systemdevelopment, psychomotor retardation, dysmorphic features,hypotonia, coagulation disorders, and immunodeficiency. The broadspectrum of features reflects the critical role of N-glycoproteinsduring embryonic development, differentiation, and maintenance ofcell functions.

Defects in COG5 are the cause of congenital disorder ofglycosylation type 2I (CDG2I) [MIM:613612]. A multisystem disordercaused by a defect in glycoprotein biosynthesis and characterizedby under-glycosylated serum glycoproteins. Congenital disorders ofglycosylation result in a wide variety of clinical features, suchas defects in the nervous system development, psychomotorretardation, dysmorphic features, hypotonia, coagulationdisorders, and immunodeficiency. The broad spectrum of featuresreflects the critical role of N-glycoproteins during embryonicdevelopment, differentiation, and maintenance of cell functions.Congenital disorder of glycosylation type 2I is characterized bymild neurological impairments.

Defects in COG7 are the cause of congenital disorder ofglycosylation type 2E (CDG2E) [MIM:608779]. CDGs are a family ofsevere inherited diseases caused by a defect in protein N-glycosylation. They are characterized by under-glycosylated serumproteins. These multisystem disorders present with a wide varietyof clinical features, such as disorders of the nervous systemdevelopment, psychomotor retardation, dysmorphic features,hypotonia, coagulation disorders, and immunodeficiency. The broadspectrum of features reflects the critical role of N-glycoproteinsduring embryonic development, differentiation, and maintenance ofcell functions.

Defects in COL17A1 are a cause of generalized atrophicbenign epidermolysis bullosa (GABEB) [MIM:226650]. GABEB is a non-lethal, adult form of junctional epidermolysis bullosacharacterized by life-long blistering of the skin, associated withhair and tooth abnormalities.

Defects in COL18A1 are a cause of Knobloch syndrome (KNO)[MIM:267750]. KNO is an autosomal recessive disorder defined bythe occurrence of high myopia, vitreoretinal degeneration withretinal detachment, macular abnormalities and occipitalencephalocele.

Defects in COLQ are the cause of congenital myasthenicsyndrome Engel type (CMSE) [MIM:603034], also known as end-plateacetylcholinesterase deficiency or congenital myasthenic syndrometype IC (CMS-IC). CMSE is a rare autosomal recessive congenitalmyasthenic syndrome characterized by onset during childhood,generalized weakness, abnormal fatigability on exertion,refrectoriness to acetylcholinesterase drugs, decrementalelectromyographic response and morphological abnormalities of theneuromuscular junctions.

Defects in COMP are the cause of multiple epiphysealdysplasia type 1 (EDM1) [MIM:132400]. EDM is a generalizedskeletal dysplasia associated with significant morbidity. Jointpain, joint deformity, waddling gait, and short stature are themain clinical signs and symptoms. EDM is broadly categorized intothe more severe Fairbank and the milder Ribbing types.

Defects in COMP are the cause of pseudoachondroplasia(PSACH) [MIM:177170]. PSAC is a dominantly inheritedchondrodysplasia characterized by short stature and early-onsetosteoarthrosis. PSACH is more severe than EDM1 and is recognizedin early childhood.

Defects in COQ2 are a cause of coenzyme Q10 deficiency[MIM:607426]. Coenzyme Q10 deficiency is an autosomal recessivedisorder with variable manifestations. It can be associated withthree main clinical phenotypes: a predominantly myopathic formwith central nervous system involvement, an infantileencephalomyopathy with renal dysfunction and an ataxic form withcerebellar atrophy.

Defects in COQ9 are a cause of coenzyme Q10 deficiency[MIM:607426]. Coenzyme Q10 deficiency is an autosomal recessivedisorder with variable manifestations. It can be associated withthree main clinical phenotypes: a predominantly myopathic formwith central nervous system involvement, an infantileencephalomyopathy with renal dysfunction and an ataxic form withcerebellar atrophy.

Defects in COX10 are a cause of mitochondrial complex IVdeficiency (MT-C4D) [MIM:220110], also known as cytochrome coxidase deficiency. A disorder of the mitochondrial respiratorychain with heterogeneous clinical manifestations, ranging fromisolated myopathy to severe multisystem disease affecting severaltissues and organs. Features include hypertrophic cardiomyopathy,hepatomegaly and liver dysfunction, hypotonia, muscle weakness,excercise intolerance, developmental delay, delayed motordevelopment and mental retardation. A subset of patients manifestLeigh syndrome.

Defects in COX10 are a cause of Leigh syndrome (LS)[MIM:256000]. LS is a severe neurological disorder characterizedby bilaterally symmetrical necrotic lesions in subcortical brainregions.

Defects in COX15 are a cause of mitochondrial complex IVdeficiency (MT-C4D) [MIM:220110], also known as cytochrome coxidase deficiency. A disorder of the mitochondrial respiratorychain with heterogeneous clinical manifestations, ranging fromisolated myopathy to severe multisystem disease affecting severaltissues and organs. Features include hypertrophic cardiomyopathy,hepatomegaly and liver dysfunction, hypotonia, muscle weakness,excercise intolerance, developmental delay, delayed motordevelopment and mental retardation. A subset of patients manifestLeigh syndrome.

Defects in COX15 are a cause of Leigh syndrome[MIM:256000]. Leigh syndrome is an early-onset progressiveneurodegenerative disorder characterized by delayed onset ofsymptoms, hypotonia, feeding difficulties, failure to thrive,motor regression and brainstem signs. Diagnosis is confirmed bythe presence of focal, bilateral lesions in one or more areas ofthe central nervous system including the brainstem, thalamus,basal ganglia, cerebellum and spinal cord.

Defects in MT-CO1 are a cause of Leber hereditary opticneuropathy (LHON) [MIM:535000]. LHON is a maternally inheriteddisease resulting in acute or subacute loss of central vision, dueto optic nerve dysfunction. Cardiac conduction defects andneurological defects have also been described in some patients.LHON results from primary mitochondrial DNA mutations affectingthe respiratory chain complexes.

Defects in MT-CO1 are a cause of anemia sideroblasticacquired idiopathic (AISA) [MIM:516030], a disease characterizedby inadequate formation of heme and excessive accumulation of ironin mitochondria.

Defects in MT-CO1 are a cause of mitochondrial complex IVdeficiency (MT-C4D) [MIM:220110], also known as cytochrome coxidase deficiency. A disorder of the mitochondrial respiratorychain with heterogeneous clinical manifestations, ranging fromisolated myopathy to severe multisystem disease affecting severaltissues and organs. Features include hypertrophic cardiomyopathy,hepatomegaly and liver dysfunction, hypotonia, muscle weakness,excercise intolerance, developmental delay, delayed motordevelopment and mental retardation. A subset of patients manifestLeigh syndrome.

Defects in MT-CO1 are associated with recurrentmyoglobinuria mitochondrial (RM-MT) [MIM:550500]. Recurrentmyoglobinuria is characterized by recurrent attacks ofrhabdomyolysis (necrosis or disintegration of skeletal muscle)associated with muscle pain and weakness, and followed byexcretion of myoglobin in the urine.

Defects in MT-CO1 are a cause of deafness sensorineuralmitochondrial (DFNM) [MIM:500008]. DFNM is a form of non-syndromicdeafness with maternal inheritance. Affected individuals manifestprogressive, postlingual, sensorineural hearing loss involvinghigh frequencies.

Defects in MT-CO1 are a cause of colorectal cancer (CRC)[MIM:114500].

Defects in MT-CO2 are a cause of mitochondrial complex IVdeficiency (MT-C4D) [MIM:220110], also known as cytochrome coxidase deficiency. A disorder of the mitochondrial respiratorychain with heterogeneous clinical manifestations, ranging fromisolated myopathy to severe multisystem disease affecting severaltissues and organs. Features include hypertrophic cardiomyopathy,hepatomegaly and liver dysfunction, hypotonia, muscle weakness,excercise intolerance, developmental delay, delayed motordevelopment and mental retardation. A subset of patients manifestLeigh syndrome.

Defects in COX4I2 are the cause of exocrine pancreaticinsufficiency dyserythropoietic anemia and calvarial hyperostosis(EPIDACH) [MIM:612714]. Patients present with pancreaticinsufficiency, intestinal malabsorption, failure to thrive, andanemia soon after birth.

Defects in C16orf57 are the cause of poikiloderma withneutropenia (PN) [MIM:604173]. PN is a genodermatosischaracterized by poikiloderma, pachyonychia and chronicneutropenia. The disorder starts as a papular erythematous rash onthe limbs during the first year of life. It gradually spreadscentripetally and, as the papular rash resolves, hypo- andhyperpigmentation result, with development of telangiectasias.Another skin manifestation is pachyonychia, but alopecia andleukoplakia are distinctively absent. One of the most importantextracutaneous symptoms is an increased susceptibility toinfections, mainly affecting the respiratory system, primarily dueto a chronic neutropenia and to neutrophil functional defects.Bone marrow abnormalities account for neutropenia and may evolveinto myelodysplasia associated with the risk of leukemictransformation. Poikiloderma with neutropenia shows phenotypicoverlap with Rothmund-Thomson syndrome.

Defects in CYP11A1 are the cause of adrenal insufficiencycongenital with 46,XY sex reversal (AICSR) [MIM:613743]. A raredisorder that can present as acute adrenal insufficiency ininfancy or childhood. ACTH and plasma renin activity are elevatedand adrenal steroids are inappropriately low or absent, the 46,XYpatients have female external genitalia, sometimes withclitoromegaly. The phenotypic spectrum ranges from prematurity,complete underandrogenization, and severe early-onset adrenalfailure to term birth with clitoromegaly and later-onset adrenalfailure. Patients with congenital adrenal insufficiency do notmanifest the massive adrenal enlargement typical of congenitallipoid adrenal hyperplasia.

Defects in CYP17A1 are the cause of adrenal hyperplasiatype 5 (AH5) [MIM:202110]. AH5 is a form of congenital adrenalhyperplasia, a common recessive disease due to defective synthesisof cortisol. Congenital adrenal hyperplasia is characterized byandrogen excess leading to ambiguous genitalia in affectedfemales, rapid somatic growth during childhood in both sexes withpremature closure of the epiphyses and short adult stature. Fourclinical types: "salt wasting" (SW, the most severe type), "simplevirilizing" (SV, less severely affected patients), with normalaldosterone biosynthesis, "non-classic form" or late onset (NC orLOAH), and "cryptic" (asymptomatic).

Defects in CYP19A1 are a cause of aromatase excesssyndrome (AEXS) [MIM:139300], also known as familial gynecomastia.AEXS is characterized by an estrogen excess due to an increasedaromatase activity.

Defects in CYP19A1 are the cause of aromatase deficiency(AROD) [MIM:613546]. AROD is a rare disease in which fetalandrogens are not converted into estrogens due to placentalaromatase deficiency. Thus, pregnant women exhibit a hirsutism,which spontaneously resolves after post-partum. At birth, femalebabies present with pseudohermaphroditism due to virilization ofextern genital organs. In adult females, manifestations includedelay of puberty, breast hypoplasia and primary amenorrhoea withmulticystic ovaries.

Defects in CYP1B1 are the cause of primary congenitalglaucoma type 3A (GLC3A) [MIM:231300]. GLC3A is an autosomalrecessive form of primary congenital glaucoma (PCG). PCG ischaracterized by marked increase of intraocular pressure at birthor early childhood, large ocular globes (buphthalmos) and cornealedema. It results from developmental defects of the trabecularmeshwork and anterior chamber angle of the eye that preventadequate drainage of aqueous humor.

Defects in CYP1B1 are a cause of primary open angleglaucoma (POAG) [MIM:137760]. POAG is a complex and geneticallyheterogeneous ocular disorder characterized by a specific patternof optic nerve and visual field defects. The angle of the anteriorchamber of the eye is open, and usually the intraocular pressureis increased. The disease is asymptomatic until the late stages,by which time significant and irreversible optic nerve damage hasalready taken place. In some cases, POAG shows digenic inheritanceinvolving mutations in CYP1B1 and MYOC genes.

Defects in CYP1B1 are a cause of Peters anomaly (PAN)[MIM:604229]. Peters anomaly is a congenital defect of theanterior chamber of the eye.

Defects in CYP21A2 are the cause of adrenal hyperplasiatype 3 (AH3) [MIM:201910]. AH3 is a form of congenital adrenalhyperplasia, a common recessive disease due to defective synthesisof cortisol. Congenital adrenal hyperplasia is characterized byandrogen excess leading to ambiguous genitalia in affectedfemales, rapid somatic growth during childhood in both sexes withpremature closure of the epiphyses and short adult stature. Fourclinical types: 'salt wasting' (SW, the most severe type), 'simplevirilizing' (SV, less severely affected patients), with normalaldosterone biosynthesis, 'non-classic form' or late onset (NC orLOAH), and 'cryptic' (asymptomatic).

Defects in CYP27A1 are the cause of cerebrotendinousxanthomatosis (CTX) [MIM:213700]. CTX is a rare sterol storagedisorder characterized clinically by progressive neurologicdysfunction, premature atherosclerosis, and cataracts.

Defects in CYP27B1 are the cause of rickets vitamin D-dependent type 1A (VDDR1A) [MIM:264700], also known aspseudovitamin D deficiency rickets (PDDR). A disorder caused by aselective deficiency of the active form of vitamin D (1,25-dihydroxyvitamin D3) and resulting in defective bonemineralization and clinical features of rickets.

Defects in CYP2R1 are the cause of rickets vitamin D-dependent type 1B (VDDR1B) [MIM:600081], also known aspseudovitamin D(3) deficiency rickets due to 25-hydroxylasedeficiency. A disorder caused by a selective deficiency of theactive form of vitamin D (1,25-dihydroxyvitamin D3) and resultingin defective bone mineralization and clinical features of rickets.The patients sera have low calcium concentrations, low phosphateconcentrations, elevated alkaline phosphatase activityand lowlevels of 25-hydroxyvitamin D.

Defects in CYP4F22 are the cause of ichthyosis lamellartype 3 (LI3) [MIM:604777]. LI is a non-bullous ichthyosis, a skindisorder characterized by abnormal cornification of the epidermis.It is one the most severe forms of ichthyoses apparent at birthand persisting throughout life. LI patients are born encased in atight, shiny, translucent covering called collodion membrane. Overthe first weeks of life, the collodion membrane is graduallyreplaced by generalized large, dark brown, plate-like scales withminimal to no erythroderma. Tautness of facial skin commonlyresults in ectropion, eclabium and scarring alopecia of the scalp.Common complications are severe heat intolerance and recurrent earinfections.

Defects in CYP4V2 are a cause of Bietti crystallinecorneoretinal dystrophy (BCD) [MIM:210370]. BCD is an autosomalrecessive retinal dystrophy characterized by multiple glisteningintraretinal crystals scattered over the fundus, a characteristicdegeneration of the retina, and sclerosis of the choroidalvessels, ultimately resulting in progressive night blindness andconstriction of the visual field. Most cases have similar crystalsat the corneoscleral limbus. Clinically, BCD is progressive.Patients develop decreased vision, nyctalopia, and paracentralscotomata between the 2nd and 4th decade of life. Later, patientsdevelop peripheral visual field loss and marked visual impairment,usually progressing to legal blindness by the 5th or 6th decade oflife.

Defects in CYP7B1 are the cause of spastic paraplegiaautosomal recessive type 5A (SPG5A) [MIM:270800]. Spasticparaplegia is a neurodegenerative disorder characterized by aslow, gradual, progressive weakness and spasticity of the lowerlimbs. Rate of progression and the severity of symptoms are quitevariable. Initial symptoms may include difficulty with balance,weakness and stiffness in the legs, muscle spasms, and draggingthe toes when walking. In some forms of the disorder, bladdersymptoms (such as incontinence) may appear, or the weakness andstiffness may spread to other parts of the body.

Defects in CYP7B1 are the cause of congenital bile acidsynthesis defect type 3 (CBAS3) [MIM:603711]. Clinical featuresinclude severe cholestasis, cirrhosis and liver synthetic failure.Hepatic microsomal oxysterol 7-alpha-hydroxylase activity isundetectable.

Defects in CPS1 are the cause of carbamoyl phosphatesynthetase 1 deficiency (CPS1D) [MIM:237300]. CPS1D is anautosomal recessive disorder of the urea cycle causinghyperammonemia. Clinical features include protein intolerance,intermittent ataxia, seizures, lethargy, developmental delay andmental retardation.

Note=Genetic variations in CPS1 influence theavailability of precursors for nitric oxide (NO) synthesis andplay a role in clinical situations where endogenous NO productionis critically important, such as neonatal pulmonary hypertension,increased pulmonary artery pressure following surgical repair ofcongenital heart defects or hepatovenocclusive disease followingbone marrow transplantation. Infants with neonatal pulmonaryhypertension homozygous for Thr-1406 have lower L-arginineconcentrations than neonates homozygous for Asn-1406.

Defects in CPT1A are the cause of carnitinepalmitoyltransferase 1A deficiency (CPT1AD) [MIM:255120], alsoknown as CPT-I deficiency or CPT1A deficiency. CPT1AD is a rareautosomal recessive metabolic disorder of long-chain fatty acidoxidation characterized by severe episodes of hypoketotichypoglycemia usually occurring after fasting or illness. Onset isin infancy or early childhood.

Defects in CPT2 are the cause of carnitinepalmitoyltransferase 2 deficiency (CPT2D) [MIM:255110, 600649],also known as CPT-II deficiency or CPT2 deficiency. CPT2D is anautosomal recessive disorder characterized by recurrentmyoglobinuria, episodes of muscle pain, stiffness, andrhabdomyolysis. These symptoms are triggered by prolongedexercise, fasting or viral infection and patients are usuallyyoung adults. In addition to this classical, late-onset, musculartype, a hepatic or hepatocardiomuscular form has been reported ininfants. Clinical pictures in these children or neonates includehypoketotic hypoglycemia, liver dysfunction, cardiomyopathy andsudden death.

Defects in CPT2 are the cause of carnitinepalmitoyltransferase 2 deficiency, lethal neonatal (CPT2D-LN)[MIM:608836], also known as lethal neonatal CPT-II deficiency. Itis a lethal neonatal form of CPT2D. This rarely presentation isantenatal with cerebral periventricular cysts and cysticdysplastic kidneys. The clinical variability of the disease islikely attributed to the variable residual enzymatic activity.

Genetic variations in CR2 are associated withsusceptibility to systemic lupus erythematosus type 9 (SLEB9)[MIM:610927]. Systemic lupus erythematosus (SLE) is a chronicautoimmune disease with a complex genetic basis. SLE is aninflammatory, and often febrile multisystemic disorder ofconnective tissue characterized principally by involvement of theskin, joints, kidneys, and serosal membranes. It is thought torepresent a failure of the regulatory mechanisms of the autoimmunesystem.

Note=A chromosomal aberration involving CREB3L2 is foundin low grade fibromyxoid sarcoma (LGFMS). Translocationt(7,16)(q33,p11) with FUS.

Defects in CRYBA1 are the cause of cataract congenitalzonular with sutural opacities (CCZS) [MIM:600881]. A form ofzonular cataract. Zonular or lamellar cataracts are concentricopacities, broad or narrow, usually consisting of powdery whitedots affecting one lamella or zonule of an otherwise clear lens.

Defects in CRYBA4 are the cause of cataract zonular type2 (CZ2) [MIM:610425], also known as lamellar cataract 2. A form ofzonular cataract. Zonular or lamellar cataracts are opacities,broad or narrow, usually consisting of powdery white dotsaffecting only certain layers or zones between the cortex andnucleus of an otherwise clear lens. The opacity may be so dense asto render the entire central region of the lens completely opaque,or so translucent that vision is hardly if at all impeded. Zonularcataracts generally do not involve the embryonic nucleus, thoughsometimes they involve the fetal nucleus. Usually sharplyseparated from a clear cortex outside them, they may haveprojections from their outer edges known as riders or spokes.

Defects in CRYBA4 are a cause of microphthalmia isolatedwith cataract type 4 (MCOPCT4) [MIM:610426]. Microphthalmia is aclinically heterogeneous disorder of eye formation, ranging fromsmall size of a single eye to complete bilateral absence of oculartissues. Ocular abnormalities like opacities of the cornea andlens, scaring of the retina and choroid, cataractand otherabnormalities like cataract may also be present.

Defects in CRYBB1 are the cause of cataract congenitalnuclear autosomal recessive type 3 (CATCN3) [MIM:611544]. Acongenital cataract affecting the central nucleus of the eye.Nuclear cataracts are often not highly visually significant. Thedensity of the opacities varies greatly from fine dots to a dense,white and chalk-like, central cataract. The condition is usuallybilateral. Nuclear cataracts are often combined with opacifiedcortical fibers encircling the nuclear opacity, which are referredto as cortical riders.

Defects in CRYBB2 are the cause of cataract congenitalcerulean type 2 (CCA2) [MIM:601547], also known as congenitalcataract blue dot type 2. A cerulean form of autosomal dominantcongenital cataract. Cerulean cataract is characterized byperipheral bluish and white opacifications organized in concentriclayers with occasional central lesions arranged radially. Theopacities are observed in the superficial layers of the fetalnucleus as well as the adult nucleus of the lens. Involvement isusually bilateral. Visual acuity is only mildly reduced inchildhood. In adulthood, the opacifications may progress, makinglens extraction necessary. Histologically the lesions aredescribed as fusiform cavities between lens fibers which contain adeeply staining granular material. Although the lesions may takeon various colors, a dull blue is the most common appearance andis responsible for the designation cerulean cataract.

Defects in CRYBB2 are the cause of cataract sutural withpunctate and cerulean opacities (CSPC) [MIM:607133]. A form ofcataract characterized by white opacification around the anteriorand posterior Y sutures, and grayish and bluish, spindle shaped,oval punctate and cerulean opacities of various sizes arranged inlamellar form. The spots are more concentrated towards theperipheral layers and do not delineate the embryonal or fetalnucleus. Phenotypic variation with respect to the size and densityof the sutural opacities as well as the number and position ofpunctate and cerulean spots is observed among affected subjects.

Defects in CRYBB2 are a cause of cataract Coppock-like(CCL) [MIM:604307]. A congenital pulverulent disk-like opacityinvolving the embryonic nucleus with many tiny white dots in thelamellar portion of the lens. It is usually bilateral anddominantly inherited.

Defects in CRYBB3 are the cause of cataract congenitalnuclear autosomal recessive type 2 (CATCN2) [MIM:609741]. Acongenital cataract affecting the central nucleus of the eye.Nuclear cataracts are often not highly visually significant. Thedensity of the opacities varies greatly from fine dots to a dense,white and chalk-like, central cataract. The condition is usuallybilateral. Nuclear cataracts are often combined with opacifiedcortical fibers encircling the nuclear opacity, which are referredto as cortical riders.

Defects in CRBN are the cause of mental retardationautosomal recessive type 2A (MRT2A) [MIM:607417]. MRT2A patientsdisplay mild mental retardation with a standard IQ ranged from 50to 70. IQ scores are lower in males than females. Developmentalmilestones are mildly delayed. There are no dysmorphic or autisticfeatures. Non-syndromic mental retardation patients do notmanifest other clinical signs.

Defects in ORAI1 are the cause of immune dysfunction withT-cell inactivation due to calcium entry defect type 1 (IDTICED1)[MIM:612782]. IDTICED1 is an immune disorder characterized byrecurrent infections, impaired T-cell activation and proliferativeresponse, decreased T-cell production of cytokines, and normallymphocytes counts and serum immunoglobulin levels. In survivingpatients ectodermal dysplasia with anhydrosis and non-progressivemyopathy may be observed.

Defects in CREB1 may be a cause of angiomatoid fibroushistiocytoma (AFH) [MIM:612160]. A distinct variant of malignantfibrous histiocytoma that typically occurs in children andadolescents and is manifest by nodular subcutaneous growth.Characteristic microscopic features include lobulated sheets ofhistiocyte-like cells intimately associated with areas ofhemorrhage and cystic pseudovascular spaces, as well as a strikingcuffing of inflammatory cells, mimicking a lymph node metastasis.Note=A chromosomal aberration involving CREB1 is found in apatient with angiomatoid fibrous histiocytoma. Translocationt(2,22)(q33,q12) with CREB1 generates a EWSR1/CREB1 fusion genethat is most common genetic abnormality in this tumor type.

Defects in CRELD1 may be the cause of susceptibility toatrioventricular septal defect type 2 (AVSD2) [MIM:606217,600309]. AVSD is a spectrum of cardiac malformations that resultin a persistent common atrioventricular canal. The complete formof AVSD involves underdevelopment of the lower part of the atrialseptum and the upper part of the ventricular septum. A less severeform, known as partial AVSD or ostium primum atrial septal defecthas a deficiency of the atrial septum. Complete AVSD areclinically apparent at birth, whereas less severe forms, such asan isolated cleft mitral valve or small defects of the atrial orventricular septa may go undetected.

Defects in CRYGC are a cause of cataract autosomaldominant (ADC) [MIM:604219]. Cataract is an opacification of thecrystalline lens of the eye that frequently results in visualimpairment or blindness. Opacities vary in morphology, are oftenconfined to a portion of the lens, and may be static orprogressive. In general, the more posteriorly located and dense anopacity, the greater the impact on visual function. Cataract isthe most common treatable cause of visual disability in childhood.

Defects in CRYGC are a cause of cataract Coppock-like(CCL) [MIM:604307]. A congenital pulverulent disk-like opacityinvolving the embryonic nucleus with many tiny white dots in thelamellar portion of the lens. It is usually bilateral anddominantly inherited.

Defects in CRYGD are a cause of cataract autosomaldominant (ADC) [MIM:604219]. Cataract is an opacification of thecrystalline lens of the eye that frequently results in visualimpairment or blindness. Opacities vary in morphology, are oftenconfined to a portion of the lens, and may be static orprogressive. In general, the more posteriorly located and dense anopacity, the greater the impact on visual function. Cataract isthe most common treatable cause of visual disability in childhood.

Defects in CRYGD are the cause of cataract congenitalnon-nuclear polymorphic autosomal dominant (CCP) [MIM:601286],also known as polymorphic congenital cataract. A congenitalcataract characterized by a non-progressive phenotype and partialopacity that has a variable location between the fetal nucleus ofthe lens and the equator. The fetal nucleus is normal. Theopacities are irregular and look similar to a bunch of grapes andmay be present simultaneously in different lens layers.

Defects in CRYGD are the cause of cataract congenitalcerulean type 3 (CCA3) [MIM:608983], also known as congenitalcataract blue dot type 3. A cerulean form of autosomal dominantcongenital cataract. Cerulean cataract is characterized byperipheral bluish and white opacifications organized in concentriclayers with occasional central lesions arranged radially. Theopacities are observed in the superficial layers of the fetalnucleus as well as the adult nucleus of the lens. Involvement isusually bilateral. Visual acuity is only mildly reduced inchildhood. In adulthood, the opacifications may progress, makinglens extraction necessary. Histologically the lesions aredescribed as fusiform cavities between lens fibers which contain adeeply staining granular material. Although the lesions may takeon various colors, a dull blue is the most common appearance andis responsible for the designation cerulean cataract.

Defects in CRYGD are the cause of cataract crystallineaculeiform (CACA) [MIM:115700]. A congenital crystalline cataractcharacterized by fiberglass-like or needle-like crystalsprojecting in different directions, through or close to the axialregion of the lens. The opacity causes a variable degree of visionloss.

Defects in CRLF1 are the cause of cold-induced sweatingsyndrome type 1 (CISS1) [MIM:272430]. Cold-induced sweatingsyndrome (CISS) is an autosomal recessive disorder characterizedby profuse sweating induced by cool surroundings (temperatures of7 to 18 degrees Celsius). Additional abnormalities include a high-arched palate, nasal voice, depressed nasal bridge, inability tofully extend the elbows and kyphoscoliosis.

Defects in CRLF1 are the cause of Crisponi syndrome(CRISPS) [MIM:601378]. Crisponi syndrome is a rare autosomalrecessive disorder characterized by congenital muscularcontractions of facial muscles, with trismus in response tostimuli, dysmorphic features, bilateral camptodactyly, majorfeeding and respiratory difficulties, and access of hyperthermialeading to death in the first months of life.

Defects in CRTAP are the cause of osteogenesis imperfectatype 2B (OI2B) [MIM:610854]. A connective tissue disordercharacterized by bone fragility, with many perinatal fractures,severe bowing of long bones, undermineralization, and death in theperinatal period due to respiratory insufficiency.

Defects in CRTAP are the cause of osteogenesis imperfectatype 7 (OI7) [MIM:610682]. A connective tissue disordercharacterized by mild short stature, short humeri and femora, coxavara, white sclera, and the absence of dentinogenesis imperfecta.Multiple fractures are present at birth, but fracture frequencydecreases with age.

Note=A chromosomal aberration involving CRTC1 is found inmucoepidermoid carcinomas, benign Warthin tumors and clear cellhidradenomas. Translocation t(11,19)(q21,p13) with MAML2. Thefusion protein consists of the N-terminus of CRTC1 joined to theC-terminus of MAML2. The reciprocal fusion protein consisting ofthe N-terminus of MAML2 joined to the C-terminus of CRTC1 has beendetected in a small number of mucoepidermoid carcinomas.

Defects in CRB1 are the cause of retinitis pigmentosatype 12 (RP12) [MIM:600105]. RP leads to degeneration of retinalphotoreceptor cells. Patients typically have night visionblindness and loss of midperipheral visual field. As theircondition progresses, they lose their far peripheral visual fieldand eventually central vision as well. RP12 is an autosomalrecessive severe form characterized by a preserved paraarteriolarretinal pigment epithelium (PPRPE). RP12 occurs from earlychildhood and patients experiment progressive visual field losswith severe visual impairment before the age of twenty.

Defects in CRB1 are the cause of Leber congenitalamaurosis type 8 (LCA8) [MIM:604210]. LCA designates a clinicallyand genetically heterogeneous group of childhood retinaldegenerations, generally inherited in an autosomal recessivemanner. Affected infants have little or no retinal photoreceptorfunction as tested by electroretinography. LCA represents the mostcommon genetic cause of congenital visual impairment in infantsand children.

Defects in CRB1 are the cause of pigmented paravenouschorioretinal atrophy (PPCRA) [MIM:172870]. PPCRA is an unusualretinal degeneration characterized by accumulation of pigmentationalong retinal veins. PPCRA is dominantly inherited, but exhibitedvariable expressivity. Males are more likely to exhibit a severephenotype, whereas females may remain virtually asymptomatic evenin later years. The PPCRA phenotype is associated with a mutationin CRB1 gene which is likely to affect the structure of the CRB1protein.

Defects in CRX are the cause of Leber congenitalamaurosis type 7 (LCA7) [MIM:602225]. LCA designates a clinicallyand genetically heterogeneous group of childhood retinaldegenerations, generally inherited in an autosomal recessivemanner. Affected infants have little or no retinal photoreceptorfunction as tested by electroretinography. LCA represents the mostcommon genetic cause of congenital visual impairment in infantsand children.

Defects in CRX are the cause of cone-rod dystrophy type 2(CORD2) [MIM:120970], also known as cone-rod retinal dystrophy 2(CRD2). CORDs are inherited retinal dystrophies belonging to thegroup of pigmentary retinopathies. CORDs are characterized byretinal pigment deposits visible on fundus examination,predominantly in the macular region, and initial loss of conephotoreceptors followed by rod degeneration. This leads todecreased visual acuity and sensitivity in the central visualfield, followed by loss of peripheral vision. Severe loss ofvision occurs earlier than in retinitis pigmentosa.

Defects in CRX are a cause of retinitis pigmentosa (RP)[MIM:268000]. RP leads to degeneration of retinal photoreceptorcells. Patients typically have night vision blindness and loss ofmidperipheral visual field. As their condition progresses, theylose their far peripheral visual field and eventually centralvision as well.

Defects in CRYAA are a cause of cataract autosomaldominant (ADC) [MIM:604219]. Cataract is an opacification of thecrystalline lens of the eye that frequently results in visualimpairment or blindness. Opacities vary in morphology, are oftenconfined to a portion of the lens, and may be static orprogressive. In general, the more posteriorly located and dense anopacity, the greater the impact on visual function. Cataract isthe most common treatable cause of visual disability in childhood.

Defects in CRYAB are the cause of myofibrillar alpha-Bcrystallin-related (MFM-CRYAB) [MIM:608810]. A neuromusculardisorder that results in weakness of the proximal and distal limbmuscles, weakness of the neck, velopharynx and trunk muscles,hypetrophic cardiomyopathy, and cataract in a subset of patients.

Defects in CRYAB are the cause of cataract posteriorpolar type 2 (CTPP2) [MIM:613763]. A subcapsular opacity, usuallydisk-shaped, located at the back of the lens. It can have a markedeffect on visual acuity.

Defects in CSF2RA are the cause of pulmonary surfactantmetabolism dysfunction type 4 (SMDP4) [MIM:300770]. A rare lungdisorder due to impaired surfactant homeostasis. It ischaracterized by alveolar filling with floccular material thatstains positive using the periodic acid-Schiff method and isderived from surfactant phospholipids and protein components.Excessive lipoproteins accumulation in the alveoli results insevere respiratory distress.

Defects in CSF3R are the cause of hereditary neutrophilia(NEUTROPHILIA) [MIM:162830]. A form of lifelong, persistentneutrophilia, a condition characterized by an increase in thenumber of neutrophils in the blood.

Defects in CASK are the cause of mental retardation X-linked CASK-related (MRXCASK) [MIM:300749]. Mental retardation ischaracterized by significantly below average general intellectualfunctioning associated with impairments in adaptative behavior andmanifested during the developmental period. Patients with mentalretardation X-linked CASK-related can manifest a severe phenotypeconsisting of severe intellectual deficit, congenital or postnatalmicrocephaly, disproportionate brainstem and cerebellar hypoplasia(MICPCH Syndrome). A milder phenotype consists of mentalretardation alone or associated with nystagmus.

Defects in CASK are the cause of FG syndrome type 4(FGS4) [MIM:300422]. FG syndrome (FGS) is an X-linked disordercharacterized by mental retardation, relative macrocephaly,hypotonia and constipation.

Defects in VCAN are the cause of Wagner syndrome type 1(WGN1) [MIM:143200]. WGN is a dominantly inheritedvitreoretinopathy characterized by an optically empty vitreouscavity with fibrillary condensations and a preretinal avascularmembrane. Other optical features include progressive chorioretinalatrophy, perivascular sheating, subcapsular cataract and myopia.Systemic manifestations are absent in WGN.

Defects in CSRP3 are the cause of cardiomyopathy dilatedtype 1M (CMD1M) [MIM:607482]. Dilated cardiomyopathy is a disordercharacterized by ventricular dilation and impaired systolicfunction, resulting in congestive heart failure and arrhythmia.Patients are at risk of premature death.

Defects in CSRP3 are the cause of cardiomyopathy familialhypertrophic type 12 (CMH12) [MIM:612124]. Familial hypertrophiccardiomyopathy is a hereditary heart disorder characterized byventricular hypertrophy, which is usually asymmetric and ofteninvolves the interventricular septum. The symptoms includedyspnea, syncope, collapse, palpitations, and chest pain. They canbe readily provoked by exercise. The disorder has inter- andintrafamilial variability ranging from benign to malignant formswith high risk of cardiac failure and sudden cardiac death.

Defects in C20orf7 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinical disorders,from lethal neonatal disease to adult-onset neurodegenerativedisorders. Phenotypes include macrocephaly with progressiveleukodystrophy, non-specific encephalopathy, cardiomyopathy,myopathy, liver disease, Leigh syndrome, Leber hereditary opticneuropathy, and some forms of Parkinson disease.

Defects in CTDP1 are a cause of congenital cataractsfacial dysmorphism and neuropathy syndrome (CCFDN) [MIM:604168].CCFDN is an autosomal recessive developmental disorder that occursin an endogamous group of Vlax Roma (Gypsies). The syndrome ischaracterized by a complex clinical phenotype with seeminglyunrelated features involving multiple organs and systems.Developmental abnormalities include congenital cataracts andmicrocorneae, hypomyelination of the peripheral nervous system,impaired physical growth, delayed early motor and intellectualdevelopment, facial dysmorphism and hypogonadism. Central nervoussystem involvement, with cerebral and spinal cord atrophy, may bethe result of disrupted development with superimposed degenerativechanges. Affected individuals are prone to severe rhabdomyolysisafter viral infections and to serious complications related togeneral anesthesia (such as pulmonary edema and epilepticseizures).

Note=Autoantibodies against CTAGE5 are present in severalcancer types, including benign meningioma and cutaneous T-celllymphoma (CTCL).

Note=An interstitial deletion causing the fusion of exon10 of CTL4 with the 3'-UTR of NEU has been detected in twopatients affected by sialidosis.

Genetic variation in CTLA4 influences susceptibility tosystemic lupus erythematosus (SLE) [MIM:152700]. SLE is a chronic,inflammatory and often febrile multisystemic disorder ofconnective tissue. It affects principally the skin, joints,kidneys and serosal membranes. SLE is thought to represent afailure of the regulatory mechanisms of the autoimmune system.

Note=Genetic variations in CTLA4 may influencesusceptibility to Graves disease, an autoimmune disorderassociated with overactivity of the thyroid gland andhyperthyroidism.

Genetic variation in CTLA4 is the cause of susceptibilityto diabetes mellitus insulin-dependent type 12 (IDDM12)[MIM:601388]. A multifactorial disorder of glucose homeostasisthat is characterized by susceptibility to ketoacidosis in theabsence of insulin therapy. Clinical fetaures are polydipsia,polyphagia and polyuria which result from hyperglycemia-inducedosmotic diuresis and secondary thirst. These derangements resultin long-term complications that affect the eyes, kidneys, nerves,and blood vessels.

Genetic variation in CTLA4 is the cause of susceptibilityto celiac disease type 3 (CELIAC3) [MIM:609755]. It is amultifactorial disorder of the small intestine that is influencedby both environmental and genetic factors. It is characterized bymalabsorption resulting from inflammatory injury to the mucosa ofthe small intestine after the ingestion of wheat gluten or relatedrye and barley proteins. In its classic form, celiac disease ischaracterized in children by malabsorption and failure to thrive.

Defects in CTNNB1 are associated with colorectal cancer(CRC) [MIM:114500].

Note=Activating mutations in CTNNB1 have oncogenicactivity resulting in tumor development. Somatic mutations arefound in various tumor types, including colon cancers, ovarian andprostate carcinomas, hepatoblastoma (HB), hepatocellular carcinoma(HCC). HBs are malignant embryonal tumors mainly affecting youngchildren in the first three years of life.

Defects in CTNNB1 are a cause of pilomatrixoma (PTR)[MIM:132600], a common benign skin tumor.

Defects in CTNNB1 are a cause of medulloblastoma (MDB)[MIM:155255]. MDB is a malignant, invasive embryonal tumor of thecerebellum with a preferential manifestation in children.

Defects in CTNNB1 are a cause of susceptibility toovarian cancer (OC) [MIM:167000]. Ovarian cancer common malignancyoriginating from ovarian tissue. Although many histologic types ofovarian neoplasms have been described, epithelial ovariancarcinoma is the most common form. Ovarian cancers are oftenasymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients arediagnosed with advanced disease.

Note=A chromosomal aberration involving CTNNB1 is foundin salivary gland pleiomorphic adenomas, the most common benignepithelial tumors of the salivary gland. Translocationt(3,8)(p21,q12) with PLAG1.

Defects in CTNS are the cause of cystinosis nephropathictype (CTNS) [MIM:219800]. It is a form of cystinosis, a lysosomalstorage disease due to defective transport of cystine across thelysosomal membrane. This results in cystine accumulation andcrystallization in the cells causing widespread tissue damage. Theclassical nephropathic form has onset in the first year of lifeand is characterized by a polyuro-polydipsic syndrome, markedheight-weight growth delay, generalized impaired proximal tubularreabsorptive capacity, with severe fluid-electrolyte balancealterations, renal failure, ocular symptoms and other systemiccomplications.

Defects in CTNS are the cause of cystinosis adult non-nephropathic type (CTNSANN) [MIM:219750]. It is a form ofcystinosis, a lysosomal storage disease due to defective transportof cystine across the lysosomal membrane. This results in cystineaccumulation and crystallization in the cells causing widespreadtissue damage. Cystinosis adult non-nephropathic type ischaracterized by ocular features and a benigne course. Patientsmanifest mild photophobia due to conjunctival and corneal cystinecrystals.

Defects in CTNS are the cause of cystinosis late-onsetjuvenile or adolescent nephropathic type (CTNSJAN) [MIM:219900].It is a form of cystinosis, a lysosomal storage disease due todefective transport of cystine across the lysosomal membrane. Thisresults in cystine accumulation and crystallization in the cellscausing widespread tissue damage. Late-onset juvenile oradolescent nephropathic cystinosis manifests itself first at age10 to 12 years with proteinuria due to glomerular damage ratherthan with the manifestations of tubular damage that occur first ininfantile cystinosis. There is no excess amino aciduria andstature is normal. Photophobia, late development of pigmentaryretinopathy, and chronic headaches are features.

Variations in CTRC influence susceptibility to chronicpancreatitis [MIM:167800]. Chronic pancreatitis is a persistentinflammatory disorder characterized by permanent destruction ofthe pancreatic parenchyma.

Defects in CATSPER1 are the cause of male infertilitynon-syndromic autosomal recessive (MIAR) [MIM:612997]. Maleinfertility is a common barrier that prevents successfulconception and represents a reproductive difficulty affecting 15%of couples.

Defects in CATSPER2 are a cause of deafness-infertilitysyndrome (DIS) [MIM:611102]. DIS is characterized by deafness andinfertility and is caused by large contiguous gene deletions at15q15.3 that removes both STRC and CATSPER2 genes.

Defects in CUBN are a cause of recessive hereditarymegaloblastic anemia 1 (RH-MGA1) [MIM:261100], also known as MGA1Norwegian type or Imerslund-Grasbeck syndrome (I-GS). RH-MGA1 isdue to selective malabsorption of vitamin B12. Defects in vitaminB12 absorption lead to impaired function of thymidine synthase. Asa consequence DNA synthesis is interrupted. Rapidly dividing cellsinvolved in erythropoiesis are particularly affected.

Defects in CUL4B are the cause of mental retardationsyndromic X-linked Cabezas type (MRXC) [MIM:300354], also known asmental retardation syndromic X-linked type 15. A syndromic form ofX-linked mental retardation characterized by severe intellectualdeficit associated with short stature, craniofacial dysmorphism,small testes, muscle wasting in lower legs, kyphosis, jointhyperextensibility, pes cavus, small feet, and abnormalities ofthe toes. Additional neurologic manifestations include speechdelay and impairment, tremor, seizures, gait ataxia, hyperactivityand decreased attention span.

Defects in CUL7 are the cause of 3M syndrome type 1 (3M1)[MIM:273750]. An autosomal recessive disorder characterized bysevere pre- and postnatal growth retardation, facial dysmorphism,large head circumference, and normal intelligence and endocrinefunction. Skeletal changes include long slender tubular bones andtall vertebral bodies.

Defects in COX6B1 are a cause of mitochondrial complex IVdeficiency (MT-C4D) [MIM:220110], also known as cytochrome coxidase deficiency. A disorder of the mitochondrial respiratorychain with heterogeneous clinical manifestations, ranging fromisolated myopathy to severe multisystem disease affecting severaltissues and organs. Features include hypertrophic cardiomyopathy,hepatomegaly and liver dysfunction, hypotonia, muscle weakness,excercise intolerance, developmental delay, delayed motordevelopment and mental retardation. A subset of patients manifestLeigh syndrome.

Defects in GJA1 are the cause of autosomal dominantoculodentodigital dysplasia (ODDD) [MIM:164200], also known asoculodentoosseous dysplasia. ODDD is a highly penetrant syndromepresenting with craniofacial (ocular, nasal, dental) and limbdysmorphisms, spastic paraplegia, and neurodegeneration.Craniofacial anomalies tipically include a thin nose withhypoplastic alae nasi, small anteverted nares, prominentcolumnella, and microcephaly. Brittle nails and hair abnormalitiesof hypotrichosis and slow growth are present. Ocular defectsinclude microphthalmia, microcornea, cataracts, glaucoma, andoptic atrophy. Syndactyly type 3 and conductive deafness can occurin some cases. Cardiac abnormalities are observed in rareinstances.

Defects in GJA1 are the cause of autosomal recessiveoculodentodigital dysplasia (ODDD autosomal recessive)[MIM:257850].

Defects in GJA1 may be the cause of syndactyly type 3(SDTY3) [MIM:186100]. Syndactyly is an autosomal dominant traitand is the most common congenital anomaly of the hand or foot. Itis marked by persistence of the webbing between adjacent digits,so they are more or less completely attached. In this type thereis usually complete and bilateral syndactyly between the fourthand fifth fingers. Usually it is soft tissue syndactyly butoccasionally the distal phalanges are fused. The fifth finger isshort with absent or rudimentary middle phalanx. The feet are notaffected.

Defects in GJA1 are a cause of hypoplastic left heartsyndrome (HLHS) [MIM:241550]. HLHS refers to the abnormaldevelopment of the left-sided cardiac structures, resulting inobstruction to blood flow from the left ventricular outflow tract.In addition, the syndrome includes underdevelopment of the leftventricle, aorta, and aortic arch, as well as mitral atresia orstenosis.

Defects in GJA1 are a cause of Hallermann-Streiffsyndrome (HSS) [MIM:234100]. HSS is a disorder characterized by atypical skull shape (brachycephaly with frontal bossing),hypotrichosis, microphthalmia, cataracts, beaked nose,micrognathia, skin atrophy, dental anomalies and proportionateshort stature. Mental retardation is present in a minority ofcases.

Defects in GJA3 are the cause of cataract zonularpulverulent cataract type 3 (CZP3) [MIM:601885]. A form of zonularcataract. Zonular or lamellar cataracts are opacities, broad ornarrow, usually consisting of powdery white dots affecting onlycertain layers or zones between the cortex and nucleus of anotherwise clear lens. The opacity may be so dense as to render theentire central region of the lens completely opaque, or sotranslucent that vision is hardly if at all impeded. Zonularcataracts generally do not involve the embryonic nucleus, thoughsometimes they involve the fetal nucleus. Usually sharplyseparated from a clear cortex outside them, they may haveprojections from their outer edges known as riders or spokes.

Defects in GJA5 are a cause of familial atrial standstill(FAS) [MIM:108770]. Atrial standstill is an extremely rarearrhythmia, characterized by the absence of electrical andmechanical activity in the atria. Electrocardiographically, it ischaracterized by bradycardia, the absence of P waves, and ajunctional narrow complex escape rhythm.

Defects in GJA8 are the cause of cataract zonularpulverulent type 1 (CZP1) [MIM:116200]. A form of zonularcataract. Zonular or lamellar cataracts are opacities, broad ornarrow, usually consisting of powdery white dots affecting onlycertain layers or zones between the cortex and nucleus of anotherwise clear lens. The opacity may be so dense as to render theentire central region of the lens completely opaque, or sotranslucent that vision is hardly if at all impeded. Zonularcataracts generally do not involve the embryonic nucleus, thoughsometimes they involve the fetal nucleus. Usually sharplyseparated from a clear cortex outside them, they may haveprojections from their outer edges known as riders or spokes.

Defects in GJA8 are the cause of cataract-microcorneasyndrome (CAMIS) [MIM:116150]. Cataract-microcornea syndrome ischaracterized by the association of congenital cataract andmicrocornea without any other systemic anomaly or dysmorphism.Clinical findings include a corneal diameter inferior to 10 mm inboth meridians in an otherwise normal eye, and an inheritedcataract, which is most often bilateral posterior polar withopacification in the lens periphery. The cataract progresses toform a total cataract after visual maturity has been achieved,requiring cataract extraction in the first to third decade oflife. Microcornea-cataract syndrome can be associated with otherrare ocular manifestations, including myopia, iris coloboma,sclerocornea and Peters anomaly. Transmission is in most casesautosomal dominant, but cases of autosomal recessive transmissionhave recently been described.

Defects in GJB1 are the cause of Charcot-Marie-Toothdisease X-linked type 1 (CMTX1) [MIM:302800], also designated CMT-X. CMTX1 is a form of Charcot-Marie-Tooth disease, the most commoninherited disorder of the peripheral nervous system. Charcot-Marie-Tooth disease is classified in two main groups on the basisof electrophysiologic properties and histopathology: primaryperipheral demyelinating neuropathies characterized by severelyreduced motor nerve conduction velocities (NCVs) (less than 38m/s)and segmental demyelination and remyelination, and primaryperipheral axonal neuropathies characterized by normal or mildlyreduced NCVs and chronic axonal degeneration and regeneration onnerve biopsy. CMTX1 has both demyelinating and axonal features.Central nervous system involvement may occur.

Defects in GJB1 may contribute to the phenotype ofDejerine-Sottas syndrome (DSS) [MIM:145900], also known asDejerine-Sottas neuropathy (DSN) or hereditary motor and sensoryneuropathy III (HMSN3). DSS is a severe degenerating neuropathy ofthe demyelinating Charcot-Marie-Tooth disease category, with onsetby age 2 years. DSS is characterized by motor and sensoryneuropathy with very slow nerve conduction velocities, increasedcerebrospinal fluid protein concentrations, hypertrophic nervechanges, delayed age of walking as well as areflexia. There areboth autosomal dominant and autosomal recessive forms of Dejerine-Sottas syndrome.

Defects in GJB2 are the cause of deafness autosomalrecessive type 1A (DFNB1A) [MIM:220290]. DFNB1A is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in GJB2 are the cause of deafness autosomaldominant type 3A (DFNA3A) [MIM:601544].

Defects in GJB2 are a cause of Vohwinkel syndrome (VS)[MIM:124500]. VS is an autosomal dominant disease characterized byhyperkeratosis, constriction on finger and toes and congenitaldeafness.

Defects in GJB2 are a cause of palmoplantar keratodermawith deafness (PPKDFN) [MIM:148350]. PPKDFN is an autosomaldominant disorder characterized by the association of palmoplantarhyperkeratosis with progressive, bilateral, high-frequency,sensorineural deafness.

Defects in GJB2 are a cause of keratitis-ichthyosis-deafness syndrome (KID syndrome) [MIM:148210], an autosomaldominant form of ectodermal dysplasia. Ectodermal dysplasias (EDs)constitute a heterogeneous group of developmental disordersaffecting tissues of ectodermal origin. EDs are characterized byabnormal development of two or more ectodermal structures such ashair, teeth, nails and sweat glands, with or without anyadditional clinical sign. Each combination of clinical featuresrepresents a different type of ectodermal dysplasia. KID syndromeis characterized by the association of hyperkeratotic skin lesionswith vascularizing keratitis and profound sensorineural hearingloss. Clinical features include deafness, ichthyosis, photobia,absent or decreased eyebrows, sparse or absent scalp hair,decreased sweating and dysplastic finger and toenails.

Defects in GJB2 are the cause of Bart-Pumphrey syndrome(BPS) [MIM:149200]. BPS is an autosomal dominant disordercharacterized by sensorineural hearing loss, palmoplantarkeratoderma, knuckle pads, and leukonychia, It shows considerablephenotypic variability.

Defects in GJB2 are the cause of ichthyosis hystrix-likewith deafness syndrome (HID syndrome) [MIM:602540]. HID syndromeis an autosomal-dominant inherited keratinizing disordercharacterized by sensorineural deafness and spiky hyperkeratosisaffecting the entire skin. HID syndrome is considered to differfrom the similar KID syndrome in the extent and time of occurrenceof skin symptoms and the severity of the associated keratitis.

Defects in GJB3 are a cause of erythrokeratodermiavariabilis (EKV) [MIM:133200]. EKV is a genodermatosischaracterized by the appearance of two independent skin lesions:transient figurate erythematous patches and hyperkeratosis that isusually localized but occasionally occurs in its generalized form.Clinical presentation varies significantly within a family andfrom one family to another. Palmoplantar keratoderma is present inaround 50% of cases.

Defects in GJB3 are the cause of deafness autosomaldominant type 2B (DFNA2B) [MIM:612644]. DFNA2 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in GJB4 are a cause of erythrokeratodermiavariabilis (EKV) [MIM:133200]. EKV is a genodermatosischaracterized by the appearance of two independent skin lesions:transient figurate erythematous patches and hyperkeratosis that isusually localized but occasionally occurs in its generalized form.Clinical presentation varies significantly within a family andfrom one family to another. Palmoplantar keratoderma is present inaround 50% of cases.

Defects in GJB6 are the cause of ectodermal dysplasiatype 2 (ED2) [MIM:129500], also known as Clouston syndrome.Ectodermal dysplasia defines a heterogeneous group of disordersdue to abnormal development of two or more ectodermal structures.ED2 is an autosomal dominant condition characterized byatrichosis, nail hypoplasia and deformities, hyperpigmentation ofthe skin, normal teeth, normal sweat and sebaceous gland function.Palmoplantar hyperkeratosis is a frequent features. Hearingimpairment has been detected in few cases of ED2.

Defects in GJB6 are the cause of deafness autosomalrecessive type 1B (DFNB1B) [MIM:612645]. DFNB1B is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in GJB6 are the cause of deafness autosomaldominant type 3B (DFNA3B) [MIM:612643].

Defects in CXCR4 are a cause of WHIM syndrome (WHIM)[MIM:193670], also known as warts, hypogammaglobulinemia,infections and myelokathexis. WHIM syndrome is an immunodeficiencydisease characterized by neutropenia, hypogammaglobulinemia andextensive human papillomavirus (HPV) infection. Despite theperipheral neutropenia, bone marrow aspirates from affectedindividuals contain abundant mature myeloid cells, a conditiontermed myelokathexis.

Defects in GJC2 are the cause of leukodystrophyhypomyelinating type 2 (HLD2) [MIM:608804], also known asPelizaeus-Merzbacher-like disease autosomal recessive type 1. HLD2is an autosomal recessive hypomyelinating leukodystrophycharacterized by nystagmus, impaired motor development, ataxia,choreoathetotic movements, dysarthria and progressive spasticity.

Defects in GJC2 are the cause of spastic paraplegiaautosomal recessive type 44 (SPG44) [MIM:613206]. A form ofspastic paraplegia, a neurodegenerative disorder characterized bya slow, gradual, progressive weakness and spasticity of the lowerlimbs. Rate of progression and the severity of symptoms are quitevariable. Initial symptoms may include difficulty with balance,weakness and stiffness in the legs, muscle spasms, and draggingthe toes when walking. In some forms of the disorder, bladdersymptoms (such as incontinence) may appear, or the weakness andstiffness may spread to other parts of the body.

Defects in GJC2 are the cause of lymphedema hereditarytype 1C (LMPH1C) [MIM:613480]. LMPH1C is a chronic disablingcondition which results in swelling of the extremities due toaltered lymphatic flow. Patients with lymphedema suffer fromrecurrent local infections and physical impairment.

Defects in CYBA are a cause of chronic granulomatousdisease autosomal recessive cytochrome-b-negative (ARCGD)[MIM:233690]. Chronic granulomatous disease is a geneticallyheterogeneous disorder characterized by the inability ofneutrophils and phagocytes to kill microbes that they haveingested. Patients suffer from life-threatening bacterial/fungalinfections.

Defects in CYBB are a cause of chronic granulomatousdisease X-linked (XCGD) [MIM:306400]. Chronic granulomatousdisease is a genetically heterogeneous disorder characterized bythe inability of neutrophils and phagocytes to kill microbes thatthey have ingested. Patients suffer from life-threateningbacterial/fungal infections.

Defects in CYB5A are the cause of methemoglobinemiaCYB5A-related (METHB-CYB5A) [MIM:250790]. A form ofmethemoglobinemia, a hematologic disease characterized by thepresence of excessive amounts of methemoglobin in blood cells,resulting in decreased oxygen carrying capacity of the blood,cyanosis and hypoxia.

Note=Defects in MT-CYB are a rare cause of mitochondrialdysfunction underlying different myopathies. They includemitochondrial encephalomyopathy, hypertrophic cardiomyopathy(HCM), and sporadic mitochondrial myopathy (MM). In mitochondrialmyopathy, exercise intolerance is the predominant symptom.Additional features include lactic acidosis, muscle weaknessand/or myoglobinuria. Defects in MTCYB are also found in cases ofexercise intolerance accompanied by deafness, mental retardation,retinitis pigmentosa, cataract, growth retardation, epilepsy(multisystem disorder).

Defects in MT-CYB are the cause of cardiomyopathyinfantile histiocytoid (CMIH) [MIM:500000]. CMIH is characterizedby the presence of pale granular foamy histiocyte-like cellswithin the myocardium. It usually affects children younger than 2years of age, with a clear predominance of females over males.Infants present with dysrhythmia or cardiac arrest, and theclinical course is usually fulminant, sometimes simulating suddeninfant death syndrome.

Defects in MT-CYB contribute to Leber hereditary opticneuropathy (LHON) [MIM:535000]. LHON is a maternally inheriteddisease resulting in acute or subacute loss of central vision, dueto optic nerve dysfunction. Cardiac conduction defects andneurological defects have also been described in some patients.LHON results from primary mitochondrial DNA mutations affectingthe respiratory chain complexes.

Defects in CYCS are the cause of thrombocytopenia type 4(THC4) [MIM:612004], also known as autosomal dominantthrombocytopenia type 4. Thrombocytopenia is the presence ofrelatively few platelets in blood. THC4 is a non-syndromic form ofthrombocytopenia. Clinical manifestations of thrombocytopenia areabsent or mild. THC4 may be caused by dysregulated plateletformation.

Defects in CYLD are the cause of familial cylindromatosis(FCYL) [MIM:132700], also known as Ancell-Spiegler cylindromas orturban tumor syndrome or dermal eccrine cylindromatosis. CYLD isan autosomal dominant and highly tumor type-specific disorder. Thetumors (known as cylindromas because of their characteristicmicroscopic architecture) are believed to arise from orrecapitulate the appearance of the eccrine or apocrine cells ofthe skin that secrete sweat and scent respectively. Cylindromasarise predominantly in hairy parts of the body with approximately90% on the head and neck. The development of a confluent masswhich may ulcerate or become infected has led to the designation'turban tumor syndrome'. The skin tumors show differentiation inthe direction of hair structures, hence the synonymtrichoepithelioma.

Defects in CYLD are the cause of multiple familialtrichoepithelioma type 1 (MFT1) [MIM:601606], also known asepithelioma adenoides cysticum of Brooke (EAC) or hereditarymultiple benign cystic epithelioma or Brooke-Fordycetrichoepitheliomas. MFT1 is an autosomal dominant dermatosischaracterized by the presence of many skin tumors predominantly onthe face. Since histologic examination shows dermal aggregates ofbasaloid cells with connection to or differentiation toward hairfollicles, this disorder has been thought to represent a benignhamartoma of the pilosebaceous apparatus. Trichoepitheliomas candegenerate into basal cell carcinoma.

Defects in CYLD are the cause of Brooke-Spiegler syndrome(BRSS) [MIM:605041]. BRSS is an autosomal dominant disordercharacterized by the appearance of multiple skin appendage tumorssuch as cylindroma, trichoepithelioma, and spiradenoma. Thesetumors are typically located in the head and neck region, appearin early adulthood, and gradually increase in size and numberthroughout life.

Defects in CSTB are the cause of progressive myoclonicepilepsy type 1 (EPM1) [MIM:254800]. EPM1 is an autosomalrecessive disorder characterized by severe, stimulus-sensitivemyoclonus and tonic-clonic seizures. The onset, occurring between6 and 13 years of age, is characterized by convulsions. Myoclonusbegins 1 to 5 years later. The twitchings occur predominantly inthe proximal muscles of the extremities and are bilaterallysymmetrical, although asynchronous. At first small, they becomelate in the clinical course so violent that the victim is thrownto the floor. Mental deterioration and eventually dementiadevelop.

Defects in CST3 are the cause of amyloidosis type 6(AMYL6) [MIM:105150], also known as hereditary cerebral hemorrhagewith amyloidosis (HCHWA), cerebral amyloid angiopathy (CAA) orcerebroarterial amyloidosis Icelandic type. AMYL6 is a hereditarygeneralized amyloidosis due to cystatin C amyloid deposition.Cystatin C amyloid accumulates in the walls of arteries,arterioles, and sometimes capillaries and veins of the brain, andin various organs including lymphoid tissue, spleen, salivaryglands, and seminal vesicles. Amyloid deposition in the cerebralvessels results in cerebral amyloid angiopathy, cerebralhemorrhage and premature stroke. Cystatin C levels in thecerebrospinal fluid are abnormally low.

Genetic variations in CST3 are associated with age-related macular degeneration type 11 (ARMD11) [MIM:611953]. ARMDis a multifactorial eye disease and the most common cause ofirreversible vision loss in the developed world. In most patients,the disease is manifest as ophthalmoscopically visible yellowishaccumulations of protein and lipid that lie beneath the retinalpigment epithelium and within an elastin-containing structureknown as Bruch membrane.

Note=A chromosomal aberration involving CYTSB may be acause of juvenile myelomonocytic leukemia. Translocationt(5,17)(q33,p11.2) with PDGFRB.

Defects in DPY19L2 are a cause of globozoospermia(GLOBZOOS) [MIM:102530], also known as round-headed spermatozoa.Most prominent feature of this defect is the malformation of thesperm acrosome leading to infertility. Note=Deletions in DPY19L2are probably the major cause of GLOBZOOS.

Defects in D2HGDH are the cause of D-2-hydroxyglutaricaciduria type 1 (D2HGA1) [MIM:600721]. D2HGA1 is a rare recessiveneurometabolic disorder causing developmental delay, epilepsy,hypotonia, and dysmorphic features. Both a mild and a severephenotype exist. The severe phenotype is homogeneous and ischaracterized by early infantile-onset epileptic encephalopathyand cardiomyopathy. The mild phenotype has a more variableclinical presentation. Diagnosis is based on the presence of anexcess of D-2-hydroxyglutaric acid in the urine.

Note=A chromosomal aberration involving DAB2IP is foundin a patient with acute myeloid leukemia (AML). Translocationt(9,11)(q34,q23) with MLL. May give rise to a MLL-DAB2IP fusionprotein lacking the PH domain.

Note=Abherrent glycosylation and defective ligand-bindingproperties of DAG1 are associated with several forms of congenitalmuscular dystrophy.

AZFc deletions in the Yq11.23 region including the DAZgenes are a cause of spermatogenic failure non-obstructive Y-linked (SFNOY) [MIM:415000]. A disorder resulting in the absence(azoospermia) or reduction (oligozoospermia) of sperm in thesemen, leading to male infertility.

AZFc deletions in the Yq11.23 region including the DAZgenes are a cause of spermatogenic failure non-obstructive Y-linked (SFNOY) [MIM:415000]. A disorder resulting in the absence(azoospermia) or reduction (oligozoospermia) of sperm in thesemen, leading to male infertility.

AZFc deletions in the Yq11.23 region including the DAZgenes are a cause of spermatogenic failure non-obstructive Y-linked (SFNOY) [MIM:415000]. A disorder resulting in the absence(azoospermia) or reduction (oligozoospermia) of sperm in thesemen, leading to male infertility.

AZFc deletions in the Yq11.23 region including the DAZgenes are a cause of spermatogenic failure non-obstructive Y-linked (SFNOY) [MIM:415000]. A disorder resulting in the absence(azoospermia) or reduction (oligozoospermia) of sperm in thesemen, leading to male infertility.

Defects in DCAF17 are the cause of Woodhouse-Sakatisyndrome (WoSaS) [MIM:241080], also abbreviated WSS. WoSaS is arare autosomal recessive disorder characterized by hypogonadism,alopecia, diabetes mellitus, mental retardation, andextrapyramidal syndrome.

Defects in DCC are the cause of congenital mirrormovements (MIMOC) [MIM:157600]. Mirror movements are contralateralinvoluntary movements that mirror voluntary ones. While mirrormovements are occasionally found in young children, persistencebeyond the age of 10 is abnormal. Mirror movements occur morecommonly in the upper extremities.

Defects in DCDC2 may be a cause of susceptibility todyslexia type 2 (DYX2) [MIM:600202], also known as specificreading disability type 2. Dyslexia is a relatively common,complex cognitive disorder that affects 5% to 10% of school-agedchildren. The disorder is characterized by an impairment ofreading performance despite adequate motivational, educational andintellectual opportunities and in the absence of sensory orneurological disability.

Defects in GAD1 are the cause of cerebral palsy spasticquadriplegic type 1 (CPSQ1) [MIM:603513]. A non-progressivedisorder of movement and/or posture resulting from defects in thedeveloping central nervous system. Affected individuals manifestsymmetrical, non-progressive spasticity and no adverse perinatalhistory or obvious underlying alternative diagnosis. Developmentaldelay, mental retardation and sometimes epilepsy can be part ofthe clinical picture.

Defects in MLYCD are the cause of malonyl-CoAdecarboxylase deficiency (MLYCD deficiency) [MIM:248360]. MLYCDdeficiency is an autosomal recessive disease characterized byabdominal pain, chronic constipation, episodic vomiting, metabolicacidosis and malonic aciduria.

Defects in DCLRE1B may be a cause of Hoyeraal-Hreidarssonsyndrome (HHS) [MIM:300240]. HHS is a multisystem disorderaffecting males and is characterized by aplastic anemia,immunodeficiency, microcephaly, cerebellar hypoplasia, and growthretardation. Note=An aberrant splice variant designated Apollo-Delta has been found in a patient with Hoyeraal-Hreidarssonsyndrome. Apollo-Delta hampers the proper replication oftelomeres, leading to major telomeric dysfunction and cellularsenescence, but maintains its DNA interstrand cross-link repairfunction in the whole genome.

Defects in DCLRE1C are a cause of severe combinedimmunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-positive with sensitivity to ionizing radiation(RSSCID) [MIM:602450]. SCID refers to a genetically and clinicallyheterogeneous group of rare congenital disorders characterized byimpairment of both humoral and cell-mediated immunity, leukopenia,and low or absent antibody levels. Patients with SCID present ininfancy with recurrent, persistent infections by opportunisticorganisms. The common characteristic of all types of SCID isabsence of T-cell-mediated cellular immunity due to a defect in T-cell development. Individuals affected by RS-SCID show defects inthe DNA repair machinery necessary for coding joint formation andthe completion of V(D)J recombination. A subset of cells from suchpatients show increased radiosensitivity.

Defects in DCLRE1C are the cause of severe combinedimmunodeficiency Athabaskan type (SCIDA) [MIM:602450]. SCIDA is avariety of RS-SCID caused by a founder mutation in Athabascan-speaking native Americans, being inherited as an autosomalrecessive trait with an estimated gene frequency of 2.1% in theNavajo population. Affected individuals exhibit clinical symptomsand defects in DNA repair comparable to those seen in RS-SCID.

Defects in DCLRE1C are a cause of Omenn syndrome (OS)[MIM:603554]. OS is characterized by severe combinedimmunodeficiency associated with erythrodermia,hepatosplenomegaly, lymphadenopathy and alopecia. Affectedindividuals have elevated T-lymphocyte counts with a restricted T-cell receptor (TCR) repertoire. They also generally lack B-lymphocytes, but have normal natural killer (NK) cell function (T+B- NK+).

Defects in DCTN1 are the cause of distal hereditary motorneuronopathy type 7B (HMN7B) [MIM:607641], also known asprogressive lower motor neuron disease (PLMND). HMN7B is aneuromuscular disorder. Distal hereditary motor neuronopathiesconstitute a heterogeneous group of neuromuscular disorders causedby selective degeneration of motor neurons in the anterior horn ofthe spinal cord, without sensory deficit in the posterior horn.The overall clinical picture consists of a classical distalmuscular atrophy syndrome in the legs without clinical sensoryloss. The disease starts with weakness and wasting of distalmuscles of the anterior tibial and peroneal compartments of thelegs. Later on, weakness and atrophy may expand to the proximalmuscles of the lower limbs and/or to the distal upper limbs.

Defects in DCTN1 are a cause of susceptibility toamyotrophic lateral sclerosis (ALS) [MIM:105400]. ALS is aneurodegenerative disorder affecting upper and lower motorneurons, and resulting in fatal paralysis. Sensory abnormalitiesare absent. Death usually occurs within 2 to 5 years. The etiologyis likely to be multifactorial, involving both genetic andenvironmental factors.

Defects in DCTN1 are the cause of Perry syndrome (PERRYS)[MIM:168605], also called parkinsonism with alveolarhypoventilation and mental depression. Perry syndrome is aneuropsychiatric disorder characterized by mental depression notresponsive to antidepressant drugs or electroconvulsive therapy,sleep disturbances, exhaustion and marked weight loss.Parkinsonism develops later and respiratory failure occurredterminally.

Defects in UROD are the cause of familial porphyriacutanea tarda (FPCT) [MIM:176100], also known as porphyria cutaneatarda type II. FPCT is an autosomal dominant disordercharacterized by light-sensitive dermatitis, with onset in laterlife. It is associated with the excretion of large amounts ofuroporphyrin in the urine. Iron overload is often present inassociation with varying degrees of liver damage. Besides thefamilial form of PCT, a relatively common idiosyncratic form isknown in which only the liver enzyme is reduced. This form isreferred to as porphyria cutanea tarda "sporadic" type or type I[MIM:176090]. PCT type I occurs sporadically as an unusualaccompaniment of common hepatic disorders such as alcohol-associated liver disease.

Defects in UROD are the cause of hepatoerythropoieticporphyria (HEP) [MIM:176100]. HEP is a rare autosomal recessivedisorder. It is the severe form of cutaneous porphyria, andpresents in infancy. The level of UROD is very low in erythrocytesand cultured skin fibroblasts, suggesting that HEP is thehomozygous state for porphyria cutanea tarda.

Note=The enzyme defect in pentosuria has been shown toinvolve L-xylulose reductase. Essential pentosuria is an inbornerror of metabolism characterized by the excessive urinaryexcretion of the pentose L-xylulose.

Defects in DCX are the cause of lissencephaly X-linkedtype 1 (LISX1) [MIM:300067], also called X-LIS or LIS. LISX1 is aclassic lissencephaly characterized by mental retardation andseizures that are more severe in male patients. Affected boys showan abnormally thick cortex with absent or severely reduced gyri.Clinical manifestations include feeding problems, abnormalmuscular tone, seizures and severe to profound psychomotorretardation. Female patients display a less severe phenotypereferred to as 'doublecortex'.

Defects in DCX are the cause of subcortical bandheterotopia X-linked (SBHX) [MIM:300067], also known as doublecortex or subcortical laminar heterotopia (SCLH). SBHX is a mildbrain malformation of the lissencephaly spectrum. It ischaracterized by bilateral and symmetric plates or bands of graymatter found in the central white matter between the cortex andcerebral ventricles, cerebral convolutions usually appearingnormal.

Note=A chromosomal aberration involving DCX is found inlissencephaly. Translocation t(X,2)(q22.3,p25.1).

Defects in DDB2 are a cause of xeroderma pigmentosumcomplementation group E (XP-E) [MIM:278740], also known asxeroderma pigmentosum V (XP5). XP-E is a rare human autosomalrecessive disease characterized by solar sensitivity, highpredisposition for developing cancers on areas exposed to sunlightand, in some cases, neurological abnormalities.

Defects in DDC are the cause of aromatic L-amino-aciddecarboxylase deficiency (AADCD) [MIM:608643]. AADCD deficiency isan inborn error in neurotransmitter metabolism that leads tocombined serotonin and catecholamine deficiency. It causesdevelopmental and psychomotor delay, poor feeding, lethargy,ptosis, intermittent hypothermia, gastrointestinal disturbances.The onset is early in infancy and inheritance is autosomalrecessive.

Note=A chromosomal aberration involving DDIT3 is found ina patient with malignant myxoid liposarcoma. Translocationt(12,16)(q13,p11) with FUS.

Defects in DDR2 are the cause of spondyloepimetaphysealdysplasia short limb-hand type (SEMD-SL) [MIM:271665]. A bonedisease characterized by short-limbed dwarfism, a narrow chestwith pectus excavatum, brachydactyly in the hands and feet, acharacteristic craniofacial appearance and prematurecalcifications. The radiological findings are distinctive andcomprise short long bones throughout the skeleton with strikingepiphyses that are stippled, flattened and fragmented and flared,irregular metaphyses. Platyspondyly in the spine with wideintervertebral spaces is observed and some vertebral bodies arepear-shaped with central humps, anterior protrusions and posteriorscalloping.

Defects in DDX11 are the cause of Warsaw breakagesyndrome (WBRS) [MIM:613398]. It is a syndrome characterized bysevere microcephaly, pre- and postnatal growth retardation, facialdysmorphism and abnormal skin pigmentation. Additional featuresinclude high arched palate, coloboma of the right optic disk,deafness, ventricular septal defect, toes and fingersabnormalities. At cellular level, drug-induced chromosomalbreakage, a feature of Fanconi anemia, and sister chromatidcohesion defects, a feature of Roberts syndrome, coexist.

Note=DDX3Y is located in the 'azoospermia factor a'(AZFa) region on chromosome Y which is deleted in Sertoli cell-only syndrome. This is an infertility disorder in which no germcells are visible in seminiferous tubules leading to azoospermia.

Note=A chromosomal aberration involving DDX6 may be acause of hematopoietic tumors such as B-cell lymphomas.Translocation t(11,14)(q23,q32).

Note=A chromosomal aberration involving DEK is found in asubset of acute myeloid leukemia (AML), also known as acute non-lymphocytic leukemia. Translocation t(6,9)(p23,q34) withNUP214/CAN. It results in the formation of a DEK-CAN fusion gene.

Defects in DES are the cause of myopathy myofibrillardesmin-related (MFM-DES) [MIM:601419], also known as desmin-related myopathy (DRM). A neuromuscular disorder characterized byskeletal muscle weakness associated with cardiac conductionblocks, arrhythmias, restrictive heart failure, and bymyofibrillar destruction with intracytoplasmic accumulation ofdesmin-reactive deposits in cardiac and skeletal muscle cells.

Defects in DES are the cause of cardiomyopathy dilatedtype 1I (CMD1I) [MIM:604765]. Dilated cardiomyopathy is a disordercharacterized by ventricular dilation and impaired systolicfunction, resulting in congestive heart failure and arrhythmia.Patients are at risk of premature death.

Defects in DES are the cause of neurogenicscapuloperoneal syndrome Kaeser type (Kaeser syndrome)[MIM:181400]. Kaeser syndrome is an autosomal dominant disorderwith a peculiar scapuloperoneal distribution of weakness andatrophy. A large clinical variability is observed ranging fromscapuloperoneal, limb grindle and distal phenotypes with variablecardiac or respiratory involvement. Facial weakness, dysphagia andgynaecomastia are frequent additional symptoms. Affected menseemingly bear a higher risk of sudden, cardiac death as comparedto affected women. Histological and immunohistochemicalexamination of muscle biopsy specimens reveal a wide spectrum offindings ranging from near normal or unspecific pathology totypical, myofibrillar changes with accumulation of desmin.

Defects in DSP are the cause of palmoplantar keratodermastriate type 2 (SPPK2) [MIM:612908], also known as keratosispalmoplantaris striata II. SPPK2 is characterized by skinthickening in the palms (linear pattern) and the soles (island-like pattern) and flexor aspect of the fingers. Abnormalities ofthe nails, the teeth and the hair are rarely present.

Defects in DSP are the cause of cardiomyopathy dilatedwith woolly hair and keratoderma (DCWHK) [MIM:605676], also knownas Carvajal syndrome or palmoplantar keratoderma with leftventricular cardiomyopathy and woolly hair. DCWHK is an autosomalrecessive cardiocutaneous syndrome characterized by a generalizedstriate keratoderma particularly affecting the palmoplantarepidermis, woolly hair, and dilated left ventricularcardiomyopathy.

Defects in DSP are the cause of familial arrhythmogenicright ventricular dysplasia type 8 (ARVD8) [MIM:607450], alsoknown as arrhythmogenic right ventricular cardiomyopathy 8(ARVC8). ARVD is an autosomal dominant disease characterized bypartial degeneration of the myocardium of the right ventricle,electrical instability, and sudden death. It is clinically definedby electrocardiographic and angiographic criteria, pathologicfindings, replacement of ventricular myocardium with fatty andfibrous elements, preferentially involve the right ventricularfree wall.

Defects in DSP are the cause of skin fragility-woollyhair syndrome (SFWHS) [MIM:607655]. SFWHS is an autosomalrecessive genodermatosis characterized by focal and diffusepalmoplantar keratoderma, hyperkeratotic plaques on the trunk andlimbs, and woolly hair with varying degrees of alopecia.

Defects in DSP are the cause of epidermolysis bullosalethal acantholytic (EBLA) [MIM:609638]. EBLA is characterized bysevere fragility of skin and mucous membranes. The phenotype islethal in the neonatal period because of immense transcutaneousfluid loss. Typical features include universal alopecia, neonatalteeth, and nail loss. Histopathology of the skin shows suprabasalclefting and acantholysis throughout the spinous layer, mimickingpemphigus.

Defects in DFNA5 are the cause of deafness autosomaldominant type 5 (DFNA5) [MIM:600994]. DFNA5 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in DGUOK are the cause of mitochondrial DNAdepletion syndrome type 3 (MTDPS3) [MIM:251880]. A disordercharacterized by onset in infancy of progressive liver failure,hypoglycemia, increased lactate in body fluids, and neurologicabnormalities including hypotonia, encephalopathy, peripheralneuropathy. Affected tissues show both decreased activity of themtDNA-encoded respiratory chain complexes and mtDNA depletion.

Defects in HSD17B3 are the cause of malepseudohermaphrodism with gynecomastia (MPH) [MIM:264300]. Theseindividuals have unambiguous female external genitalia at birth,but fail to menstruate at the time of expected puberty and insteadvirilize as evidenced by growth of the phallus. Breast developmentmay or may not take place.

Defects in HSD17B4 are a cause of D-bifunctional proteindeficiency (DBPD) [MIM:261515]. DBPD is a disorder of peroxisomalfatty acid beta-oxidation.

Defects in DHCR24 are the cause of desmosterolosis(DESMOS) [MIM:602398]. It is a rare autosomal recessive disordercharacterized by multiple congenital anomalies and elevated levelsof the cholesterol precursor desmosterol in plasma, tissue, andcultured cells.

Defects in DHCR7 are the cause of Smith-Lemli-Opitzsyndrome (SLOS) [MIM:270400], also known as SLO syndrome or RSHsyndrome. SLOS is an autosomal recessive frequent inborn disorderof sterol metabolism with characteristic congenital malformationsand dysmorphias. All patients suffer from mental retardation.Children with SLOS have elevated serum 7-dehydrocholesterol (7-DHC) levels and low serum cholesterol levels. SLOS occurs inrelatively high frequency: approximately 1 in 20,000 to 30,000births in populations of northern and central European background.Historically, a clinical distinction often was made betweenclassic ('type I') SLOS and the more severely affected ('type II')patients. There is, in reality, a clinical and biochemicalcontinuum from mild to severe SLOS.

Defects in GLUD1 are the cause of familialhyperinsulinemic hypoglycemia type 6 (HHF6) [MIM:606762], alsoknown as hyperinsulinism-hyperammonemia syndrome (HHS). Familialhyperinsulinemic hypoglycemia [MIM:256450], also referred to ascongenital hyperinsulinism, nesidioblastosis, or persistenthyperinsulinemic hypoglycemia of infancy (PPHI), is the mostcommon cause of persistent hypoglycemia in infancy and is due todefective negative feedback regulation of insulin secretion by lowglucose levels. In HHF6 elevated oxidation rate of glutamate toalpha-ketoglutarate stimulates insulin secretion in the pancreaticbeta cells, while they impair detoxification of ammonium in theliver.

Defects in DHH may be the cause of partial gonadaldysgenesis with minifascicular neuropathy 46,XY (PGD)[MIM:607080]. PGD is characterized by the presence of a testis onone side and a streak or an absent gonad at the other, persistenceof Muellerian duct structures, and a variable degree of genitalambiguity.

Defects in DHH may be the cause of complete pure gonadaldysgenesis 46,XY type (GDXYM) [MIM:233420], also known as male-limited gonadal dysgenesis 46,XY. GDXYM is a type of hypogonadismin which no functional gonads are present to induce puberty in anexternally female person whose karyotype is then found to be XY.The gonads are found to be non-functional streaks.

Defects in HSD11B1 are a cause of cortisone reductasedeficiency (CRD) [MIM:604931]. In CRD, activation of cortisone tocortisol does not occur, resulting in adrenocorticotropin-mediatedandrogen excess and a phenotype resembling polycystic ovarysyndrome (PCOS).

Defects in HSD11B2 are the cause of apparentmineralocorticoid excess (AME) [MIM:218030]. AME is a potentiallyfatal disease characterized by severe juvenile low-reninhypertension, sodium retention, hypokalemia and low levels ofaldosterone. It often leads to nephrocalcinosis.

Defects in QDPR are the cause of BH4-deficienthyperphenylalaninemia type C (HPABH4C) [MIM:261630], also calleddihydropteridine reductase deficiency (DHPR deficiency) orhyperphenylalaninemia tetrahydrobiopterin-deficient due to DHPRdeficiency or quinoid dihydropteridine reductase deficiency (QDPRdeficiency). HPABH4C is a rare autosomal recessive disordercharacterized by hyperphenylalaninemia and severe neurologicsymptoms (malignant hyperphenylalaninemia) including axialhypotonia and truncal hypertonia, abnormal thermogenesis, andmicrocephaly. These signs are attributable to depletion of theneurotransmitters dopamine and serotonin, whose syntheses arecontrolled by tryptophan and tyrosine hydroxylases that use BH-4as cofactor. These patients do not respond to phenylalanine-restricted diet. HPABH4C is lethal if untreated.

Defects in SDHB are a cause of susceptibility topheochromocytoma (PCC) [MIM:171300]. A catecholamine-producingtumor of chromaffin tissue of the adrenal medulla or sympatheticparaganglia. The cardinal symptom, reflecting the increasedsecretion of epinephrine and norepinephrine, is hypertension,which may be persistent or intermittent.

Defects in SDHB are the cause of hereditaryparagangliomas type 4 (PGL4) [MIM:115310], also known as familialnon-chromaffin paragangliomas type 4. Paragangliomas refer to rareand mostly benign tumors that arise from any component of theneuroendocrine system. PGL4 is characterized by the development ofmostly benign, highly vascular, slow growing tumors in the headand neck. In the head and neck region, the carotid body is thelargest of all paraganglia and is also the most common site of thetumors.

Defects in SDHB are a cause of paraganglioma and gastricstromal sarcoma (PGGSS) [MIM:606864], also called Carney-Stratakissyndrome. Gastrointestinal stromal tumors may be sporadic orinherited in an autosomal dominant manner, alone or as a componentof a syndrome associated with other tumors, such as in the contextof neurofibromatosis type 1 (NF1). Patients have bothgastrointestinal stromal tumors and paragangliomas. Susceptibilityto the tumors was inherited in an apparently autosomal dominantmanner, with incomplete penetrance.

Defects in SDHB are a cause of Cowden-like syndrome(CWDLS) [MIM:612359]. Cowden-like syndrome is a cancerpredisposition syndrome associated with elevated risk for tumorsof the breast, thyroid, kidney and uterus.

Defects in SDHD are a cause of hereditary paragangliomastype 1 (PGL1) [MIM:168000], also known as familial non-chromaffinparagangliomas type 1. Paragangliomas refer to rare and mostlybenign tumors that arise from any component of the neuroendocrinesystem. PGL1 is a rare autosomal dominant disorder which ischaracterized by the development of mostly benign, highlyvascular, slowly growing tumors in the head and neck. In the headand neck region, the carotid body is the largest of allparaganglia and is also the most common site of the tumors.Penetrance of PGL1 is incomplete when the disease is transmittedthrough fathers. No disease phenotype is transmitted maternally.

Defects in SDHD are a cause of susceptibility topheochromocytoma (PCC) [MIM:171300]. A catecholamine-producingtumor of chromaffin tissue of the adrenal medulla or sympatheticparaganglia. The cardinal symptom, reflecting the increasedsecretion of epinephrine and norepinephrine, is hypertension,which may be persistent or intermittent.

Defects in SDHD may be a cause of susceptibility tointestinal carcinoid tumor (ICT) [MIM:114900]. A yellow, well-differentiated, circumscribed tumor that arises fromenterochromaffin cells in the small intestine or, less frequently,in other parts of the gastrointestinal tract.

Defects in SDHD are a cause of paraganglioma and gastricstromal sarcoma (PGGSS) [MIM:606864], also called Carney-Stratakissyndrome. Gastrointestinal stromal tumors may be sporadic orinherited in an autosomal dominant manner, alone or as a componentof a syndrome associated with other tumors, such as in the contextof neurofibromatosis type 1 (NF1). Patients have bothgastrointestinal stromal tumors and paragangliomas. Susceptibilityto the tumors was inherited in an apparently autosomal dominantmanner, with incomplete penetrance.

Defects in SDHD are a cause of Cowden-like syndrome(CWDLS) [MIM:612359]. Cowden-like syndrome is a cancerpredisposition syndrome associated with elevated risk for tumorsof the breast, thyroid, kidney and uterus.

Defects in DIAPH1 are the cause of deafness autosomaldominant type 1 (DFNA1) [MIM:124900]. DFNA1 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in DIAPH2 are the cause of premature ovarianfailure type 2A (POF2A) [MIM:300511]. An ovarian disorder definedas the cessation of ovarian function under the age of 40 years. Itis characterized by oligomenorrhea or amenorrhea, in the presenceof elevated levels of serum gonadotropins and low estradiol.

Defects in DICER1 are a cause of pleuropulmonary blastoma(PPB) [MIM:601200]. PPB is a rare pediatric tumor of the lung thatarises during fetal lung development and is often part of aninherited cancer syndrome. PPBs contain both epithelial andmesenchymal cells. Early in tumorigenesis, cysts form in lungairspaces, and these cysts are lined with benign-appearingepithelium. Mesenchymal cells susceptible to malignanttransformation reside within the cyst walls and form a dense'cambium' layer beneath the epithelial lining. In a subset ofpatients, overgrowth of the mesenchymal cells produces a sarcoma,a transition that is associated with a poorer prognosis.

Note=A chromosomal aberration involving DIRC1 isassociated with familial clear cell renal carcinoma. Translocationt(2,3)(q33,q21).

Note=A chromosomal aberration involving DIRC2 has beenfound in a family with renal carcinoma. Translocationt(2,3)(q35,q21).

Note=A chromosomal aberration involving DISC1 segregateswith schizophrenia and related psychiatric disorders in a largeScottish family. Translocation t(1,11)(q42.1,q14.3). The truncatedDISC1 protein produced by this translocation is unable to interactwith ATF4, ATF5 and NDEL1.

Genetic variation in DISC1 is associated withsusceptibility to schizophrenia type 9 (SCZD9) [MIM:604906]. Acomplex, multifactorial psychotic disorder or group of disorderscharacterized by disturbances in the form and content of thought(e.g. delusions, hallucinations), in mood (e.g. inappropriateaffect), in sense of self and relationship to the external world(e.g. loss of ego boundaries, withdrawal), and in behavior (e.gbizarre or apparently purposeless behavior). Although it affectsemotions, it is distinguished from mood disorders in which suchdisturbances are primary. Similarly, there may be mild impairmentof cognitive function, and it is distinguished from the dementiasin which disturbed cognitive function is considered primary. Somepatients manifest schizophrenic as well as bipolar disordersymptoms and are often given the diagnosis of schizoaffectivedisorder.

Note=DNAJC30 is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.

Defects in DKC1 are a cause of dyskeratosis congenita X-linked recessive (XDKC) [MIM:305000]. XDKC is a rare, progressivebone marrow failure syndrome characterized by the triad ofreticulated skin hyperpigmentation, nail dystrophy, and mucosalleukoplakia. Early mortality is often associated with bone marrowfailure, infections, fatal pulmonary complications, or malignancy.

Defects in DKC1 are the cause of Hoyeraal-Hreidarssonsyndrome (HHS) [MIM:300240]. HHS is a multisystem disorderaffecting males and is characterized by aplastic anemia,immunodeficiency, microcephaly, cerebellar hypoplasia, and growthretardation.

Note=Defects in DLD are involved in the development ofcongenital infantile lactic acidosis.

Defects in DLD are a cause of maple syrup urine disease(MSUD) [MIM:248600]. MSUD is characterized by mental and physicalretardation, feeding problems and a maple syrup odor to the urine.The keto acids of the branched-chain amino acids are present inthe urine, resulting from a block in oxidative decarboxylation.

Note=DLEC1 silencing due to promoter methylation andaberrant transcription are implicated in the development ofdifferent cancers, including esophageal, renal and lung cancers.

Defects in DLG3 are the cause of mental retardation X-linked type 90 (MRX90) [MIM:300189]. Mental retardation ischaracterized by significantly sub-average general intellectualfunctioning associated with impairments in adaptative behavior andmanifested during the developmental period. Non-syndromic mentalretardation patients do not manifest other clinical signs.

Defects in DLL3 are the cause of spondylocostaldysostosis type 1 (SCDO1) [MIM:277300]. An autosomal recessivecondition of variable severity associated with vertebral and ribsegmentation defects. The main skeletal malformations includefusion of vertebrae, hemivertebrae, fusion of certain ribs, andother rib malformations. Deformity of the chest and spine (severescoliosis, kyphoscoliosis and lordosis) is a natural consequenceof the malformation and leads to a dwarf-like appearance. As thethorax is small, infants frequently have respiratory insufficiencyand repeated respiratory infections resulting in life-threateningcomplications in the first year of life.

Defects in PDSS2 are a cause of coenzyme Q10 deficiency[MIM:607426]. Coenzyme Q10 deficiency is an autosomal recessivedisorder with variable manifestations. It can be associated withthree main clinical phenotypes: a predominantly myopathic formwith central nervous system involvement, an infantileencephalomyopathy with renal dysfunction and an ataxic form withcerebellar atrophy.

Defects in DLX3 are a cause of trichodentoosseoussyndrome (TDO) [MIM:190320]. TDO is an autosomal dominant syndromecharacterized by enamel hypoplasia and hypocalcification withassociated strikingly curly hair.

Defects in DLX3 are the cause of amelogenesis imperfectatype 4 (AI4) [MIM:104510], also known as amelogenesis imperfectahypomaturation-hypoplastic type with taurodontism. AI4 is anautosomal dominant defect of enamel formation associated withenlarged pulp chambers.

Defects in DMBT1 are involved in the development ofglioma (GLM) [MIM:137800]. Gliomas are central nervous systemneoplasms derived from glial cells and comprise astrocytomas,glioblastoma multiforme, oligodendrogliomas, and ependymomas.Note=Homozygous deletions may be the predominant mechanism ofDMBT1 inactivation playing a role in carcinogenesis. DMBT1 isdeleted in medulloblastoma and glioblastoma cell lines, pointmutations have also been reported in patients with glioma. A lossor reduction of DMBT1 expression has been seen in esophageal,gastric, lung and colorectal carcinomas as well.

Defects in DMD are the cause of Duchenne musculardystrophy (DMD) [MIM:310200]. DMD is the most common form ofmuscular dystrophy, a sex-linked recessive disorder. It typicallypresents in boys aged 3 to 7 year as proximal muscle weaknesscausing waddling gait, toe-walking, lordosis, frequent falls, anddifficulty in standing up and climbing up stairs. The pelvicgirdle is affected first, then the shoulder girdle. Progression issteady and most patients are confined to a wheelchair by age of 10or 12. Flexion contractures and scoliosis ultimately occur. About50% of patients have a lower IQ than their genetic expectationswould suggest. There is no treatment.

Defects in DMD are the cause of Becker muscular dystrophy(BMD) [MIM:300376]. BMD resembles DMD in hereditary and clinicalfeatures but is later in onset and more benign.

Defects in DMD are a cause of cardiomyopathy dilated X-linked type 3B (CMD3B) [MIM:302045], also known as X-linkeddilated cardiomyopathy (XLCM). Dilated cardiomyopathy is adisorder characterized by ventricular dilation and impairedsystolic function, resulting in congestive heart failure andarrhythmia. Patients are at risk of premature death.

Defects in DMP1 are the cause of autosomal recessivehypophosphatemic rickets (ARHR) [MIM:241520]. ARHR ischaracterized by rickets, osteomalacia, elevated FGF23 serumlevels and hypophosphatemia.

Defects in FAM20C are the cause of Raine syndrome (RNS)[MIM:259775]. RNS is an autosomal recessive osteosclerotic bonedysplasia with neonatal lethal outcome. Clinical features includegeneralized osteosclerosis, craniofacial dysplasia andmicrocephaly.

Defects in DMPK are the cause of dystrophia myotonicatype 1 (DM1) [MIM:160900], also known as Steinert disease. Amuscular disorder characterized by myotonia, muscle wasting in thedistal extremities, cataract, hypogonadism, defective endocrinefunctions, male baldness and cardiac arrhythmias. Note=Thecausative mutation is a CTG expansion in the 3'-UTR of the DMPKgene. A length exceeding 50 CTG repeats is pathogenic, whilenormal individuals have 5 to 37 repeats. Intermediate alleles with35-49 triplets are not disease-causing but show instability inintergenerational transmissions. Disease severity varies with thenumber of repeats: mildly affected persons have 50 to 150 repeats,patients with classic DM have 100 to 1,000 repeats, and those withcongenital onset can have more than 2,000 repeats.

Defects in DNAI1 are the cause of primary ciliarydyskinesia type 1 (CILD1) [MIM:244400]. CILD1 is an autosomalrecessive disorder characterized by axonemal abnormalities ofmotile cilia. Respiratory infections leading to chronicinflammation and bronchiectasis are recurrent, due to defects inthe respiratory cilia, reduced fertility is often observed in malepatients due to abnormalities of sperm tails. Half of the patientsexhibit situs inversus, due to dysfunction of monocilia at theembryonic node and randomization of left-right body asymmetry.Primary ciliary dyskinesia associated with situs inversus isreferred to as Kartagener syndrome.

Defects in DNAI1 are the cause of Kartagener syndrome(KTGS) [MIM:244400]. KTGS is an autosomal recessive disordercharacterized by the association of primary ciliary dyskinesiawith situs inversus. Clinical features include recurrentrespiratory infections, bronchiectasis, infertility, and lateraltransposition of the viscera of the thorax and abdomen. The situsinversus is most often total, although it can be partial in somecases (isolated dextrocardia or isolated transposition ofabdominal viscera).

Defects in DNAI2 are the cause of primary ciliarydyskinesia type 9 (CILD9) [MIM:612444]. CILD is an autosomalrecessive disorder characterized by axonemal abnormalities ofmotile cilia. Respiratory infections leading to chronicinflammation and bronchiectasis are recurrent, due to defects inthe respiratory cilia, reduced fertility is often observed in malepatients due to abnormalities of sperm tails. Half of the patientsexhibit situs inversus, due to dysfunction of monocilia at theembryonic node and randomization of left-right body asymmetry.Primary ciliary dyskinesia associated with situs inversus isreferred to as Kartagener syndrome.

Defects in LIG4 are the cause of LIG4 syndrome (LIG4S)[MIM:606593]. This disease is characterized by immunodeficiencyand developmental and growth delay. Patients display unusualfacial features, microcephaly, growth and/or developmental delay,pancytopenia, and various skin abnormalities.

Defects in LIG4 are a cause of severe combinedimmunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-positive with sensitivity to ionizing radiation(RSSCID) [MIM:602450]. SCID refers to a genetically and clinicallyheterogeneous group of rare congenital disorders characterized byimpairment of both humoral and cell-mediated immunity, leukopenia,and low or absent antibody levels. Patients with SCID present ininfancy with recurrent, persistent infections by opportunisticorganisms. The common characteristic of all types of SCID isabsence of T-cell-mediated cellular immunity due to a defect in T-cell development. Individuals affected by RS-SCID show defects inthe DNA repair machinery necessary for coding joint formation andthe completion of V(D)J recombination. A subset of cells from suchpatients show increased radiosensitivity.

Note=May be associated with Alzheimer disease throughbeta-amyloid-induced increased S-nitrosylation of DNM1L, whichtriggers, directly or indirectly, excessive mitochondrial fission,synaptic loss and neuronal damage.

Defects in DNMT3B are a cause of immunodeficiency-centromeric instability-facial anomalies syndrome (ICF)[MIM:242860]. ICF is a rare autosomal recessive disordercharacterized by a variable immunodeficiency, mild facialanomalies, and centromeric heterochromatin instability involvingchromosomes 1, 9, and 16. ICF is biochemically characterized byhypomethylation of CpG sites in some regions of heterochromatin.

Note=A chromosomal aberration involving DOCK3 has beenfound in a family with early-onset behavioral/developmentaldisorder with features of attention deficit-hyperactivity disorderand intellectual disability. Inversion inv(3)(p14:q21). Theinversion disrupts DOCK3 and SLC9A9.

Defects in DOCK8 are the cause of hyperimmunoglobulin Erecurrent infection syndrome autosomal recessive (AR-HIES)[MIM:243700]. It is a rare disorder of immunity characterized byimmunodeficiency, recurrent infections, eczema, increased serumIgE, eosinophilia and lack of connective tissue and skeletalinvolvement.

Defects in DOK7 are the cause of familial limb-girdlemyasthenia autosomal recessive (LGM) [MIM:254300], also calledcongenital myasthenic syndrome type 1B or CMS1B. LGM is acongenital myasthenic syndrome characterized by a typical 'limbgirdle' pattern of muscle weakness with small, simplifiedneuromuscular junctions but normal acetylcholine receptor andacetylcholinesterase function.

Defects in DOLK are the cause of congenital disorder ofglycosylation type 1M (CDG1M) [MIM:610768], also known as dolicholkinase deficiency. CDGs are a family of severe inherited diseasescaused by a defect in glycoprotein biosynthesis. They arecharacterized by under-glycosylated serum glycoproteins. Thesemultisystem disorders present with a wide variety of clinicalfeatures, such as disorders of the nervous system development,psychomotor retardation, dysmorphic features, hypotonia,coagulation disorders, and immunodeficiency. The broad spectrum offeatures reflects the critical role of N-glycoproteins duringembryonic development, differentiation, and maintenance of cellfunctions. CDG1M is a very severe disorder with death occurring inearly infancy.

Defects in DBH are the cause of dopamine beta-hydroxylasedeficiency (DBH deficiency) [MIM:223360], also known asnorepinephrine deficiency or noradrenaline deficiency. Thisdisorder is characterized by profound deficits in autonomic andcardiovascular function, but apparently only subtle signs, if any,of central nervous system dysfunction.

Defects in DUOXA2 are the cause of congenitalhypothyroidism due to dyshormonogenesis type 5 (CHDH5)[MIM:274900]. A disorder due to thyroid dyshormonogenesis, causinghypothyroidism, goiter, and variable mental deficits derived fromunrecognized and untreated hypothyroidism.

Defects in DPM1 are the cause of congenital disorder ofglycosylation type 1E (CDG1E) [MIM:608799]. CDGs are metabolicdeficiencies in glycoprotein biosynthesis that usually causesevere mental and psychomotor retardation. They are characterizedby under-glycosylated serum glycoproteins. CDG1E is an autosomalrecessive disorder, characterized by severe developmental delay,hypotnia, seizures, and dysmorphic features.

Defects in DPM3 are the cause of congenital disorder ofglycosylation type 1O (CDG1O) [MIM:612937]. A multisystem disordercaused by a defect in glycoprotein biosynthesis and characterizedby under-glycosylated serum glycoproteins. Congenital disorders ofglycosylation result in a wide variety of clinical features, suchas defects in the nervous system development, psychomotorretardation, dysmorphic features, hypotonia, coagulationdisorders, and immunodeficiency. The broad spectrum of featuresreflects the critical role of N-glycoproteins during embryonicdevelopment, differentiation, and maintenance of cell functions.

Defects in POLG are the cause of progressive externalophthalmoplegia with mitochondrial DNA deletions autosomaldominant type 1 (PEOA1) [MIM:157640]. Progressive externalophthalmoplegia is characterized by progressive weakness of ocularmuscles and levator muscle of the upper eyelid. In a minority ofcases, it is associated with skeletal myopathy, whichpredominantly involves axial or proximal muscles and which causesabnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A largeproportion of chronic ophthalmoplegias are associated with othersymptoms, leading to a multisystemic pattern of this disease.Additional symptoms are variable, and may include cataracts,hearing loss, sensory axonal neuropathy, ataxia, depression,hypogonadism, and parkinsonism.

Defects in POLG are a cause of progressive externalophthalmoplegia with mitochondrial DNA deletions autosomalrecessive (PEOB) [MIM:258450]. PEOB is a severe form ofprogressive external ophthalmoplegia. It is clinically moreheterogeneous than the autosomal dominant forms. Can be moresevere.

Defects in POLG are a cause of sensory ataxic neuropathydysarthria and ophthalmoparesis (SANDO) [MIM:607459]. SANDO is asystemic disorder resulting from mitochondrial dysfunctionassociated with mitochondrial depletion in skeletal muscle andperipheral nerve tissue. The clinical triad of symptoms consistsof sensory ataxic neuropathy, dysarthria, and ophthalmoparesis.However, the phenotype varies widely, even within the same family,and can also include myopathy, seizures, and hearing loss. Anatypical form of the disease is characterized by headaches and/orseizures manifesting in childhood or adolescence, followed bydevelopment of cerebellar and sensory ataxia, dysarthria,progressive external ophthalmoplegia, and myoclonus in earlyadulthood.

Defects in POLG are the cause of mitochondrial DNAdepletion syndrome type 4A (MTDPS4A) [MIM:203700], also calledAlpers diffuse degeneration of cerebral gray matter with hepaticcirrhosis. An autosomal recessive hepatocerebral syndrome. Thetypical course of the disease includes severe developmental delay,intractable seizures, liver failure, and death in childhood.Refractory seizures, cortical blindness, progressive liverdysfunction, and acute liver failure after exposure to valproicacid are considered diagnostic features. The neuropathologicalhallmarks are neuronal loss, spongiform degeneration, andastrocytosis of the visual cortex. Liver biopsy results showsteatosis, often progressing to cirrhosis.

Defects in POLG are the cause of mitochondrial DNAdepletion syndrome type 4B (MTDPS4B) [MIM:613662], also known asmitochondrial DNA depletion syndrome 4B MNGIE type ormitochondrial neurogastrointestinal encephalopathy syndrome POLG-related. An autosomal recessive progressive multisystem disorderclinically characterized by chronic gastrointestinal dysmotilityand pseudo-obstruction, cachexia, progressive externalophthalmoplegia, axonal sensory ataxic neuropathy, and muscleweakness.

Defects in POLG are a cause of Leigh syndrome (LS)[MIM:256000]. LS is a severe neurological disorder characterizedby bilaterally symmetrical necrotic lesions in subcortical brainregions.

Defects in POLG2 are the cause of progressive externalophthalmoplegia with mitochondrial DNA deletions autosomaldominant type 4 (PEOA4) [MIM:610131]. Progressive externalophthalmoplegia is characterized by progressive weakness of ocularmuscles and levator muscle of the upper eyelid. In a minority ofcases, it is associated with skeletal myopathy, whichpredominantly involves axial or proximal muscles and which causesabnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A largeproportion of chronic ophthalmoplegias are associated with othersymptoms, leading to a multisystemic pattern of this disease.Additional symptoms are variable, and may include cataracts,hearing loss, sensory axonal neuropathy, ataxia, depression,hypogonadism, and parkinsonism.

Genetic variations in DPP10 are associated withsusceptibility to asthma (ASTHMA) [MIM:600807]. The most commonchronic disease affecting children and young adults. It is acomplex genetic disorder with a heterogeneous phenotype, largelyattributed to the interactions among many genes and between thesegenes and the environment. It is characterized by recurrentattacks of paroxysmal dyspnea, with weezing due to spasmodiccontraction of the bronchi.

A genetic variation 340 bases upstream from the ATG startsite of the DPP6 gene is the cause of ventricular fibrillationparoxysmal familial type 2 (VF2) [MIM:612956]. A cardiacarrhythmia marked by fibrillary contractions of the ventricularmuscle due to rapid repetitive excitation of myocardial fiberswithout coordinated contraction of the ventricle and by absence ofatrial activity.

Defects in PDSS1 are a cause of coenzyme Q10 deficiency[MIM:607426]. Coenzyme Q10 deficiency is an autosomal recessivedisorder with variable manifestations. It can be associated withthree main clinical phenotypes: a predominantly myopathic formwith central nervous system involvement, an infantileencephalomyopathy with renal dysfunction and an ataxic form withcerebellar atrophy.

Defects in DPYD are the cause of dihydropyrimidinedehydrogenase deficiency (DPYD deficiency) [MIM:274270], alsoknown as hereditary thymine-uraciluria or familial pyrimidinemia.DPYD deficiency is a disease characterized by persistent urinaryexcretion of excessive amounts of uracil, thymine and 5-hydroxymethyluracil. Patients suffering from this disease show asevere reaction to the anticancer drug 5-fluorouracil. Thisreaction includes stomatitis, Leukopenia, thrombocytopenia, hairloss, diarrhea, fever, marked weight loss, cerebellar ataxia, andneurologic symptoms, progressing to semicoma.

Defects in DPYS are the cause of dihydropyrimidinasedeficiency (DHPD) [MIM:222748]. DHPD is an autosomal recessivedisorder characterized by dihydropyrimidinuria and associated witha variable clinical phenotype: epileptic or convulsive attacks,dysmorphic features and severe developmental delay, and congenitalmicrovillous atrophy.

Defects in DRD2 are associated with dystonia type 11(DYT11) [MIM:159900], also known as alcohol-responsive dystonia.DYT11 is a myoclonic dystonia. Dystonia is defined by the presenceof sustained involuntary muscle contractions, often leading toabnormal postures. DYT11 is characterized by involuntary lightningjerks and dystonic movements and postures alleviated by alcohol.Inheritance is autosomal dominant. The age of onset, pattern ofbody involvement, presence of myoclonus and response to alcoholare all variable.

Genetic variation in DRD3 is associated with essentialtremor hereditary type 1 (ETM1) [MIM:190300]. ETM1 is the mostcommon movement disorder. The main feature is postural tremor ofthe arms. Head, legs, trunk, voice, jaw, and facial muscles alsomay be involved. The condition can be aggravated by emotions,hunger, fatigue and temperature extremes, and may cause afunctional disability or even incapacitation. Inheritance isautosomal dominant.

Defects in DRD5 are a cause of benign essentialblepharospasm (BEB) [MIM:606798]. BEB is a primary focal dystoniaaffecting the orbicularis oculi muscles. Dystonia is defined bythe presence of sustained involuntary muscle contraction, oftenleading to abnormal postures. BEB usually begins in middle age.Initial symptoms include eye irritation and frequent blinking,progressing to involuntary spasms of eyelid closure. Patients havenormal eyes. The visual disturbance is due solely to the forcedclosure of the eyelids. In severe cases, this can lead tofunctional blindness.

Defects in DSC2 are the cause of familial arrhythmogenicright ventricular dysplasia type 11 (ARVD11) [MIM:610476], alsoknown as arrhythmogenic right ventricular cardiomyopathy 11(ARVC11). ARVD is an autosomal dominant disease characterized bypartial degeneration of the myocardium of the right ventricle,electrical instability, and sudden death. It is clinically definedby electrocardiographic and angiographic criteria, pathologicfindings, replacement of ventricular myocardium with fatty andfibrous elements, preferentially involve the right ventricularfree wall.

Defects in DSC3 are the cause of hypotrichosis andrecurrent skin vesicles (HRSV) [MIM:613102]. A disordercharacterized by hypotrichosis and the appearance of recurrentskin vesicle formation. Affected individuals show sparse andfragile hair on scalp, as well as absent eyebrows and eyelashes.Vesicles filled with thin, watery fluid are observed on the scalpand skin of most of the boby. Mucosal vesicles are absent.

Defects in DSG1 are the cause of palmoplantar keratodermastriate type 1 (SPPK1) [MIM:148700], also known as keratosispalmoplantaris striata I. SPPK1 is a dermatoligical disordercharacterized by thickening of the skin on the palms and soles,and longitudinal hyperkeratotic lesions on the palms, running thelength of each finger.

Defects in DSG2 are the cause of familial arrhythmogenicright ventricular dysplasia type 10 (ARVD10) [MIM:610193], alsoknown as arrhythmogenic right ventricular cardiomyopathy 10(ARVC10). ARVD is an autosomal dominant disease characterized bypartial degeneration of the myocardium of the right ventricle,electrical instability, and sudden death. It is clinically definedby electrocardiographic and angiographic criteria, pathologicfindings, replacement of ventricular myocardium with fatty andfibrous elements, preferentially involve the right ventricularfree wall.

Genetic variations in DSG2 are the cause ofsusceptibility to cardiomyopathy dilated type 1BB (CMD1BB)[MIM:612877]. A disorder characterized by ventricular dilation andimpaired systolic function, resulting in congestive heart failureand arrhythmia. Patients are at risk of premature death.

Defects in DSG4 are the cause of hypotrichosis localizedautosomal recessive type 1 (LAH1) [MIM:607903]. A conditioncharacterized by the presence of less than the normal amount ofhair, involving mainly the scalp, chest, arms and legs. It ischaracterized by abnormal hair follicles and shafts, which arethin and atrophic.

Note=Autoantibodies against DSG4 are found in patientswith pemphigus vulgaris. Pemphigus vulgaris is a potentiallylethal skin disease in which epidermal blisters occur as theresult of the loss of cell-cell adhesion.

Defects in DSPP are the cause of deafness autosomaldominant type 39 with dentinogenesis imperfecta 1 (DFNA39/DGI1)[MIM:605594]. Affected individuals present DGI1 associated withearly onset progressive sensorineural high-frequency hearing loss.

Defects in DSPP are the cause of dentinogenesisimperfecta type 1 (DGI1) [MIM:125490], also known asdentinogenesis imperfecta Shields type 2 (DGI2). DGI1 is anautosomal dominant disorder in which both the primary and thepermanent teeth are affected. It occurs with an incidence of1:8000 live births. The teeth are amber and opalescent, the pulpchamber being obliterated by abnormal dentin. The enamel, althoughunaffected, tends to fracture, which makes dentin undergo rapidattrition, leading to shortening of the teeth.

Defects in DSPP are a cause of dentinogenesis imperfectaShields type 3 (DGI3) [MIM:125500]. Patients with DGI3 do not havestigmata of osteogenesis imperfecta. The finding that a singledefects in the DSPP gene causes both phenotypic patterns of DGI2and DGI3 strongly supports the conclusion that these two disordersare not separate diseases but rather the phenotypic variation of asingle genetic defect.

Defects in DSPP are the cause of dentin dysplasia type 2(DTDP2) [MIM:125420], also known as dentin dysplasia Shields type2. DTDP2 is an autosomal dominant disorder in which mineralizationof the dentine of the primary teeth is abnormal. On the basis ofthe phenotypic overlap between, and shared chromosomal locationwith DGI2 it has been proposed that DTDP2 and DGI2 are allelic.From the results of recent studies, it is clear that differenttypes of mutations in DSPP lead to the two different phenotypes.

Defects in ADAR are a cause of dyschromatosis symmetricalhereditaria (DSH) [MIM:127400], also known as reticulateacropigmentation of Dohi. DSH is a pigmentary genodermatosis ofautosomal dominant inheritance characterized by a mixture ofhyperpigmented and hypopigmented macules distributed on the dorsalparts of the hands and feet.

Defects in DTNBP1 are the cause of Hermansky-Pudlaksyndrome type 7 (HPS7) [MIM:203300]. Hermansky-Pudlak syndrome(HPS) is a genetically heterogeneous, rare, autosomal recessivedisorder characterized by oculocutaneous albinism, bleeding due toplatelet storage pool deficiency, and lysosomal storage defects.This syndrome results from defects of diverse cytoplasmicorganelles including melanosomes, platelet dense granules andlysosomes. Ceroid storage in the lungs is associated withpulmonary fibrosis, a common cause of premature death inindividuals with HPS.

Defects in DTNA are the cause of left ventricular non-compaction type 1 (LVNC1) [MIM:604169]. Left ventricular non-compaction is due to an arrest of myocardial morphogenesis. Thedisorder is characterized by a hypertrophic left ventricule withdeep trabeculations and with poor systolic function, with orwithout associated left ventricular dilation. In some cases, it isassociated with other congenital heart anomalies such asventricular septal defects, pulmonic stenosis and atrial septaldefects. The right ventricle may also be affected.

Defects in DUOX2 are a cause of congenital hypothyroidismdue to dyshormonogenesis type 6 (CHDH6) [MIM:607200]. CHDH6 is dueto defective conversion of accumulated iodide to organically boundiodine. The iodide organification defect can be partial orcomplete.

Defects in DUX4 may be the cause of facioscapulohumeralmuscular dystrophy (FSHD) [MIM:158900]. FSHD is characterized byweakness of the muscles of the face, upper-arm and shouldergirdle. Severity is highly variable. Weakness is slowlyprogressive and about 20% of affected individuals eventuallyrequire a wheelchair. Approximately 70-90% of individuals haveinherited the disease-causing deletion from a parent, andapproximately 10-30% of affected individuals have FSHD as theresult of a de novo deletion. Offsprings of an affected individualhave a 50% chance of inheriting the deletion.

Defects in DNAH11 are a cause of Kartagener syndrome(KTGS) [MIM:244400]. KTGS is an autosomal recessive disordercharacterized by the association of primary ciliary dyskinesiawith situs inversus. Clinical features include recurrentrespiratory infections, bronchiectasis, infertility, and lateraltransposition of the viscera of the thorax and abdomen. The situsinversus is most often total, although it can be partial in somecases (isolated dextrocardia or isolated transposition ofabdominal viscera).

Defects in DNAH11 are the cause of primary ciliarydyskinesia type 7 (CILD7) [MIM:611884]. CILD is an autosomalrecessive disorder characterized by axonemal abnormalities ofmotile cilia. Respiratory infections leading to chronicinflammation and bronchiectasis are recurrent, due to defects inthe respiratory cilia, reduced fertility is often observed in malepatients due to abnormalities of sperm tails. Half of the patientsexhibit situs inversus, due to dysfunction of monocilia at theembryonic node and randomization of left-right body asymmetry.Primary ciliary dyskinesia associated with situs inversus isreferred to as Kartagener syndrome.

Defects in DNAH5 are the cause of primary ciliarydyskinesia type 3 (CILD3) [MIM:608644]. CILD3 is an autosomalrecessive disorder characterized by axonemal abnormalities ofmotile cilia. Respiratory infections leading to chronicinflammation and bronchiectasis are recurrent, due to defects inthe respiratory cilia, reduced fertility is often observed in malepatients due to abnormalities of sperm tails. Half of the patientsexhibit situs inversus, due to dysfunction of monocilia at theembryonic node and randomization of left-right body asymmetry.Primary ciliary dyskinesia associated with situs inversus isreferred to as Kartagener syndrome.

Defects in DNAH5 are a cause of Kartagener syndrome(KTGS) [MIM:244400]. KTGS is an autosomal recessive disordercharacterized by the association of primary ciliary dyskinesiawith situs inversus. Clinical features include recurrentrespiratory infections, bronchiectasis, infertility, and lateraltransposition of the viscera of the thorax and abdomen. The situsinversus is most often total, although it can be partial in somecases (isolated dextrocardia or isolated transposition ofabdominal viscera).

Defects in DYNC2H1 are the cause of asphyxiating thoracicdystrophy type 3 (ATD3) [MIM:613091]. ATD3 is an autosomalrecessive osteochondrodysplasia which often leads to death ininfancy because of a severely constricted thoracic cage andrespiratory insufficiency.

Defects in DYNC2H1 are the cause of short rib-polydactylysyndrome type 3 (SRPS3) [MIM:263510], also called Verma-Naumoffsyndrome. A lethal skeletal dysplasia characterized by markedlyshort ribs, short limbs, polydactyly, narrow thorax, and multipleanomalies of major organs, including heart, intestines, genitalia,kidney, liver, and pancreas.

Defects in DYM are the cause of Dyggve-Melchior-Clausensyndrome (DMC) [MIM:223800]. DMC is a rare autosomal recessivedisorder characterized by short trunk dwarfism, microcephaly andpsychomotor retardation. Electron microscopic study of cutaneouscells of affected patients shows dilated rough endoplasmicreticulum, enlarged and aberrant vacuoles and numerous vesicles.DMC is progressive.

Defects in DYM are the cause of Smith-McCort dysplasia(SMC) [MIM:607326]. SMC is a rare autosomal recessiveosteochondrodysplasia characterized by short limbs and trunk withbarrel-shaped chest. The radiographic phenotype includesplatyspondyly, generalized abnormalities of the epiphyses andmetaphyses, and a distinctive lacy appearance of the iliac crest,features identical to those of Dyggve-Melchior-Clausen syndrome.

Defects in DNM2 are a cause of centronuclear myopathyautosomal dominant (ADCNM) [MIM:160150], also known as autosomaldominant myotubular myopathy. Centronuclear myopathies (CNMs) arecongenital muscle disorders characterized by progressive muscularweakness and wasting involving mainly limb girdle, trunk, and neckmuscles. It may also affect distal muscles. Weakness may bepresent during childhood or adolescence or may not become evidentuntil the third decade of life. Ptosis is a frequent clinicalfeature. CNMs comprise a wide spectrum of phenotypes, ranging fromsevere neonatal to mild late-onset familial forms. The mostprominent histopathologic features include high frequency ofcentrally located nuclei in muscle fibers not secondary toregeneration, radial arrangement of sarcoplasmic strands aroundthe central nuclei, and predominance and hypotrophy of type 1fibers.

Defects in DNM2 are the cause of Charcot-Marie-Toothdisease dominant intermediate type B (CMTDIB) [MIM:606482].Charcot-Marie-Tooth disease (CMT) is a clinically and geneticallyheterogeneous disorder of the peripheral nervous system,characterized by progressive weakness and atrophy, initially ofthe peroneal muscles and later of the distal muscles of the arms.CMTDIB is a form of Charcot-Marie-Tooth disease characterized byclinical and pathologic features intermediate betweendemyelinating and axonal peripheral neuropathies, and motor mediannerve conduction velocities ranging from 25 to 45 m/sec.

Defects in DYSF are the cause of limb-girdle musculardystrophy type 2B (LGMD2B) [MIM:253601]. LGMD2B is an autosomalrecessive degenerative myopathy characterized by weakness andatrophy starting in the proximal pelvifemoral muscles, with onsetin the late teens or later, massive elevation of serum creatinekinase levels and slow progression. Scapular muscle involvement isminor and not present at onset. Upper limb girdle involvementfollows some years after the onset in lower limbs.

Defects in DYSF are the cause of Miyoshi musculardystrophy type (MMD1) [MIM:254130]. MMD1 is a late-onset musculardystrophy involving the distal lower limb musculature. It ischaracterized by weakness that initially affects the gastrocnemiusmuscle during early adulthood. Otherwise the phenotype overlapswith LGMD2B, especially in age at onset and creatine kinaseelevation.

Defects in DYSF are the cause of distal myopathy withanterior tibial onset (DMAT) [MIM:606768]. Onset of the disorderis between 14 and 28 years of age and the anterior tibial musclesare the first muscle group to be involved. Inheritance isautosomal recessive.

Defects in DYX1C1 may be a cause of susceptibility todyslexia type 1 (DYX1) [MIM:127700]. A relatively common, complexcognitive disorder characterized by an impairment of readingperformance despite adequate motivational, educational andintellectual opportunities. It is a multifactorial trait, withevidence for familial clustering and heritability. Note=Achromosomal aberration involving DYX1C1 has been found in a familyaffected by dyslexia. Translocation t(2,15)(q11,q21).

Defects in EIF2AK3 are the cause of Wolcott-Rallisonsyndrome (WRS) [MIM:226980], also known as multiple epiphysealdysplasia with early-onset diabetes mellitus. WRS is a rareautosomal recessive disorder, characterized by permanent neonatalor early infancy insulin-dependent diabetes and, at a later age,epiphyseal dysplasia, osteoporosis, growth retardation and othermultisystem manifestations, such as hepatic and renaldysfunctions, mental retardation and cardiovascular abnormalities.

Defects in SLC1A3 are the cause of episodic ataxia type 6(EA6) [MIM:612656]. EA6 is characterized by episodic ataxia,seizures, migraine and alternating hemiplegia.

Defects in EBP are the cause of chondrodysplasia punctataX-linked dominant type 2 (CDPX2) [MIM:302960], also known asConradi-Hunermann-Happle syndrome. CDP is a clinically andgenetically heterogeneous disorder characterized by punctiformcalcification of the bones. The key clinical features of CDPX2 arechondrodysplasia punctata, linear ichthyosis, cataracts and shortstature. CDPX2 is a rare disorder of defective cholesterolbiosynthesis, biochemically characterized by an increased amountof 8-dehydrocholesterol and cholest-8(9)-en-3-beta-ol in theplasma and tissues.

Defects in ECE1 are a cause of Hirschsprung disease,cardiac defects and autonomic dysfunction (HSCRCDAD) [MIM:600423].It is a form of Hirschsprung disease with skip-lesions defects,craniofacial abnormalities and other dysmorphic features, andautonomic dysfunction.

Defects in HADHA are a cause of trifunctional proteindeficiency (TFP deficiency) [MIM:609015]. The clinicalmanifestations are very variable and include hypoglycemia,cardiomyopathy and sudden death. Phenotypes with mainly hepaticand neuromyopathic involvement can also be distinguished.Biochemically, TFP deficiency is defined by the loss of all enzymeactivities of the TFP complex.

Defects in HADHA are the cause of long-chain 3-hydroxyl-CoA dehydrogenase deficiency (LCHAD deficiency) [MIM:609016]. Theclinical features are very similar to TFP deficiency.Biochemically, LCHAD deficiency is characterized by reduced long-chain 3-hydroxyl-CoA dehydrogenase activity, while the otherenzyme activities of the TFP complex are normal or only slightlyreduced.

Defects in HADHA are a cause of maternal acute fattyliver of pregnancy (AFLP) [MIM:609016]. AFLP is a severe maternalillness occurring during pregnancies with affected fetuses. Thisdisease is associated with LCHAD deficiency and characterized bysudden unexplained infant death or hypoglycemia and abnormal liverenzymes (Reye-like syndrome).

Defects in HADHB are a cause of trifunctional proteindeficiency (TFP deficiency) [MIM:609015]. The clinicalmanifestations are very variable and include hypoglycemia,cardiomyopathy and sudden death. Phenotypes with mainly hepaticand neuromyopathic involvement can also be distinguished.Biochemically, TFP deficiency is defined by the loss of all threeenzyme activities of the TFP complex.

Defects in ECM1 are the cause of lipoid proteinosis (LiP)[MIM:247100], also known as lipoid proteinosis of Urbach andWiethe or hyalinosis cutis et mucosae. LiP is a rare autosomalrecessive disorder characterized by generalized thickening ofskin, mucosae and certain viscera. Classical features includebeaded eyelid papules and laryngeal infiltration leading tohoarseness. Histologically, there is widespread deposition ofhyaline material and disruption/reduplication of basementmembrane.

Defects in EDARADD are a cause of ectodermal dysplasiaanhidrotic (EDA) [MIM:224900], also known ectodermal dysplasiahypohidrotic autosomal recessive (HED). Ectodermal dysplasiadefines a heterogeneous group of disorders due to abnormaldevelopment of two or more ectodermal structures. EDA ischaracterized by sparse hair (atrichosis or hypotrichosis),abnormal or missing teeth and the inability to sweat due to theabsence of sweat glands.

Defects in EDAR are a cause of ectodermal dysplasiaanhidrotic (EDA) [MIM:224900], also known ectodermal dysplasiahypohidrotic autosomal recessive (HED). Ectodermal dysplasiadefines a heterogeneous group of disorders due to abnormaldevelopment of two or more ectodermal structures. EDA ischaracterized by sparse hair (atrichosis or hypotrichosis),abnormal or missing teeth and the inability to sweat due to theabsence of sweat glands.

Defects in EDAR are the cause of ectodermal dysplasiatype 3 (ED3) [MIM:129490], also known as ectodermal dysplasiahypohidrotic autosomal dominant or EDA3. ED3 is an autosomaldominant condition characterized by hypotrichosis, abnormal ormissing teeth, and hypohidrosis due to the absence of sweatglands.

Defects in EDA are the cause of ectodermal dysplasia type1 (ED1) [MIM:305100], also known as Christ-Siemens-Tourainesyndrome or X-linked hypohidrotic ectodermal dysplasia (XLHED).Ectodermal dysplasia defines a heterogeneous group of disordersdue to abnormal development of two or more ectodermal structures.ED1 is a disease characterized by sparse hair (atrichosis orhypotrichosis), abnormal or missing teeth and the inability tosweat due to the absence of sweat glands. ED1 is the most commonform of over 150 clinically distinct ectodermal dysplasias.

Defects in EDA are the cause of tooth agenesis selectiveX-linked type 1 (STHAGX1) [MIM:313500]. A form of selective toothagenesis, a common anomaly characterized by the congenital absenceof one or more teeth. Selective tooth agenesis without associatedsystemic disorders has sometimes been divided into 2 types:oligodontia, defined as agenesis of 6 or more permanent teeth, andhypodontia, defined as agenesis of less than 6 teeth. The numberin both cases does not include absence of third molars (wisdomteeth).

Defects in EDN3 are the cause of Hirschsprung diseasetype 4 (HSCR4) [MIM:613712], also known as aganglionic megacolon(MGC). A genetic disorder of neural crest developmentcharacterized by the absence of intramural ganglion cells in thehindgut, often resulting in intestinal obstruction.

Defects in EDN3 are a cause of congenital centralhypoventilation syndrome (CCHS) [MIM:209880], also known ascongenital failure of autonomic control or Ondine curse. CCHS is arare disorder characterized by abnormal control of respiration inthe absence of neuromuscular or lung disease, or an identifiablebrain stem lesion. A deficiency in autonomic control ofrespiration results in inadequate or negligible ventilatory andarousal responses to hypercapnia and hypoxemia.

Defects in EDN3 are a cause of Waardenburg syndrome type4 (WS4B) [MIM:613265], also known as Waardenburg-Shah syndrome.WS4B is characterized by the association of Waardenburg features(depigmentation and deafness) and the absence of enteric gangliain the distal part of the intestine (Hirschsprung disease).

Defects in EDNRB are a cause of Waardenburg syndrome type4A (WS4A) [MIM:277580], also known as Waardenburg-Shah syndrome.WS4A is characterized by the association of Waardenburg features(depigmentation and deafness) and the absence of enteric gangliain the distal part of the intestine (Hirschsprung disease).

Defects in EDNRB are the cause of Hirschsprung diseasetype 2 (HSCR2) [MIM:600155], also known as aganglionic megacolon(MGC). HSCR2 is a congenital disorder characterized by absence ofenteric ganglia along a variable length of the intestine. It isthe most common cause of congenital intestinal obstruction. Earlysymptoms range from complete acute neonatal obstruction,characterized by vomiting, abdominal distention and failure topass stool, to chronic constipation in the older child.

Defects in EDNRB are the cause of ABCD syndrome (ABCDS)[MIM:600501]. ABCD syndrome is an autosomal recessive syndromecharacterized by albinism, black lock at temporal occipitalregion, bilateral deafness, aganglionosis of the large intestineand total absence of neurocytes and nerve fibers in the smallintestine.

Defects in GFM1 are the cause of combined oxidativephosphorylation deficiency type 1 (COXPD1) [MIM:609060]. It leadsto early fatal progressive hepatoencephalopathy.

Defects in EFHC1 are the cause of juvenile myoclonicepilepsy type 1 (EJM1) [MIM:254770]. EJM1 is a subtype ofidiopathic generalized epilepsy (IGE). Patients have afebrileseizures only, with onset in adolescence (rather than inchildhood) and myoclonic jerks which usually occur after awakeningand are triggered by sleep deprivation and fatigue.

Genetic variations in EFHC1 are the cause ofsusceptibility to juvenile absence epilepsy type 1 (JAE1)[MIM:607631]. JAE is a subtype of idiopathic generalized epilepsycharacterized by onset occurring around puberty, absence seizures,generalized tonic-clonic seizures (GTCS), GTCS on awakening, andmyoclonic seizures.

Defects in EFNB1 are a cause of craniofrontonasalsyndrome (CFNS) [MIM:304110], also known as craniofrontonasaldysplasia (CFND). CFNS is an X-linked inherited syndromecharacterized by hypertelorism, coronal synostosis withbrachycephaly, downslanting palpebral fissures, clefting of thenasal tip, joint anomalies, longitudinally grooved fingernails andother digital anomalies.

Defects in TSFM are the cause of combined oxidativephosphorylation deficiency type 3 (COXPD3) [MIM:610505]. Defectsin the mitochondrial oxidative phosphorylation system result indevastating, mainly multisystem, diseases. COXPD3 symptoms includesevere metabolic acidosis with encephalomyopathy or withhypertrophic cardiomyopathy. Patients show a severe defect inmitochondrial translation leading to a failure to assembleadequate amounts of three of the oxidative phosphorylationcomplexes.

Defects in TUFM are the cause of combined oxidativephosphorylation deficiency type 4 (COXPD4) [MIM:610678]. COXPD4 ischaracterized by neonatal lactic acidosis, rapidly progressiveencephalopathy, severely decreased mitochondrial proteinsynthesis, and combined deficiency of mtDNA-related mitochondrialrespiratory chain complexes.

Defects in EGFR are associated with lung cancer (LNCR)[MIM:211980].

Defects in EGF are the cause of hypomagnesemia type 4(HOMG4) [MIM:611718], also known as renal hypomagnesemianormocalciuric. HOMG4 is a disorder characterized by massive renalhypomagnesemia and normal levels of serum calcium and calciumexcretion. Clinical features include seizures, mild-to mederatepsychomotor retardation, and brisk tendon reflexes.

Defects in EGLN1 are the cause of erythrocytosis familialtype 3 (ECYT3) [MIM:609820]. ECYT3 is an autosomal dominantdisorder characterized by increased serum red blood cell mass,elevated serum hemoglobin and hematocrit, and normal serumerythropoietin levels.

Defects in ENG are the cause of hereditary hemorrhagictelangiectasia type 1 (HHT1) [MIM:187300, 108010], also known asOsler-Rendu-Weber syndrome 1 (ORW1). HHT1 is an autosomal dominantmultisystemic vascular dysplasia, characterized by recurrentepistaxis, muco-cutaneous telangiectases, gastro-intestinalhemorrhage, and pulmonary (PAVM), cerebral (CAVM) and hepaticarteriovenous malformations, all secondary manifestations of theunderlying vascular dysplasia. Although the first symptom of HHT1in children is generally nose bleed, there is an importantclinical heterogeneity.

Defects in EGR2 are a cause of congenital hypomyelinationneuropathy (CHN) [MIM:605253]. Inheritance can be autosomaldominant or recessive. Recessive CHN is also known as Charcot-Marie-Tooth disease type 4E (CMT4E). CHN is characterizedclinically by early onset of hypotonia, areflexia, distal muscleweakness, and very slow nerve conduction velocities.

Defects in EGR2 are a cause of Charcot-Marie-Toothdisease type 1D (CMT1D) [MIM:607678]. CMT1D is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of theperipheral nervous system. Charcot-Marie-Tooth disease isclassified in two main groups on the basis of electrophysiologicproperties and histopathology: primary peripheral demyelinatingneuropathy or CMT1, and primary peripheral axonal neuropathy orCMT2. Neuropathies of the CMT1 group are characterized by severelyreduced nerve conduction velocities (less than 38 m/sec),segmental demyelination and remyelination with onion bulbformations on nerve biopsy, slowly progressive distal muscleatrophy and weakness, absent deep tendon reflexes, and hollowfeet.

Defects in EGR2 are a cause of Dejerine-Sottas syndrome(DSS) [MIM:145900], also known as Dejerine-Sottas neuropathy (DSN)or hereditary motor and sensory neuropathy III (HMSN3). DSS is asevere degenerating neuropathy of the demyelinating Charcot-Marie-Tooth disease category, with onset by age 2 years. DSS ischaracterized by motor and sensory neuropathy with very slow nerveconduction velocities, increased cerebrospinal fluid proteinconcentrations, hypertrophic nerve changes, delayed age of walkingas well as areflexia. There are both autosomal dominant andautosomal recessive forms of Dejerine-Sottas syndrome.

Defects in EHBP1 are a cause of susceptibility toprostate cancer hereditary type 12 (HPC12) [MIM:611868]. It is acondition associated with familial predisposition to cancer of theprostate. Most prostate cancers are adenocarcinomas that developin the acini of the prostatic ducts. Other rare histopathologictypes of prostate cancer that occur in approximately 5% ofpatients include small cell carcinoma, mucinous carcinoma,prostatic ductal carcinoma, transitional cell carcinoma, squamouscell carcinoma, basal cell carcinoma, adenoid cystic carcinoma(basaloid), signet-ring cell carcinoma and neuroendocrinecarcinoma.

Defects in EHMT1 are the cause of chromosome 9qsubtelomeric deletion syndrome (9q- syndrome) [MIM:610253]. Commonfeatures seen in these patients are severe mental retardation,hypotonia, brachy(micro)cephaly, epileptic seizures, flat facewith hypertelorism, synophrys, anteverted nares, cupid bow ortented upper lip, everted lower lip, prognathism, macroglossia,conotruncal heart defects, and behavioral problems.

Defects in EIF2B1 are a cause of leukodystrophy withvanishing white matter (VWM) [MIM:603896]. VWM is a leukodystrophythat occurs mainly in children. Neurological signs includeprogressive cerebellar ataxia, spasticity, inconstant opticatrophy and relatively preserved mental abilities. The disease ischronic-progressive with, in most individuals, additional episodesof rapid deterioration following febrile infections or minor headtrauma. While childhood onset is the most common form of thedisorder, some severe forms are apparent at birth. A severe,early-onset form seen among the Cree and Chippewayan populationsof Quebec and Manitoba is called Cree leukoencephalopathy. Milderforms may not become evident until adolescence or adulthood. Somefemales with milder forms of the disease who survive toadolescence exhibit ovarian dysfunction. This variant of thedisorder is called ovarioleukodystrophy.

Defects in EIF2B2 are a cause of leukodystrophy withvanishing white matter (VWM) [MIM:603896]. VWM is a leukodystrophythat occurs mainly in children. Neurological signs includeprogressive cerebellar ataxia, spasticity, inconstant opticatrophy and relatively preserved mental abilities. The disease ischronic-progressive with, in most individuals, additional episodesof rapid deterioration following febrile infections or minor headtrauma. While childhood onset is the most common form of thedisorder, some severe forms are apparent at birth. A severe,early-onset form seen among the Cree and Chippewayan populationsof Quebec and Manitoba is called Cree leukoencephalopathy. Milderforms may not become evident until adolescence or adulthood. Somefemales with milder forms of the disease who survive toadolescence exhibit ovarian dysfunction. This variant of thedisorder is called ovarioleukodystrophy.

Defects in EIF2B4 are a cause of leukodystrophy withvanishing white matter (VWM) [MIM:603896]. VWM is a leukodystrophythat occurs mainly in children. Neurological signs includeprogressive cerebellar ataxia, spasticity, inconstant opticatrophy and relatively preserved mental abilities. The disease ischronic-progressive with, in most individuals, additional episodesof rapid deterioration following febrile infections or minor headtrauma. While childhood onset is the most common form of thedisorder, some severe forms are apparent at birth. A severe,early-onset form seen among the Cree and Chippewayan populationsof Quebec and Manitoba is called Cree leukoencephalopathy. Milderforms may not become evident until adolescence or adulthood. Somefemales with milder forms of the disease who survive toadolescence exhibit ovarian dysfunction. This variant of thedisorder is called ovarioleukodystrophy.

Defects in EIF2B5 are a cause of leukodystrophy withvanishing white matter (VWM) [MIM:603896]. VWM is a leukodystrophythat occurs mainly in children. Neurological signs includeprogressive cerebellar ataxia, spasticity, inconstant opticatrophy and relatively preserved mental abilities. The disease ischronic-progressive with, in most individuals, additional episodesof rapid deterioration following febrile infections or minor headtrauma. While childhood onset is the most common form of thedisorder, some severe forms are apparent at birth. A severe,early-onset form seen among the Cree and Chippewayan populationsof Quebec and Manitoba is called Cree leukoencephalopathy. Milderforms may not become evident until adolescence or adulthood. Somefemales with milder forms of the disease who survive toadolescence exhibit ovarian dysfunction. This variant of thedisorder is called ovarioleukodystrophy.

Defects in EIF2B3 are a cause of leukodystrophy withvanishing white matter (VWM) [MIM:603896]. VWM is a leukodystrophythat occurs mainly in children. Neurological signs includeprogressive cerebellar ataxia, spasticity, inconstant opticatrophy and relatively preserved mental abilities. The disease ischronic-progressive with, in most individuals, additional episodesof rapid deterioration following febrile infections or minor headtrauma. While childhood onset is the most common form of thedisorder, some severe forms are apparent at birth. A severe,early-onset form seen among the Cree and Chippewayan populationsof Quebec and Manitoba is called Cree leukoencephalopathy. Milderforms may not become evident until adolescence or adulthood. Somefemales with milder forms of the disease who survive toadolescence exhibit ovarian dysfunction. This variant of thedisorder is called ovarioleukodystrophy.

A chromosomal aberration involving ELF4 is a cause ofacute myeloid leukemia (AML). Translocation t(X,21)(q25-26,q22)with ERG.

Note=A chromosomal aberration involving ELL is found inacute leukemias. Translocation t(11,19)(q23,p13.1) with MLL/HRX.The result is a rogue activator protein.

Defects in ELANE are a cause of cyclic haematopoiesis(CH) [MIM:162800], also known as cyclic neutropenia. CH is anautosomal dominant disease in which blood-cell production from thebone marrow oscillates with 21-day periodicity. Circulatingneutrophils vary between almost normal numbers and zero. Duringintervals of neutropenia, affected individuals are at risk foropportunistic infection. Monocytes, platelets, lymphocytes andreticulocytes also cycle with the same frequency.

Defects in ELANE are the cause of neutropenia severecongenital autosomal dominant type 1 (SCN1) [MIM:202700]. SCN1 isa disorder of hematopoiesis characterized by a maturation arrestof granulopoiesis at the level of promyelocytes with peripheralblood absolute neutrophil counts below 0.5 x 10(9)/l and earlyonset of severe bacterial infections.

Defects in ELN are a cause of autosomal dominant cutislaxa (ADCL) [MIM:123700]. Cutis laxa is a rare connective tissuedisorder characterized by loose, hyperextensible skin withdecreased resilience and elasticity leading to a premature agedappearance. The skin changes are often accompanied byextracutaneous manifestations, including pulmonary emphysema,bladder diverticula, pulmonary artery stenosis and pyloricstenosis.

Defects in ELN are the cause of supravalvular aorticstenosis (SVAS) [MIM:185500]. SVAS is a congenital narrowing ofthe ascending aorta which can occur sporadically, as an autosomaldominant condition, or as one component of Williams-Beurensyndrome.

Note=ELN is located in the Williams-Beuren syndrome (WBS)critical region. WBS results from a hemizygous deletion of severalgenes on chromosome 7q11.23, thought to arise as a consequence ofunequal crossing over between highly homologous low-copy repeatsequences flanking the deleted region. Haploinsufficiency of ELNmay be the cause of certain cardiovascular and musculo-skeletalabnormalities observed in the disease.

Defects in ELOVL4 are the cause of Stargardt disease type3 (STGD3) [MIM:600110]. STGD is one of the most frequent causes ofmacular degeneration in childhood. It is characterized by maculardystrophy with juvenile-onset, rapidly progressive course,alterations of the peripheral retina, and subretinal deposition oflipofuscin-like material. STGD3 inheritance is autosomal dominant.

Defects in IKBKAP are the cause of hereditary sensory andautonomic neuropathy type 3 (HSAN3) [MIM:223900], also known asRiley-Day syndrome or familial dysautonomia (FD). This autosomalrecessive disorder is due to the poor development and survival,and progressive degeneration of the sensory, sympathetic andparasympathetic neurons. HSAN3 individuals are affected with avariety of symptoms such as decreased sensitivity to pain andtemperature, cardiovascular instability, recurrent pneumonias,vomiting crises, and gastrointestinal dysfunction. It is primarilyconfined to individuals of Ashkenazi Jewish descent, with anincidence of 1/3'600 live births.

Defects in EMD are the cause of Emery-Dreifuss musculardystrophy type 1 (EDMD1) [MIM:310300]. A degenerative myopathycharacterized by weakness and atrophy of muscle withoutinvolvement of the nervous system, early contractures of theelbows Achilles tendons and spine, and cardiomyopathy associatedwith cardiac conduction defects.

Defects in EMX2 are the cause of schizencephaly (SCHZC)[MIM:269160]. Schizencephaly is an extremely rare human congenitaldisorder characterized by a full-thickness cleft within thecerebral hemispheres. These clefts are lined with gray matter andmost commonly involve the parasylvian regions. Large portions ofthe cerebral hemispheres may be absent and replaced by cerebro-spinal fluid.

Defects in ENAM are the cause of amelogenesis imperfectahypoplastic type 1B (AI1B) [MIM:104500]. AI1B is an autosomaldominant defect of enamel formation. Clinical manifestations maybe variable. Some cases present with generalized enamel hypoplasiaresulting in small, smooth, yellow and spaced teeth (smoothhypoplastic AI). Others show horizontal rows of pits, grooves or ahypoplastic area in the enamel (local hypoplastic AI).

Defects in ENAM are the cause of amelogenesis imperfectatype 1C (AI1C) [MIM:204650], also known as amelogenesis imperfectahypoplastic with or without openbite malocclusion. AI1C is anautosomal recessive defect of dental enamel formation. Teeth showhypoplastic and unmineralized enamel, and a yellow-browndiscoloration. Enamel defects can be associated with facial andoral features including vertical dysgnathia and anterior openbitemalocclusion.

Note=A chromosomal aberration involving MLLT1 isassociated with acute leukemias. Translocation t(11,19)(q23,p13.3)with MLL/HRX. The result is a rogue activator protein.

Defects in ENO3 are the cause of glycogen storage diseasetype 13 (GSD13) [MIM:612932]. A metabolic disorder that results inexercise-induced myalgias, generalized muscle weakness andfatigability. It is characterized by increased serum creatinekinase and decreased enolase 3 activity. Dramatically reducedprotein levels with focal sarcoplasmic accumulation of glycogen-beta particles are detected on ultrastructural analysis.

Defects in ENPP1 are a cause of increased susceptibilityfor ossification of the posterior longitudinal ligament of thespine (OPLL) [MIM:602475]. OPLL is a common form of humanmyelopathy with a prevalence of as much as 4% in a variety ofethnic groups.

Defects in ENPP1 are a cause of idiopathic infantilearterial calcification (IIAC) [MIM:208000], also known asgeneralized arterial calcification of infancy. IIAC ischaracterized by calcification of the internal elastic lamina ofmuscular arteries and stenosis due to myointimal proliferation.

Defects in ENPP1 are associated with obesity, glucoseintolerance, and type II diabetes non-insulin dependent (NIDDM)[MIM:125853].

Defects in ENPP1 are the cause of ricketshypophosphatemic autosomal recessive type 2 (ARHR2) [MIM:613312].ARHR2 is a hereditary form of hypophosphatemic rickets, a disorderof proximal renal tubule function that causes phosphate loss,hypophosphatemia and skeletal deformities, including rickets andosteomalacia unresponsive to vitamin D. Symptoms are bone pain,fractures and growth abnormalities.

Defects in TMPRSS15 are a cause of enterokinasedeficiency (ENTKD) [MIM:226200], a life-threatening intestinalmalabsorption disorder characterized by diarrhea and failure tothrive.

Note=A translocation t(3,10)(p24,q23) located 215 kb 3'to the EOMES gene but leading to loss of its expression wasidentified in a large consanguineous family. Homozygous silencingproduces microcephaly associated with corpus callosum agenesis,bilateral polymicrogyria, ventricular dilatation and a smallcerebellum.

Note=Defects in EP300 may play a role in epithelialcancer.

Note=Chromosomal aberrations involving EP300 may be acause of acute myeloid leukemias. Translocation t(8,22)(p11,q13)with MYST3.

Defects in EP300 are the cause of Rubinstein-Taybisyndrome type 2 (RSTS2) [MIM:613684]. A disorder characterized bycraniofacial abnormalities, postnatal growth deficiency, broadthumbs, broad big toes, mental retardation and a propensity fordevelopment of malignancies. Some individuals with RSTS2 have lesssevere mental impairment, more severe microcephaly, and a greaterdegree of changes in facial bone structure than RSTS1 patients.

Defects in EPAS1 are the cause of erythrocytosis familialtype 4 (ECYT4) [MIM:611783]. ECYT4 is an autosomal dominantdisorder characterized by increased serum red blood cell mass,elevated hemoglobin concentration and hematocrit, and normalplatelet and leukocyte counts.

Defects in EPB42 are the cause of spherocytosis type 5(SPH5) [MIM:612690], also known as hereditary spherocytosis type 5(HS5). Spherocytosis is a hematologic disorder leading to chronichemolytic anemia and characterized by numerous abnormally shapederythrocytes which are generally spheroidal. Absence of band 4.2associated with spur or target erythrocytes has also beenreported.

Defects in EPCAM are the cause of diarrhea type 5 (DIAR5)[MIM:613217]. It is an intractable diarrhea of infancycharacterized by villous atrophy and absence of inflammation, withintestinal epithelial cell dysplasia manifesting as focalepithelial tufts in the duodenum and jejunum.

Defects in EPCAM are a cause of hereditary non-polyposiscolorectal cancer type 8 (HNPCC8) [MIM:613244]. HNPCC is a diseaseassociated with marked increase in cancer susceptibility. It ischaracterized by a familial predisposition to early-onsetcolorectal carcinoma (CRC) and extra-colonic tumors of thegastrointestinal, urological and female reproductive tracts. HNPCCis reported to be the most common form of inherited colorectalcancer in the Western world. Clinically, HNPCC is often dividedinto two subgroups. Type I is characterized by hereditarypredisposition to colorectal cancer, a young age of onset, andcarcinoma observed in the proximal colon. Type II is characterizedby increased risk for cancers in certain tissues such as theuterus, ovary, breast, stomach, small intestine, skin, and larynxin addition to the colon. Diagnosis of classical HNPCC is based onthe Amsterdam criteria: 3 or more relatives affected by colorectalcancer, one a first degree relative of the other two, 2 or moregeneration affected, 1 or more colorectal cancers presentingbefore 50 years of age, exclusion of hereditary polyposissyndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can beused to describe families who do not or only partially fulfill theAmsterdam criteria, but in whom a genetic basis for colon canceris strongly suspected. Note=HNPCC8 results from heterozygousdeletion of 3-prime exons of EPCAM and intergenic regions directlyupstream of MSH2, resulting in transcriptional read-through andepigenetic silencing of MSH2 in tissues expressing EPCAM.

Genetic variations in EPHA2 are the cause ofsusceptibility to cataract cortical age-related type 2 (ARCC2)[MIM:613020]. A developmental punctate opacity common in thecortex and present in most lenses. The cataract is white orcerulean, increases in number with age, but rarely affects vision.

Defects in EPHA2 are the cause of cataract posteriorpolar type 1 (CTPP1) [MIM:116600]. A subcapsular opacity, usuallydisk-shaped, located at the back of the lens. It can have a markedeffect on visual acuity.

Note=Overexpressed in several cancer types and promotesmalignancy.

Defects in EPHA3 may be a cause of colorectal cancer(CRC) [MIM:114500].

Defects in EPHB2 may be a cause of susceptibility toprostate cancer (PC) [MIM:176807]. It is a malignancy originatingin tissues of the prostate. Most prostate cancers areadenocarcinomas that develop in the acini of the prostatic ducts.Other rare histopathologic types of prostate cancer that occur inapproximately 5% of patients include small cell carcinoma,mucinous carcinoma, prostatic ductal carcinoma, transitional cellcarcinoma, squamous cell carcinoma, basal cell carcinoma, adenoidcystic carcinoma (basaloid), signet-ring cell carcinoma andneuroendocrine carcinoma. Note=EPHB2 mutations have been found ina prostate cancer cell line derived from a brain metastasis.

Defects in EPM2A are a cause of progressive myoclonicepilepsy type 2 (EPM2) [MIM:254780], also known as Lafora disease.EPM2 is an autosomal recessive and severe form of adolescent-onsetprogressive epilepsy. Typically, as seizures increase infrequency, cognitive function declines towards dementia, andaffected individuals die usually within 10 years after onset. EPM2occurs worldwide, but it is particularly common in themediterranean countries of southern Europe and northern Africa, insouthern India and in the Middle East. At the cellular level, itis characterized by accumulation of starch-like polyglucosanscalled Lafora bodies (LBs) that are most abundant in organs withthe highest glucose metabolism: brain, heart, liver and skeletalmuscle. Among other conditions involving polyglucosans, EPM2 isunique in that the inclusions are in neuronal dendrites but notaxons and the forming polyglucosan fibrils are associated with theendoplasmic reticulum.

Defects in EPOR are the cause of erythrocytosis familialtype 1 (ECYT1) [MIM:133100]. ECYT1 is an autosomal dominantdisorder characterized by increased serum red blood cell mass,elevated hemoglobin and hematocrit, hypersensitivity of erythroidprogenitors to erythropoietin, erythropoietin low serum levels,and no increase in platelets nor leukocytes. It has a relativelybenign course and does not progress to leukemia.

Genetic variation in EPO is associated with susceptbilityto microvascular complications of diabetes type 2 (MVCD2)[MIM:612623]. These are pathological conditions that develop innumerous tissues and organs as a consequence of diabetes mellitus.They include diabetic retinopathy, diabetic nephropathy leading toend-stage renal disease, and diabetic neuropathy. Diabeticretinopathy remains the major cause of new-onset blindness amongdiabetic adults. It is characterized by vascular permeability andincreased tissue ischemia and angiogenesis.

Note=A chromosomal aberration involving EPS15 is found inacute leukemias. Translocation t(1,11)(p32,q23) with MLL/HRX. Theresult is a rogue activator protein.

Defects in ERBB2 are associated with gastric cancer[MIM:137215], also known as hereditary familial diffuse gastriccancer (HDGC).

Defects in ERBB2 are involved in the development ofglioma (GLM) [MIM:137800]. Gliomas are central nervous systemneoplasms derived from glial cells and comprise astrocytomas,glioblastoma multiforme, oligodendrogliomas, and ependymomas.

Defects in ERBB2 are a cause of susceptibility to ovariancancer (OC) [MIM:167000]. Ovarian cancer common malignancyoriginating from ovarian tissue. Although many histologic types ofovarian neoplasms have been described, epithelial ovariancarcinoma is the most common form. Ovarian cancers are oftenasymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients arediagnosed with advanced disease.

Defects in ERBB2 may be a cause of lung cancer (LNCR)[MIM:211980].

Defects in ERBB2 are a cause of gastric cancer (GASC)[MIM:613659]. A malignant disease which starts in the stomach, canspread to the esophagus or the small intestine, and can extendthrough the stomach wall to nearby lymph nodes and organs. It alsocan metastasize to other parts of the body. The term gastriccancer or gastric carcinoma refers to adenocarcinoma of thestomach that accounts for most of all gastric malignant tumors.Two main histologic types are recognized, diffuse type andintestinal type carcinomas. Diffuse tumors are poorlydifferentiated infiltrating lesions resulting in thickening of thestomach. In contrast, intestinal tumors are usually exophytic,often ulcerating, and associated with intestinal metaplasia of thestomach, most often observed in sporadic disease.

Note=Chromosomal aberrations involving ERBB2 may be acause gastric cancer. Deletions within 17q12 region producingfusion transcripts with CDK12, leading to CDK12-ERBB2 fusionleading to trunctated CDK12 protein not in-frame with ERBB2.

Defects in ERBB3 are the cause of lethal congenitalcontracture syndrome type 2 (LCCS2) [MIM:607598], also calledIsraeli Bedouin multiple contracture syndrome type A. LCCS2 is anautosomal recessive neurogenic form of a neonatally lethalarthrogryposis that is associated with atrophy of the anteriorhorn of the spinal cord. The LCCS2 syndrome is characterized bymultiple joint contractures, anterior horn atrophy in the spinalcord, and a unique feature of a markedly distended urinarybladder. The phenotype suggests a spinal cord neuropathicetiology.

Defects in ERCC1 are the cause of cerebro-oculo-facio-skeletal syndrome type 4 (COFS4) [MIM:610758]. COFS is adegenerative autosomal recessive disorder of prenatal onsetaffecting the brain, eye and spinal cord. After birth, it leads tobrain atrophy, hypoplasia of the corpus callosum, hypotonia,cataracts, microcornea, optic atrophy, progressive jointcontractures and growth failure. Facial dysmorphism is a constantfeature. Abnormalities of the skull, eyes, limbs, heart and kidneyalso occur.

Defects in ERCC2 are the cause of xeroderma pigmentosumcomplementation group D (XP-D) [MIM:278730], also known as XPgroup D (XPD). Xeroderma pigmentosum is an autosomal recessivepigmentary skin disorder characterized by solar hypersensitivityof the skin, high predisposition for developing cancers on areasexposed to sunlight and, in some cases, neurologicalabnormalities. Some XP-D patients present features of Cockaynesyndrome, including dwarfism, sensorineural deafness,microcephaly, mental retardation, pigmentary retinopathy, ataxia,decreased nerve conduction velocities.

Defects in ERCC2 are a cause of trichothiodystrophyphotosensitive (TTDP) [MIM:601675]. TTDP is an autosomal recessivedisease characterized by sulfur-deficient brittle hair and nails,ichthyosis, mental retardation, impaired sexual development,abnormal facies and cutaneous photosensitivity correlated with anucleotide excision repair (NER) defect. Neonates withtrichothiodystrophy and ichthyosis are usually born with acollodion membrane. The severity of the ichthyosis after themembrane is shed is variable, ranging from a mild to severelamellar ichthyotic phenotype. There are no reports of skin cancerassociated with TTDP.

Defects in ERCC2 are the cause of cerebro-oculo-facio-skeletal syndrome type 2 (COFS2) [MIM:610756]. COFS is adegenerative autosomal recessive disorder of prenatal onsetaffecting the brain, eye and spinal cord. After birth, it leads tobrain atrophy, hypoplasia of the corpus callosum, hypotonia,cataracts, microcornea, optic atrophy, progressive jointcontractures and growth failure. Facial dysmorphism is a constantfeature. Abnormalities of the skull, eyes, limbs, heart and kidneyalso occur.

Defects in ERCC3 are the cause of xeroderma pigmentosumcomplementation group B (XP-B) [MIM:610651], also known asxeroderma pigmentosum II (XP2) or XP group B (XPB) or xerodermapigmentosum group B combined with Cockayne syndrome (XP-B/CS).Xeroderma pigmentosum is an autosomal recessive pigmentary skindisorder characterized by solar hypersensitivity of the skin, highpredisposition for developing cancers on areas exposed to sunlightand, in some cases, neurological abnormalities. Some XP-B patientspresent features of Cockayne syndrome, including dwarfism,sensorineural deafness, microcephaly, mental retardation,pigmentary retinopathy, ataxia, decreased nerve conductionvelocities.

Defects in ERCC3 are a cause of trichothiodystrophyphotosensitive (TTDP) [MIM:601675]. TTDP is an autosomal recessivedisease characterized by sulfur-deficient brittle hair and nails,ichthyosis, mental retardation, impaired sexual development,abnormal facies and cutaneous photosensitivity correlated with anucleotide excision repair (NER) defect. Neonates withtrichothiodystrophy and ichthyosis are usually born with acollodion membrane. The severity of the ichthyosis after themembrane is shed is variable, ranging from a mild to severelamellar ichthyotic phenotype. There are no reports of skin cancerassociated with TTDP.

Defects in ERCC5 are the cause of xeroderma pigmentosumcomplementation group G (XP-G) [MIM:278780], also known asxeroderma pigmentosum VII (XP7). Xeroderma pigmentosum is anautosomal recessive pigmentary skin disorder characterized bysolar hypersensitivity of the skin, high predisposition fordeveloping cancers on areas exposed to sunlight and, in somecases, neurological abnormalities. Some XP-G patients presentfeatures of Cockayne syndrome, including dwarfism, sensorineuraldeafness, microcephaly, mental retardation, pigmentaryretinopathy, ataxia, decreased nerve conduction velocities.

Defects in ERCC6 are the cause of Cockayne syndrome typeB (CSB) [MIM:133540]. Cockayne syndrome is a rare disordercharacterized by cutaneous sensitivity to sunlight, abnormal andslow growth, cachectic dwarfism, progeroid appearance, progressivepigmentary retinopathy and sensorineural deafness. There isdelayed neural development and severe progressive neurologicdegeneration resulting in mental retardation. Two clinical formsare recognized: in the classical form or Cockayne syndrome type 1,the symptoms are progressive and typically become apparent withinthe first few years or life, the less common Cockayne syndrometype 2 is characterized by more severe symptoms that manifestprenatally. Cockayne syndrome shows some overlap with certainforms of xeroderma pigmentosum. Unlike xeroderma pigmentosum,patients with Cockayne syndrome do not manifest increasedfreckling and other pigmentation abnormalities in the skin andhave no significant increase in skin cancer.

Defects in ERCC6 are the cause of cerebro-oculo-facio-skeletal syndrome type 1 (COFS1) [MIM:214150], also known as COFSsyndrome or Pena-Shokeir syndrome type 2. COFS is a degenerativeautosomal recessive disorder of prenatal onset affecting thebrain, eye and spinal cord. After birth, it leads to brainatrophy, hypoplasia of the corpus callosum, hypotonia, cataracts,microcornea, optic atrophy, progressive joint contractures andgrowth failure. Facial dysmorphism is a constant feature.Abnormalities of the skull, eyes, limbs, heart and kidney alsooccur.

Defects in ERCC6 are a cause of De Sanctis-Cacchionesyndrome (DSC) [MIM:278800], also known as xerodermic idiocy. DSCis an autosomal recessive syndrome consisting of xerodermapigmentosum associated with mental retardation, retarded growth,gonadal hypoplasia and sometimes neurologic complications.

Defects in ERCC6 are the cause of susceptibility to age-related macular degeneration type 5 (ARMD5) [MIM:613761]. A formof age-related macular degeneration, a multifactorial eye diseaseand the most common cause of irreversible vision loss in thedeveloped world. In most patients, the disease is manifest asophthalmoscopically visible yellowish accumulations of protein andlipid that lie beneath the retinal pigment epithelium and withinan elastin-containing structure known as Bruch membrane.

Defects in ERCC6 are a cause of UV-sensitive syndrome(UVS) [MIM:600630]. UVS is a rare autosomal recessive disordercharacterized by photosensitivity and mild freckling but withoutneurological abnormalities or skin tumors.

Defects in ERCC8 are the cause of Cockayne syndrome typeA (CSA) [MIM:216400]. Cockayne syndrome is a rare disordercharacterized by cutaneous sensitivity to sunlight, abnormal andslow growth, cachectic dwarfism, progeroid appearance, progressivepigmentary retinopathy and sensorineural deafness. There isdelayed neural development and severe progressive neurologicdegeneration resulting in mental retardation. Two clinical formsare recognized: in the classical form or Cockayne syndrome type 1,the symptoms are progressive and typically become apparent withinthe first few years or life, the less common Cockayne syndrometype 2 is characterized by more severe symptoms that manifestprenatally. Cockayne syndrome shows some overlap with certainforms of xeroderma pigmentosum. Unlike xeroderma pigmentosum,patients with Cockayne syndrome do not manifest increasedfreckling and other pigmentation abnormalities in the skin andhave no significant increase in skin cancer.

Defects in ERG are a cause of Ewing sarcoma (ES)[MIM:612219]. A highly malignant, metastatic, primitive smallround cell tumor of bone and soft tissue that affects children andadolescents. It belongs to the Ewing sarcoma family of tumors, agroup of morphologically heterogeneous neoplasms that share thesame cytogenetic features. They are considered neural tumorsderived from cells of the neural crest. Ewing sarcoma representsthe less differentiated form of the tumors. Note=A chromosomalaberration involving ERG is found in patients with Erwing sarcoma.Translocation t(21,22)(q22,q12) with EWSR1.

A chromosomal aberration involving ERG is a cause ofacute myeloid leukemia (AML). Translocation t(16,21)(p11,q22) withFUS. Translocation t(X,21)(q25-26,q22) with ELF4.

Defects in ESRRB are the cause of deafness autosomalrecessive type 35 (DFNB35) [MIM:608565]. DFNB35 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in ESCO2 are the cause of Roberts syndrome (RBS)[MIM:268300]. RBS is a rare autosomal recessive disordercharacterized by pre- and postnatal growth retardation,microcephaly, bilateral cleft lip and palate, and mesomelicsymmetric limb reduction. Severely affected infants may bestillborn or die shortly after birth. RBS chromosomes have a lackof cohesion involving the heterochromatic C-banding regions aroundcentromeres and the distal portion of the long arm of the Ychromosome (known as premature centromere separation,heterochromatin repulsion or puffing, or RS effect).

Defects in ESCO2 are the cause of SC phocomelia syndrome(SCPS) [MIM:269000], also known as SC pseudothalidomide syndrome.SCPS has a milder phenotype than RBS, with a lesser degree ofsymmetric limb reduction and additionally includes flexioncontractures of various joints, midfacial hemangioma, hypoplasticcartilage of ears and nose, scant silvery-blond hair, and cloudycorneae. Although microcephaly is present, mental retardation maybe mild and survival into adulthood is common.

Defects in ESPN are the cause of deafness autosomalrecessive type 36 (DFNB36) [MIM:609006]. DFNB36 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information. DFNB36 is characterized by prelingual, profoundhearing loss and vestibular areflexia.

Defects in ESPN are the cause of deafness autosomaldominant without vestibular involvement (DFNAWVI) [MIM:606351].

Defects in ETFA are the cause of glutaric aciduria type2A (GA2A) [MIM:231680], also known as glutaricaciduria IIA. GA2Ais an autosomal recessively inherited disorder of fatty acid,amino acid, and choline metabolism. It is characterized bymultiple acyl-CoA dehydrogenase deficiencies resulting in largeexcretion not only of glutaric acid, but also of lactic,ethylmalonic, butyric, isobutyric, 2-methyl-butyric, andisovaleric acids.

Defects in ETFB are the cause of glutaric aciduria type2B (GA2B) [MIM:231680]. GA2B is an autosomal recessively inheriteddisorder of fatty acid, amino acid, and choline metabolism. It ischaracterized by multiple acyl-CoA dehydrogenase deficienciesresulting in large excretion not only of glutaric acid, but alsoof lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric,and isovaleric acids.

Defects in ETFDH are the cause of glutaric aciduria type2C (GA2C) [MIM:231680]. GA2C is an autosomal recessively inheriteddisorder of fatty acid, amino acid, and choline metabolism. It ischaracterized by multiple acyl-CoA dehydrogenase deficienciesresulting in large excretion not only of glutaric acid, but alsoof lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric,and isovaleric acids.

Defects in ETHE1 are a cause of ethylmalonicencephalopathy (EE) [MIM:602473]. EE is an autosomal recessivedisorder characterized by neurodevelopmental delay and regression,recurrent petechiae, acrocyanosis, diarrhea, leading to death inthe first decade of life. It is also associated with persistentlactic acidemia and ethylmalonic and methylsuccinic aciduria.

Defects in ETV1 are a cause of Ewing sarcoma (ES)[MIM:612219]. A highly malignant, metastatic, primitive smallround cell tumor of bone and soft tissue that affects children andadolescents. It belongs to the Ewing sarcoma family of tumors, agroup of morphologically heterogeneous neoplasms that share thesame cytogenetic features. They are considered neural tumorsderived from cells of the neural crest. Ewing sarcoma representsthe less differentiated form of the tumors. Note=A chromosomalaberration involving ETV1 is found in patients with Erwingsarcoma. Translocation t(7,22)(p22,q12) with EWSR1.

Note=A chromosomal aberration involving ETV6 is found ina form of chronic myelomonocytic leukemia (CMML). Translocationt(5,12)(q33,p13) with PDGFRB. It is characterized by abnormalclonal myeloid proliferation and by progression to acutemyelogenous leukemia (AML).

Note=Chromosomal aberrations involving ETV6 are found ina form of acute myeloid leukemia (AML). Translocationt(12,22)(p13,q11) with MN1, translocation t(4,12)(q12,p13) withCHIC2.

Note=Chromosomal aberrations involving ETV6 are found inchildhood acute lymphoblastic leukemia (ALL). Translocationst(12,21)(p12,q22) and t(12,21)(p13,q22) with RUNX1/AML1.

Note=A chromosomal aberration involving ETV6 is found ina form of pre-B acute myeloid leukemia. Translocationt(9,12)(p24,p13) with JAK2.

Note=A chromosomal aberration involving ETV6 is found inmyelodysplastic syndrome (MDS) with basophilia. Translocationt(5,12)(q31,p13) with ACSL6.

Note=A chromosomal aberration involving ETV6 is found inacute eosinophilic leukemia (AEL). Translocation t(5,12)(q31,p13)with ACSL6.

Note=A chromosomal aberration involving ETV6 is found inmyelodysplastic syndrome (MDS). Translocation t(1,12)(p36.1,p13)with MDS2.

Defects in ETV6 are a cause of myeloproliferativedisorder chronic with eosinophilia (MPE) [MIM:131440]. Ahematologic disorder characterized by malignant eosinophilsproliferation. Note=A chromosomal aberration involving ETV6 isfound in many instances of myeloproliferative disorder chronicwith eosinophilia. Translocation t(5,12) with PDGFRB on chromosome5 creating an ETV6-PDGFRB fusion protein.

Defects in ETV6 are a cause of acute myelogenous leukemia(AML) [MIM:601626]. AML is a malignant disease in whichhematopoietic precursors are arrested in an early stage ofdevelopment.

Note=A chromosomal aberration involving ETV6 is found inacute lymphoblastic leukemia. Translocation t(9,12)(p13,p13) withPAX5.

Defects in EVC are a cause of Ellis-van Creveld syndrome(EVC) [MIM:225500], also known as chondroectodermal dysplasia. EVCis an autosomal recessive disorder characterized by the clinicaltetrad of chondrodystrophy, polydactyly, ectodermal dysplasia andcardiac anomalies. Patients manifest short-limb dwarfism, shortribs, postaxial polydactyly and dysplastic nails and teeth.Congenital heart defects, most commonly an atrioventricular septaldefect, are observed in 60% of affected individuals.

Defects in EVC are a cause of acrofacial dysostosisWeyers type (WAD) [MIM:193530], also known as Curry-Hall syndrome.Acrofacial dysostoses are a heterogeneous group of disorderscombining limb defects with facial abnormalities. WAD is anautosomal dominant disorder characterized by dysplastic nails,postaxial polydactyly, acrofacial dysostosis, short limbs andshort stature. The phenotype is milder than Ellis-van Creveldsyndrome.

Note=A chromosomal aberration involving EVI1 is a causeof chronic myelogenous leukemia (CML). Translocationt(3,21)(q26,q22) with RUNX1/AML1.

Defects in EWSR1 are a cause of Ewing sarcoma (ES)[MIM:612219]. A highly malignant, metastatic, primitive smallround cell tumor of bone and soft tissue that affects children andadolescents. It belongs to the Ewing sarcoma family of tumors, agroup of morphologically heterogeneous neoplasms that share thesame cytogenetic features. They are considered neural tumorsderived from cells of the neural crest. Ewing sarcoma representsthe less differentiated form of the tumors. Note=Chromosomalaberrations involving EWSR1 are found in patients with Ewingsarcoma. Translocation t(11,22)(q24,q12) with FLI1, translocationt(7,22)(p22,q12) with ETV1, translocation t(21,22)(q22,q12) withERG, translocation t(9,22)(q22-31,q11-12) with NR4A3.Translocation t(2,21,22)(q23,q22,q12) that forms a EWSR1-FEVfusion protein with potential oncogenic activity.

Note=A chromosomal aberration involving EWSR1 isassociated with desmoplastic small round cell tumor (DSRCT).Translocation t(11,22)(p13,q12) with WT1.

Note=A chromosomal aberration involving EWSR1 isassociated with malignant melanoma of soft parts (MMSP).Translocation t(12,22)(q13,q12) with ATF-1. Malignant melanoma ofsoft parts, also known as soft tissue clear cell sarcoma, is arare tumor developing in tendons and aponeuroses.

Note=A chromosomal aberration involving EWSR1 isassociated with small round cell sarcoma. Translocationt(11,22)(p36.1,q12) with PATZ1.

Defects in EWSR1 may be a cause of angiomatoid fibroushistiocytoma (AFH) [MIM:612160]. A distinct variant of malignantfibrous histiocytoma that typically occurs in children andadolescents and is manifest by nodular subcutaneous growth.Characteristic microscopic features include lobulated sheets ofhistiocyte-like cells intimately associated with areas ofhemorrhage and cystic pseudovascular spaces, as well as a strikingcuffing of inflammatory cells, mimicking a lymph node metastasis.Note=Chromosomal aberrations involving EWSR1 are found in patientswith angiomatoid fibrous histiocytoma. Translocationt(12,22)(q13,q12) with ATF1 generates a chimeric EWSR1/ATF1protein. Translocation t(2,22)(q33,q12) with CREB1 generates aEWSR1/CREB1 fusion gene that is most common genetic abnormality inthis tumor type.

Note=EFPS arise due to chromosomal translocations inwhich EWSR1 is fused to a variety of cellular transcriptionfactors. EFPS are very potent transcriptional activators dependenton the EAD and a C-terminal DNA-binding domain contributed by thefusion partner. The spectrum of malignancies associated with EFPSare thought to arise via EFP-induced transcriptional deregulation,with the tumor phenotype specified by the EWSR1 fusion partner andcell type. Transcriptional repression of the transforming growthfactor beta type II receptor (TGF beta RII) is an important targetof the EWS-FLI1, EWS-ERG, or EWS-ETV1 oncogene.

Defects in EXT1 are a cause of hereditary multipleexostoses type 1 (EXT1) [MIM:133700]. EXT is a geneticallyheterogeneous bone disorder caused by genes segregating on humanchromosomes 8, 11, and 19 and designated EXT1, EXT2 and EXT3respectively. EXT is a dominantly inherited skeletal disorderprimarily affecting endochondral bone during growth. The diseaseis characterized by formation of numerous cartilage-capped, benignbone tumors (osteocartilaginous exostoses or osteochondromas) thatare often accompanied by skeletal deformities and short stature.In a small percentage of cases exostoses have exhibited malignanttransformation resulting in an osteosarcoma or chondrosarcoma.Osteochondromas development can also occur as a sporadic event.

Defects in EXT1 are the cause of multiple exostosesobserved in Langer-Giedon syndrome (LGS) [MIM:150230], also knownas trichorhinophalangeal syndrome type 2 (TRPS2). It is acontiguous gene syndrome due to deletions in chromosome 8q24.1 andresulting in the loss of functional copies of EXT1 and TRPS1.

Defects in EXT1 are a cause of chondrosarcoma (CHDSA)[MIM:215300]. It is a malignant neoplasm derived from cartilagecells. Chondrosarcomas range from slow-growing non-metastasizinglesions to highly aggressive metastasizing sarcomas.

Defects in EXT2 are a cause of hereditary multipleexostoses type 2 (EXT2) [MIM:133701]. EXT is a geneticallyheterogeneous bone disorder caused by genes segregating on humanchromosomes 8, 11, and 19 and designated EXT1, EXT2 and EXT3respectively. EXT is a dominantly inherited skeletal disorderprimarily affecting endochondral bone during growth. The diseaseis characterized by formation of numerous cartilage-capped, benignbone tumors (osteocartilaginous exostoses or osteochondromas) thatare often accompanied by skeletal deformities and short stature.In a small percentage of cases exostoses have exhibited malignanttransformation resulting in an osteosarcoma or chondrosarcoma.Osteochondromas development can also occur as a sporadic event.

Defects in EXT2 are the cause of Potocki-Shaffer syndrome(PSS) [MIM:601224]. It is a contiguous gene syndrome due toproximal deletion of chromosome 11p11.2, including EXT2 and ALX4.

Defects in EYA1 are the cause of branchiootorenalsyndrome type 1 (BOR1) [MIM:113650], also known as Melnick-Frasersyndrome. BOR is an autosomal dominant disorder manifested byvarious combinations of preauricular pits, branchial fistulae orcysts, lacrimal duct stenosis, hearing loss, structural defects ofthe outer, middle, or inner ear, and renal dysplasia. Associateddefects include asthenic habitus, long narrow facies, constrictedpalate, deep overbite, and myopia. Hearing loss may be due tomondini type cochlear defect and stapes fixation. Penetrance ofBOR syndrome is high, although expressivity can be extremelyvariable.

Defects in EYA1 are the cause of otofaciocervicalsyndrome (OFCS) [MIM:166780]. The syndrome is characterized bytrophic alterations of the facies and shoulder girdle in additionto the malformations seen in BOR.

Defects in EYA1 are the cause of branchiootic syndrometype 1 (BOS1) [MIM:602588], also known as BO syndrome type 1 orbranchiootic dysplasia. Individuals with BOS1 are affected by thesame branchial and otic anomalies as those seen in individualswith BOR1, but lack renal anomalies.

Defects in EYA4 are the cause of deafness autosomaldominant type 10 (DFNA10) [MIM:601316]. DFNA10 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in EYA4 are the cause of cardiomyopathy dilatedtype 1J (CMD1J) [MIM:605362]. Dilated cardiomyopathy is a disordercharacterized by ventricular dilation and impaired systolicfunction, resulting in congestive heart failure and arrhythmia.Patients are at risk of premature death.

Defects in EYS are the cause of retinitis pigmentosa type25 (RP25) [MIM:602772]. RP leads to degeneration of retinalphotoreceptor cells. Patients suffer from night blindness,beginning at approximately 25 years of age, and deterioration ofvisual acuity (central vision), beginning at approximately 30years of age. By age 55 to 60 years, many affected subjects haveno perception of light in either eye.

Defects in FAM123B are the cause of osteopathia striatawith cranial sclerosis (OSCS) [MIM:300373]. OSCS is an X-linkeddominant sclerosing bone dysplasia that presents in females withmacrocephaly, cleft palate, mild learning disabilities, sclerosisof the long bones and skull, and longitudinal striations visibleon radiographs of the long bones, pelvis, and scapulae. In malesthis entity is usually associated with fetal or neonatallethality.

Defects in FAM134B are the cause of hereditary sensoryand autonomic neuropathy type 2B (HSAN2B) [MIM:613115]. A form ofhereditary sensory and autonomic neuropathy, a genetically andclinically heterogeneous group of disorders characterized bydegeneration of dorsal root and autonomic ganglion cells, and bysensory and/or autonomic abnormalities. HSAN2B is an autosomalrecessive disorder characterized by impairment of pain,temperature and touch sensation. Onset occurs in the first orsecond decade, with impaired nociception and progressivemutilating ulceration of the hands and feet with osteomyelitis andacroosteolysis. Amputations of the hands and feet are common.Autonomic dysfunction includes hyperhidrosis, urinaryincontinence, and slow pupillary light response.

Defects in F13A1 are the cause of factor XIII subunit Adeficiency (FA13AD) [MIM:613225]. FA13AD is an autosomal recessivedisorder characterized by a life-long bleeding tendency, impairedwound healing and spontaneous abortion in affected women.

Defects in F13B are the cause of factor XIII subunit Bdeficiency (FA13BD) [MIM:613235]. FA13BD is an autosomal recessivedisorder characterized by a life-long bleeding tendency, impairedwound healing and spontaneous abortion in affected women.

Defects in FAM161A are the cause of retinitis pigmentosatype 28 (RP28) [MIM:606068]. A retinal dystrophy belonging to thegroup of pigmentary retinopathies. Retinitis pigmentosa ischaracterized by retinal pigment deposits visible on fundusexamination and primary loss of rod photoreceptor cells followedby secondary loss of cone photoreceptors. Patients typically havenight vision blindness and loss of midperipheral visual field. Astheir condition progresses, they lose their far peripheral visualfield and eventually central vision as well.

Defects in FBP1 are the cause of fructose-1,6-bisphosphatase deficiency (FBPD) [MIM:229700]. FBPD is inheritedas an autosomal recessive disorder mainly in the liver and causeslife-threatening episodes of hypoglycemia and metabolic acidosis(lactacidemia) in newborn infants or young children.

Defects in F11 are the cause of factor XI deficiency(FA11D) [MIM:612416], also known as plasma thromboplastinantecedent deficiency or Rosenthal syndrome. It is a hemorrhagicdisease characterized by reduced levels and activity of factor XIresulting in moderate bleeding symptoms, usually occurring aftertrauma or surgery. Patients usually do not present spontaneousbleeding but women can present with menorrhagia. Hemorrhages areusually moderate.

Defects in F12 are the cause of factor XII deficiency(FA12D) [MIM:234000], also known as Hageman factor deficiency.This trait is an asymptomatic anomaly of in vitro bloodcoagulation. Its diagnosis is based on finding a low plasmaactivity of the factor in coagulating assays. It is usually onlyaccidentally discovered through pre-operative blood tests. F12deficiency is divided into two categories, a cross-reactingmaterial (CRM)-negative group (negative F12 antigen detection) anda CRM-positive group (positive F12 antigen detection).

Defects in F12 are the cause of hereditary angioedematype 3 (HAE3) [MIM:610618], also known as estrogen-related HAE orhereditary angioneurotic edema with normal C1 inhibitorconcentration and function. HAE is characterized by episodic localsubcutaneous edema, and submucosal edema involving the upperrespiratory and gastrointestinal tracts. HAE3 occurs exclusivelyin women and is precipitated or worsened by high estrogen levels(e.g., during pregnancy or treatment with oral contraceptives). Itdiffers from HAE types 1 and 2 in that both concentration andfunction of C1 inhibitor are normal.

Defects in FA2H are a cause of spastic paraplegiaautosomal recessive type 35 (SPG35) [MIM:612319]. Spasticparaplegia is a neurodegenerative disorder characterized by aslow, gradual, progressive weakness and spasticity of the lowerlimbs.

Defects in FAM58A are the cause of toe syndactyly,telecanthus, and anogenital and renal malformations (STAR)[MIM:300707], also known as STAR syndrome or syndactyly with renaland anogenital malformations.

Defects in F5 are the cause of factor V deficiency (FA5D)[MIM:227400], also known as Owren parahemophilia. It is anhemorrhagic diastesis.

Defects in F5 are the cause of thrombophilia due toactivated protein C resistance (THR-APCR) [MIM:188055]. THR-APCRis a hemostatic disorder due to defective degradation of factor Vaby activated protein C. It is characterized by a pooranticoagulant response to activated protein C resulting intendency to thrombosis.

Defects in F5 are a cause of susceptibility to Budd-Chiari syndrome (BCS) [MIM:600880]. It is a syndrome caused byobstruction of hepatic venous outflow involving either the hepaticveins or the terminal segment of the inferior vena cava.Obstructions are generally caused by thrombosis and lead tohepatic congestion and ischemic necrosis. Clinical manifestationsobserved in the majority of patients include hepatomegaly, rightupper quadrant pain and abdominal ascites. Budd-Chiari syndrome isassociated with a combination of disease states including primarymyeloproliferative syndromes and thrombophilia due to factor VLeiden, protein C deficiency and antithrombin III deficiency.Budd-Chiari syndrome is a rare but typical complication inpatients with polycythemia vera.

Defects in F5 may be a cause of susceptibility toischemic stroke (ISCHSTR) [MIM:601367], also known ascerebrovascular accident or cerebral infarction. A stroke is anacute neurologic event leading to death of neural tissue of thebrain and resulting in loss of motor, sensory and/or cognitivefunction. Ischemic strokes, resulting from vascular occlusion, isconsidered to be a highly complex disease consisting of a group ofheterogeneous disorders with multiple genetic and environmentalrisk factors.

Defects in F7 are the cause of factor VII deficiency(FA7D) [MIM:227500]. FA7D is a rare hereditary hemorrhagicdisease. The clinical picture can be very severe, with the earlyoccurrence of intracerebral hemorrhages or hemarthroses, or, incontrast, moderate with cutaneous-mucosal hemorrhages (epistaxis,menorrhagia) or hemorrhages provoked by a surgical intervention.Numerous subjects are completely asymptomatic despite a very lowF7 level.

Defects in FAM83H are the cause of amelogenesisimperfecta type 3 (AI3) [MIM:130900]. AI3 is an autosomal dominanthypomineralized form of amelogenesis imperfecta, a defect ofenamel formation. AI3 is characterized by enamel of normalthickness, but soft and with cheesy consistency. Enamel is lostfrom tooth soon after eruption.

Defects in F8 are the cause of hemophilia A (HEMA)[MIM:306700]. HEMA is a common recessive X-linked coagulationdisorder. The frequency of hemophilia A is 1-2 in 10,000 malebirths in all ethnic groups. About 50% of patients have severehemophilia A with F8C activity less than 1% of normal, they havefrequent spontaneous bleeding into joints, muscles and internalorgans. Moderately severe hemophilia A occurs in about 10% ofpatients, F8C activity is 2-5% of normal, and there is bleedingafter minor trauma. Mild hemophilia A, which occurs in 30-40% ofpatients, is associated with F8C activity of 5-30% and bleedingoccurs only after significant trauma or surgery. Of particularinterest for the understanding of the function of F8C is thecategory of CRM (cross-reacting material) positive patients(approximately 5%) that have considerable amount of F8C in theirplasma (at least 30% of normal), but the protein is non-functional, i.e., the F8C activity is much less than the plasmaprotein level. CRM-reduced is another category of patients inwhich the F8C antigen and activity are reduced to approximatelythe same level. Most mutations are CRM negative, and probablyaffect the folding and stability of the protein.

Defects in F9 are the cause of recessive X-linkedhemophilia B (HEMB) [MIM:306900], also known as Christmas disease.

Note=Mutations in position 43 (Oxford-3, San Dimas) and46 (Cambridge) prevents cleavage of the propeptide, mutation inposition 93 (Alabama) probably fails to bind to cell membranes,mutation in position 191 (Chapel-Hill) or in position 226 (NagoyaOR Hilo) prevent cleavage of the activation peptide.

Defects in F9 are the cause of thrombophilia due tofactor IX defect (THR-FIX) [MIM:300807]. A hemostatic disordercharacterized by a tendency to thrombosis.

Defects in FAH are the cause of tyrosinemia type 1(TYRO1) [MIM:276700]. TYRO1 is an inborn error of metabolismcharacterized by elevations of tyrosine in the blood and urine,and hepatorenal manifestations. Typical features include hepaticnecrosis, renal tubular injury, episodic weakness, self-mutilation, and seizures. Renal tubular dysfunction is associatedwith phosphate loss and hypophosphataemic rickets. Progressiveliver disease can lead to the development of hepatocellularcarcinoma. Dietary treatment with restriction of tyrosine andphenylalanine alleviates the rickets, but liver transplantationhas so far been the only definite treatment. TYRO1 is a rarecondition, except in the Saguenay-lac-St-Jean region (province ofQuebec, Canada) where the frequency is high as the result of afounder effect.

Defects in FANCD2 are a cause of Fanconi anemiacomplementation group D type 2 (FANCD2) [MIM:227646]. It is adisorder affecting all bone marrow elements and resulting inanemia, leukopenia and thrombopenia. It is associated withcardiac, renal and limb malformations, dermal pigmentary changes,and a predisposition to the development of malignancies. At thecellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosomebreakage) and defective DNA repair.

Defects in ZMPSTE24 are the cause of mandibuloacraldysplasia with type B lipodystrophy (MADB) [MIM:608612].Mandibuloacral dysplasia (MAD) is a rare autosomal recessivedisorder characterized by mandibular and clavicular hypoplasia,acroosteolysis, delayed closure of the cranial suture, jointcontractures, and types A or B patterns of lipodystrophy. Type Blipodystrophy observed in MADB, is characterized by generalizedfat loss.

Defects in ZMPSTE24 are a cause of lethal tight skincontracture syndrome (LTSCS) [MIM:275210], also called restrictivedermopathy (RD). Lethal tight skin contracture syndrome is a raredisorder mainly characterized by intrauterine growth retardation,tight and rigid skin with erosions, prominent superficialvasculature and epidermal hyperkeratosis, facial features (smallmouth, small pinched nose and micrognathia), sparse/absenteyelashes and eyebrows, mineralization defects of the skull, thindysplastic clavicles, pulmonary hypoplasia, multiple jointcontractures and an early neonatal lethal course. Livebornchildren usually die within the first week of life. The overallprevalence of consanguineous cases suggested an autosomalrecessive inheritance.

Defects in FADD are the cause of infections recurrentassociated with encephalopathy hepatic dysfunction andcardiovascular malformations (IEHDCM) [MIM:613759]. A conditionwith biological features of autoimmune lymphoproliferativesyndrome such as high-circulating CD4(-)CD8(-)TCR-alpha-beta(+) T-cell counts, and elevated IL10 and FASL levels. Affectedindividuals suffer from recurrent, stereotypical episodes offever, encephalopathy, and mild liver dysfunction sometimesaccompanied by generalized seizures. The episodes can be triggeredby varicella zoster virus (VZV), measles mumps rubella (MMR)attenuated vaccine, parainfluenza virus, and Epstein-Barr virus(EBV).

Defects in FANCA are a cause of Fanconi anemia (FA)[MIM:227650]. FA is a genetically heterogeneous, autosomalrecessive disorder characterized by progressive pancytopenia, adiverse assortment of congenital malformations, and apredisposition to the development of malignancies. At the cellularlevel it is associated with hypersensitivity to DNA-damagingagents, chromosomal instability (increased chromosome breakage),and defective DNA repair.

Defects in FANCB are the cause of Fanconi anemiacomplementation group B (FANCB) [MIM:300514]. It is a disorderaffecting all bone marrow elements and resulting in anemia,leukopenia and thrombopenia. It is associated with cardiac, renaland limb malformations, dermal pigmentary changes, and apredisposition to the development of malignancies. At the cellularlevel it is associated with hypersensitivity to DNA-damagingagents, chromosomal instability (increased chromosome breakage)and defective DNA repair.

Defects in FANCB are the cause of X-linked VACTERL-H(XVACTERL-H) [MIM:314390], also known as X-linked VACTERLassociation with hydrocephalus syndrome. VACTERL is an acronym forvertebral anomalies, anal atresia, cardiac malformations,tracheoesophageal fistula, renal anomalies (urethral atresia withhydronephrosis), and limb anomalies (hexadactyly, humeralhypoplasia, radial aplasia, and proximally placed thumb). Somecases of VACTERL-H are associated with increased chromosomebreakage and rearrangement.

Defects in FANCC are a cause of Fanconi anemia (FA)[MIM:227650]. FA is a genetically heterogeneous, autosomalrecessive disorder characterized by progressive pancytopenia, adiverse assortment of congenital malformations, and apredisposition to the development of malignancies. At the cellularlevel it is associated with hypersensitivity to DNA-damagingagents, chromosomal instability (increased chromosome breakage),and defective DNA repair.

Defects in FANCE are a cause of Fanconi anemia (FA)[MIM:227650]. FA is a genetically heterogeneous, autosomalrecessive disorder characterized by progressive pancytopenia, adiverse assortment of congenital malformations, and apredisposition to the development of malignancies. At the cellularlevel it is associated with hypersensitivity to DNA-damagingagents, chromosomal instability (increased chromosome breakage),and defective DNA repair.

Defects in FANCF are a cause of Fanconi anemia (FA)[MIM:227650]. FA is a genetically heterogeneous, autosomalrecessive disorder characterized by progressive pancytopenia, adiverse assortment of congenital malformations, and apredisposition to the development of malignancies. At the cellularlevel it is associated with hypersensitivity to DNA-damagingagents, chromosomal instability (increased chromosome breakage),and defective DNA repair.

Defects in FANCG are a cause of Fanconi anemia (FA)[MIM:227650]. FA is a genetically heterogeneous, autosomalrecessive disorder characterized by progressive pancytopenia, adiverse assortment of congenital malformations, and apredisposition to the development of malignancies. At the cellularlevel it is associated with hypersensitivity to DNA-damagingagents, chromosomal instability (increased chromosome breakage),and defective DNA repair.

Defects in FANCI are a cause of Fanconi anemiacomplementation group I (FANCI) [MIM:609053]. It is a disorderaffecting all bone marrow elements and resulting in anemia,leukopenia and thrombopenia. It is associated with cardiac, renaland limb malformations, dermal pigmentary changes, and apredisposition to the development of malignancies. At the cellularlevel it is associated with hypersensitivity to DNA-damagingagents, chromosomal instability (increased chromosome breakage)and defective DNA repair.

Defects in BRIP1 are a cause of susceptibility to breastcancer (BC) [MIM:114480]. A common malignancy originating frombreast epithelial tissue. Breast neoplasms can be distinguished bytheir histologic pattern. Invasive ductal carcinoma is by far themost common type. Breast cancer is etiologically and geneticallyheterogeneous. Important genetic factors have been indicated byfamilial occurrence and bilateral involvement. Mutations at morethan one locus can be involved in different families or even inthe same case.

Defects in BRIP1 are the cause of Fanconi anemiacomplementation group J (FANCJ) [MIM:609054]. It is a disorderaffecting all bone marrow elements and resulting in anemia,leukopenia and thrombopenia. It is associated with cardiac, renaland limb malformations, dermal pigmentary changes, and apredisposition to the development of malignancies. At the cellularlevel it is associated with hypersensitivity to DNA-damagingagents, chromosomal instability (increased chromosome breakage)and defective DNA repair.

Defects in FANCL are a cause of Fanconi anemia (FA)[MIM:227650]. FA is a genetically heterogeneous, autosomalrecessive disorder characterized by progressive pancytopenia, adiverse assortment of congenital malformations, and apredisposition to the development of malignancies. At the cellularlevel it is associated with hypersensitivity to DNA-damagingagents, chromosomal instability (increased chromosome breakage),and defective DNA repair.

Defects in FANCM are a cause of Fanconi anemia (FA)[MIM:227650]. FA is a genetically heterogeneous, autosomalrecessive disorder characterized by progressive pancytopenia, adiverse assortment of congenital malformations, and apredisposition to the development of malignancies. At the cellularlevel it is associated with hypersensitivity to DNA-damagingagents, chromosomal instability (increased chromosome breakage),and defective DNA repair.

Note=A chromosomal aberration involving FBLN1 is found ina complex type of synpolydactyly referred to as 3/3-prime/4synpolydactyly associated with metacarpal and metatarsalsynostoses. Reciprocal translocation t(12,22)(p11.2,q13.3) withC12orf2. Fibroblasts derived from a patient with synpolydactylydisplayed alterations in the level of isoform D splice variantincorporated into the ECM and secreted into the conditionedculture medium. By contrast, the expression of isoform C was notperturbed in the patients fibroblasts. Furthermore, no aberrantpolypeptides were detected in extracts of cultured patientsfibroblasts. The translocation t(12,22) may result inhaploinsufficiency of the isoform D splice variant, which couldlead to the observed limb malformation.

Note=Elevated expression and altered processing of FBLN1protein is associated with human breast cancer.

Defects in EFEMP1 are a cause of Doyne honeycomb retinaldystrophy (DHRD) [MIM:126600], also known as malattia leventinese(MLVT) (ML). DHRD is an autosomal dominant disease characterizedby yellow-white deposits known as drusen that accumulate beneaththe retinal pigment epithelium.

Defects in EFEMP2 are a cause of cutis laxa autosomalrecessive type 1 (ARCL1) [MIM:219100]. Hereditary cutis laxarefers to a heterogeneous group of connective tissue disorderscharacterized by cutaneous abnormalities and variable systemicmanifestations. The most constant clinical feature is loose skin,sagging over the face and trunk. Hereditary cutis laxa isinherited in both autosomal dominant and autosomal recessivemodes. ARCL1 shows the most severe phenotype and has the poorestprognosis. In addition to the skin, internal organs enriched inelastic fibers, such as the lung and arteries, are affected.

Defects in FBLN5 are a cause of autosomal dominant cutislaxa (ADCL) [MIM:123700]. Hereditary cutis laxa refers to aheterogeneous group of connective tissue disorders characterizedby cutaneous abnormalities and variable systemic manifestations.The most constant clinical feature is loose skin, sagging over theface and trunk. Hereditary cutis laxa is inherited in bothautosomal dominant and autosomal recessive modes. Autosomaldominant cutis laxa is a relatively benign inherited and acquiredconnective tissue disorder.

Defects in FBLN5 are a cause of cutis laxa autosomalrecessive type 1 (ARCL1) [MIM:219100]. Hereditary cutis laxarefers to a heterogeneous group of connective tissue disorderscharacterized by cutaneous abnormalities and variable systemicmanifestations. The most constant clinical feature is loose skin,sagging over the face and trunk. Hereditary cutis laxa isinherited in both autosomal dominant and autosomal recessivemodes. ARCL1 shows the most severe phenotype and has the poorestprognosis. In addition to the skin, internal organs enriched inelastic fibers, such as the lung and arteries, are affected.

Defects in FBLN5 are the cause of age-related maculardegeneration type 3 (ARMD3) [MIM:608895]. ARMD is a multifactorialdisease and the most common cause of irreversible vision loss inthe developed world. In most patients, the disease is manifest asophthalmoscopically visible yellowish accumulations of protein andlipid (known as drusen) that lie beneath the retinal pigmentepithelium and within an elastin-containing structure known asBruch membrane.

Defects in FBN1 are a cause of Marfan syndrome (MFS)[MIM:154700]. MFS is an autosomal dominant disorder that affectsthe skeletal, ocular, and cardiovascular systems. A wide varietyof skeletal abnormalities occurs with MFS, including scoliosis,chest wall deformity, tall stature, abnormal joint mobility.Ectopia lentis occurs in up to about 80% of MFS patients and isalmost always bilateral. The leading cause of premature death inMFS patients is progressive dilation of the aortic root andascending aorta, causing aortic incompetence and dissection.Note=The majority of the more than 600 mutations in FBN1 currentlyknown are point mutations, the rest are frameshifts and splicesite mutations. Marfan syndrome has been suggested in at least 2historical figures, Abraham Lincoln and Paganini.

Defects in FBN1 are a cause of isolated ectopia lentis(EL) [MIM:129600]. The symptoms of this autosomal dominantfibrillinopathy overlap with those of Marfan syndrome, with theexclusion of the skeletal and cardiovascular manifestations.

Defects in FBN1 are the cause of Weill-Marchesanisyndrome autosomal dominant (ADWMS) [MIM:608328]. A rareconnective tissue disorder characterized by short stature,brachydactyly, joint stiffness, and eye abnormalities includingmicrospherophakia, ectopia lentis, severe myopia and glaucoma.

Defects in FBN1 are a cause of Shprintzen-Goldbergcraniosynostosis syndrome (SGS) [MIM:182212]. SGS is a very raresyndrome characterized by a marfanoid habitus, craniosynostosis,characteristic dysmorphic facial features, skeletal andcardiovascular abnormalities, mental retardation, developmentaldelay and learning disabilities.

Defects in FBN1 are a cause of MASS syndrome (MASSS)[MIM:604308]. MASS syndrome is a heritable disorder of connectivetissue characterized by involvement of the mitral valve, aorta,skeleton, and skin. MASS syndrome is closely resembling both theMarfan syndrome and the Barlow syndrome. However, no dislocationof the lenses or aneurysmal changes occur in the aorta, and themitral valve prolapse is by no means invariable.

Defects in FBN1 are a cause of stiff skin syndrome (SSKS)[MIM:184900]. It is a syndrome characterized by hard, thick skin,usually over the entire body, which limits joint mobility andcauses flexion contractures. Other occasional findings includelipodystrophy and muscle weakness.

Defects in FBN2 are the cause of congenital contracturalarachnodactyly (CCA) [MIM:121050], also known as Beals syndrome ordistal arthrogryposis type 9 (DA9). CCA is a rare, autosomaldominant connective tissue disorder characterized by contractures,arachnodactyly, scoliosis, and crumpled ears. Phenotypicallysimilar to Marfan syndrome, CCA does not affect the aorta and theeyes.

Note=A chromosomal aberration involving FBXO25 is a causeof X-linked mental retardation (XLMR). Translocationt(X,8)(p11.22,p23.3) with SHROOM4.

Defects in FBXO7 are the cause of Parkinson disease type15 (PARK15) [MIM:260300], also known as parkinsonian-pyramidalsyndrome. A neurodegenerative disorder characterized byparkinsonian and pyramidal signs. Clinical manifestations includetremor, bradykinesia, rigidity, postural instability, spasticity,mainly in the lower limbs, and hyperreflexia.

Defects in FBXW4 are a cause of split-hand/footmalformation type 3 (SHFM3) [MIM:246560]. SHFM3 is an autosomaldominant disorder characterized by hypoplasia/aplasia of thecentral digits with fusion of the remaining digits.

Note=A chromosomal aberration involving FCGR2B is foundin a follicular lymphoma. Translocation t(1,22)(q22,q11). Thetranslocation leads to the hyperexpression of the receptor. Thismay play a role in the tumor progression.

Genetic variation in FCRL3 may be a cause ofsusceptibility to rheumatoid arthritis (RA) [MIM:180300]. It is asystemic inflammatory disease with autoimmune features and acomplex genetic component. It primarily affects the joints and ischaracterized by inflammatory changes in the synovial membranesand articular structures, widespread fibrinoid degeneration of thecollagen fibers in mesenchymal tissues, and by atrophy andrarefaction of bony structures.

Genetic variation in FCRL3 may influence susceptibilityto Graves disease, an autoimmune disorder associated withoveractivity of the thyroid gland and hyperthyroidism.

Note=A chromosomal aberration involving FCRL4 is found innon-Hodgkin lymphoma (NHG). Translocation t(1,1)(p36.3, q21.1-2).

Note=A chromosomal aberration involving FCRL4 is found inmultiple myeloma (MM). Translocation t(1,14)(q21,q32) that forms aFCRL4-IGHA1 fusion protein.

Note=A chromosomal aberration involving FCRL5 has beenfound in cell lines with 1q21 abnormalities derived from Burkittlymphoma. Duplication dup(1)(q21q32).

Defects in FERMT1 are the cause of Kindler syndrome(KINDS) [MIM:173650]. Kindler syndrome is an autosomal recessivedisorder characterized by neonatal blistering, sun sensitivity,atrophy, abnormal pigmentation and fragility of the skin.

Genetic variation in FEV may be associated withsusceptibility to sudden infant death syndrome (SIDS)[MIM:272120]. SIDS remains elusive in its causes and devastatingin its consequences. Despite the impressive decline in theincidence of SIDS since the recommendation to avoid the pronesleep position, SIDS remains a leading cause of death in the firstyear of life.

Note=A chromosomal aberration involving FEV is found inEwing tumors. Translocation t(2,21,22)(q23,q22,q12) that forms aEWSR1-FEV fusion protein with a potential oncogenic activity.

Defects in FGD1 are the cause of Aarskog-Scott syndrome(AAS) [MIM:305400]. This faciogenital dysplasia is a raremultisystemic disorder characterized by disproportionately shortstature, and by facial, skeletal, and urogenital anomalies.

Note=Defects in FGD1 are found in a pateint with non-syndromal X-linked mental retardation.

Defects in FGD4 are the cause of Charcot-Marie-Toothdisease type 4H (CMT4H) [MIM:609311], also known as Charcot-Marie-Tooth disease neuropathy type 4H. CMT4H is a recessivedemyelinating form of Charcot-Marie-Tooth disease, the most commoninherited disorder of the peripheral nervous system. Charcot-Marie-Tooth disease is classified in two main groups on the basisof electrophysiologic properties and histopathology: primaryperipheral demyelinating neuropathy and primary peripheral axonalneuropathy. Demyelinating CMT neuropathies are characterized byseverely reduced nerve conduction velocities (less than 38 m/sec),segmental demyelination and remyelination with onion bulbformations on nerve biopsy, slowly progressive distal muscleatrophy and weakness, absent deep tendon reflexes, and hollowfeet. By convention, autosomal recessive forms of demyelinatingCharcot-Marie-Tooth disease are designated CMT4.

Defects in FGF10 are the cause of autosomal dominantaplasia of lacrimal and salivary glands (ALSG) [MIM:180920]. ALSGhas variable expressivity, and affected individuals may haveaplasia or hypoplasia of the lacrimal, parotid, submandibular andsublingual glands and absence of the lacrimal puncta. The disorderis characterized by irritable eyes, recurrent eye infections,epiphora (constant tearing) and xerostomia (dryness of the mouth),which increases the risk of dental erosion, dental caries,periodontal disease and oral infections.

Defects in FGF10 are a cause of lacrimo-auriculo-dento-digital syndrome (LADDS) [MIM:149730], also known as Levy-Hollister syndrome. LADDS is a form of ectodermal dysplasia, aheterogeneous group of disorders due to abnormal development oftwo or more ectodermal structures. LADDS is an autosomal dominantsyndrome characterized by aplastic/hypoplastic lacrimal andsalivary glands and ducts, cup-shaped ears, hearing loss,hypodontia and enamel hypoplasia, and distal limb segmentsanomalies. In addition to these cardinal features, facialdysmorphism, malformations of the kidney and respiratory systemand abnormal genitalia have been reported. Craniosynostosis andsevere syndactyly are not observed.

Defects in FGF14 are the cause of spinocerebellar ataxiatype 27 (SCA27) [MIM:609307]. Spinocerebellar ataxia is aclinically and genetically heterogeneous group of cerebellardisorders. Patients show progressive incoordination of gait andoften poor coordination of hands, speech and eye movements, due todegeneration of the cerebellum with variable involvement of thebrainstem and spinal cord. SCA27 is an autosomal dominantcerebellar ataxia (ADCA). It is a slowly progressive disorder,with onset in late-childhood to early adulthood, characterized byataxia with tremor, orofacial dyskinesia, psychiatric symptoms andcognitive deficits.

Defects in FGF23 are the cause of autosomal dominanthypophosphataemic rickets (ADHR) [MIM:193100]. ADHR ischaracterized by low serum phosphorus concentrations, rickets,osteomalacia, leg deformities, short stature, bone pain and dentalabscesses.

Defects in FGF23 are a cause of hyperphosphatemicfamilial tumoral calcinosis (HFTC) [MIM:211900]. HFTC is a severeautosomal recessive metabolic disorder that manifests withhyperphosphatemia and massive calcium deposits in the skin andsubcutaneous tissues.

Defects in FGF3 are a cause of deafness with labyrinthineaplasia, microtia and microdontia (LAMM) [MIM:610706], also knownas congenital deafness with inner ear agenesis, microtia andmicrodontia. LAMM consists of a unique autosomal recessivesyndrome characterized by type I microtia, microdontia, andprofound congenital deafness associated with a complete absence ofinner ear structures (Michel aplasia).

Defects in FGF8 are the cause of Kallmann syndrome type 6(KAL6) [MIM:612702]. Kallmann syndrome is a disorder thatassociates hypogonadotropic hypogonadism and anosmia. Anosmia orhyposmia is related to the absence or hypoplasia of the olfactorybulbs and tracts. Hypogonadism is due to deficiency ingonadotropin-releasing hormone and probably results from a failureof embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In some patients other developmentalanomalies can be present, which include renal agenesis, cleft lipand/or palate, selective tooth agenesis, and bimanual synkinesis.In some cases anosmia may be absent or inconspicuous.

Defects in FGF8 are a cause of idiopathichypogonadotropic hypogonadism (IHH) [MIM:146110]. IHH is definedas a deficiency of the pituitary secretion of follicle-stimulatinghormone and luteinizing hormone, which results in the impairmentof pubertal maturation and of reproductive function.

Defects in FGF9 are the cause of multiple synostosessyndrome type 3 (SYNS3) [MIM:612961]. Multiple synostoses syndromeis an autosomal dominant condition characterized by progressivejoint fusions of the fingers, wrists, ankles and cervical spine,characteristic facies and progressive conductive deafness.

Defects in FGFR1 are a cause of Pfeiffer syndrome (PS)[MIM:101600], also known as acrocephalosyndactyly type V (ACS5).PS is characterized by craniosynostosis (premature fusion of theskull sutures) with deviation and enlargement of the thumbs andgreat toes, brachymesophalangy, with phalangeal ankylosis and avarying degree of soft tissue syndactyly.

Defects in FGFR1 are a cause of idiopathichypogonadotropic hypogonadism (IHH) [MIM:146110]. IHH is definedas a deficiency of the pituitary secretion of follicle-stimulatinghormone and luteinizing hormone, which results in the impairmentof pubertal maturation and of reproductive function.

Defects in FGFR1 are the cause of Kallmann syndrome type2 (KAL2) [MIM:147950], also known as hypogonadotropic hypogonadismand anosmia. Anosmia or hyposmia is related to the absence orhypoplasia of the olfactory bulbs and tracts. Hypogonadism is dueto deficiency in gonadotropin-releasing hormone and probablyresults from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In some cases, midlinecranial anomalies (cleft lip/palate and imperfect fusion) arepresent and anosmia may be absent or inconspicuous.

Defects in FGFR1 are the cause of osteoglophonicdysplasia (OGD) [MIM:166250], also known as osteoglophonicdwarfism. OGD is characterized by craniosynostosis, prominentsupraorbital ridge, and depressed nasal bridge, as well as byrhizomelic dwarfism and nonossifying bone lesions. Inheritance isautosomal dominant.

Defects in FGFR1 are the cause of trigonocephaly non-syndromic (TRICEPH) [MIM:190440], also known as metopiccraniosynostosis. The term trigonocephaly describes the typicalkeel-shaped deformation of the forehead resulting from prematurefusion of the frontal suture. Trigonocephaly may occur also as apart of a syndrome.

Note=A chromosomal aberration involving FGFR1 may be acause of stem cell leukemia lymphoma syndrome (SCLL).Translocation t(8,13)(p11,q12) with ZMYM2. SCLL usually presentsas lymphoblastic lymphoma in association with a myeloproliferativedisorder, often accompanied by pronounced peripheral eosinophiliaand/or prominent eosinophilic infiltrates in the affected bonemarrow.

Note=A chromosomal aberration involving FGFR1 may be acause of stem cell myeloproliferative disorder (MPD).Translocation t(6,8)(q27,p11) with FGFR1OP. Insertionins(12,8)(p11,p11p22) with FGFR1OP2. MPD is characterized bymyeloid hyperplasia, eosinophilia and T-cell or B-celllymphoblastic lymphoma. In general it progresses to acute myeloidleukemia. The fusion proteins FGFR1OP2-FGFR1, FGFR1OP-FGFR1 orFGFR1-FGFR1OP may exhibit constitutive kinase activity and beresponsible for the transforming activity.

Note=A chromosomal aberration involving FGFR1 may be acause of stem cell myeloproliferative disorder (MPD).Translocation t(8,9)(p12,q33) with CEP110. MPD is characterized bymyeloid hyperplasia, eosinophilia and T-cell or B-celllymphoblastic lymphoma. In general it progresses to acute myeloidleukemia. The fusion protein CEP110-FGFR1 is found in thecytoplasm, exhibits constitutive kinase activity and may beresponsible for the transforming activity.

Defects in FGFR2 are the cause of Crouzon syndrome (CS)[MIM:123500], also called craniofacial dysostosis type I (CFD1).CS is an autosomal dominant syndrome characterized bycraniosynostosis (premature fusion of the skull sutures),hypertelorism, exophthalmos and external strabismus, parrot-beakednose, short upper lip, hypoplastic maxilla, and a relativemandibular prognathism.

Defects in FGFR2 are a cause of Jackson-Weiss syndrome(JWS) [MIM:123150]. JWS is an autosomal dominant craniosynostosissyndrome characterized by craniofacial abnormalities andabnormality of the feet: broad great toes with medial deviationand tarsal-metatarsal coalescence.

Defects in FGFR2 are a cause of Apert syndrome (APRS)[MIM:101200], also known as acrocephalosyndactyly type 1 (ACS1).APRS is a syndrome characterized by facio-cranio-synostosis,osseous and membranous syndactyly of the four extremities, andmidface hypoplasia. The craniosynostosis is bicoronal and resultsin acrocephaly of brachysphenocephalic type. Syndactyly of thefingers and toes may be total (mitten hands and sock feet) orpartial affecting the second, third, and fourth digits.Intellectual deficit is frequent and often severe, usually beingassociated with cerebral malformations.

Defects in FGFR2 are a cause of Pfeiffer syndrome (PS)[MIM:101600], also known as acrocephalosyndactyly type V (ACS5).PS is characterized by craniosynostosis (premature fusion of theskull sutures) with deviation and enlargement of the thumbs andgreat toes, brachymesophalangy, with phalangeal ankylosis and avarying degree of soft tissue syndactyly. Three subtypes ofPfeiffer syndrome have been described: mild autosomal dominantform (type 1), cloverleaf skull, elbow ankylosis, early death,sporadic (type 2), craniosynostosis, early demise, sporadic (type3).

Defects in FGFR2 are the cause of Beare-Stevenson cutisgyrata syndrome (BSCGS) [MIM:123790]. BSCGS is an autosomaldominant condition is characterized by the furrowed skin disorderof cutis gyrata, acanthosis nigricans, craniosynostosis,craniofacial dysmorphism, digital anomalies, umbilical andanogenital abnormalities and early death.

Defects in FGFR2 are the cause of familial scaphocephalysyndrome (FSPC) [MIM:609579], also known as scaphocephaly withmaxillary retrusion and mental retardation. FSPC is an autosomaldominant craniosynostosis syndrome characterized by scaphocephaly,macrocephaly, hypertelorism, maxillary retrusion, and mildintellectual disability. Scaphocephaly is the most common of thecraniosynostosis conditions and is characterized by a long, narrowhead. It is due to premature fusion of the sagittal suture or fromexternal deformation.

Defects in FGFR2 are a cause of lacrimo-auriculo-dento-digital syndrome (LADDS) [MIM:149730], also known as Levy-Hollister syndrome. LADDS is a form of ectodermal dysplasia, aheterogeneous group of disorders due to abnormal development oftwo or more ectodermal structures. LADDS is an autosomal dominantsyndrome characterized by aplastic/hypoplastic lacrimal andsalivary glands and ducts, cup-shaped ears, hearing loss,hypodontia and enamel hypoplasia, and distal limb segmentsanomalies. In addition to these cardinal features, facialdysmorphism, malformations of the kidney and respiratory systemand abnormal genitalia have been reported. Craniosynostosis andsevere syndactyly are not observed.

Defects in FGFR2 are the cause of Antley-Bixler syndrome(ABS) [MIM:207410]. ABS is a multiple congenital anomaly syndromecharacterized by craniosynostosis, radiohumeral synostosis,midface hypoplasia, malformed ears, arachnodactyly and multiplejoint contractures. ABS is a heterogeneous disorder and occurswith and without abnormal genitalia in both sexes.

Defects in FGFR3 are the cause of achondroplasia (ACH)[MIM:100800]. ACH is an autosomal dominant disease and is the mostfrequent form of short-limb dwarfism. It is characterized by along, narrow trunk, short extremities, particularly in theproximal (rhizomelic) segments, a large head with frontal bossing,hypoplasia of the midface and a trident configuration of thehands.

Defects in FGFR3 are the cause of Crouzon syndrome withacanthosis nigricans (CAN) [MIM:612247]. Classic Crouzon diseasewhich is caused by mutations in the FGFR2 gene is characterized bycraniosynostosis (premature fusion of the skull sutures), andfacial hypoplasia. Crouzon syndrome with acanthosis nigricans (askin disorder characterized by pigmentation anomalies), CAN, isconsidered to be an independent disorder from classic Crouzonsyndrome. CAN is characterized by additional more severe physicalmanifestation, such as Chiari malformation, hydrocephalus, andatresia or stenosis of the choanas, and is caused by a specificmutation (Ala-391 to Glu) in the transmembrane domain of FGFR3. Itis proposed to have an autosomal dominant mode of inheritance.

Defects in FGFR3 are a cause of thanatophoric dysplasiatype (TD) [MIM:187600, 187601], also known as thanatophoricdwarfism or platyspondylic lethal skeletal dysplasia Sand Diegotype (PLSD-SD). TD is the most common neonatal lethal skeletaldysplasia. Affected individuals display features similar to thoseseen in homozygous achondroplasia. It causes severe shortening ofthe limbs with macrocephaly, narrow thorax and short ribs. In themost common subtype, TD1, femur are curved, while in TD2, straightfemurs are associated with cloverleaf skull. Mutations affectingdifferent functional domains of FGFR3 cause different forms ofthis lethal disorder.

Defects in FGFR3 are a cause of hypochondroplasia (HCH)[MIM:146000]. HCH is an autosomal dominant disease and ischaracterized by disproportionate short stature. It resemblesachondroplasia, but with a less severe phenotype.

Defects in FGFR3 are a cause of susceptibility to bladdercancer (BLC) [MIM:109800]. A malignancy originating in tissues ofthe urinary bladder. It often presents with multiple tumorsappearing at different times and at different sites in thebladder. Most bladder cancers are transitional cell carcinomas.They begin in cells that normally make up the inner lining of thebladder. Other types of bladder cancer include squamous cellcarcinoma (cancer that begins in thin, flat cells) andadenocarcinoma (cancer that begins in cells that make and releasemucus and other fluids). Bladder cancer is a complex disorder withboth genetic and environmental influences. Note=Somatic mutationscan constitutively activate FGFR3.

Defects in FGFR3 are a cause of cervical cancer (CERCA)[MIM:603956]. A malignant neoplasm of the cervix, typicallyoriginating from a dysplastic or premalignant lesion previouslypresent at the active squamocolumnar junction. The transformationfrom mild dysplastic to invasive carcinoma generally occurs slowlywithin several years, although the rate of this process varieswidely. Carcinoma in situ is particularly known to precedeinvasive cervical cancer in most cases. Cervical cancer isstrongly associated with infection by oncogenic types of humanpapillomavirus.

Defects in FGFR3 are the cause of camptodactyly tallstature and hearing loss syndrome (CATSHL syndrome) [MIM:610474].CATSHL syndrome is an autosomal dominant syndrome characterized bypermanent and irreducible flexion of one or more fingers of thehand and/or feet, tall stature, scoliosis and/or a pectusexcavatum, and hearing loss. Affected individuals havedevelopmental delay and/or mental retardation, and several ofthese have microcephaly. Radiographic findings included tallvertebral bodies with irregular borders and broad femoralmetaphyses with long tubular shafts. On audiological exam, eachtested member have bilateral sensorineural hearing loss and absentotoacoustic emissions. The hearing loss was congenital ordeveloped in early infancy, progressed variably in earlychildhood, and range from mild to severe. Computed tomography andmagnetic resonance imaging reveal that the brain, middle ear, andinner ear are structurally normal.

Defects in FGFR3 are a cause of multiple myeloma (MM)[MIM:254500]. MM is a malignant tumor of plasma cells usuallyarising in the bone marrow and characterized by diffuseinvolvement of the skeletal system, hyperglobulinemia, Bence-Jonesproteinuria and anemia. Complications of multiple myeloma are bonepain, hypercalcemia, renal failure and spinal cord compression.The aberrant antibodies that are produced lead to impaired humoralimmunity and patients have a high prevalence of infection.Amyloidosis may develop in some patients. Multiple myeloma is partof a spectrum of diseases ranging from monoclonal gammopathy ofunknown significance (MGUS) to plasma cell leukemia. Note=Achromosomal aberration involving FGFR3 is found in multiplemyeloma. Translocation t(4,14)(p16.3,q32.3) with the IgH locus.

Defects in FGFR3 are a cause of lacrimo-auriculo-dento-digital syndrome (LADDS) [MIM:149730], also known as Levy-Hollister syndrome. LADDS is a form of ectodermal dysplasia, aheterogeneous group of disorders due to abnormal development oftwo or more ectodermal structures. LADDS is an autosomal dominantsyndrome characterized by aplastic/hypoplastic lacrimal andsalivary glands and ducts, cup-shaped ears, hearing loss,hypodontia and enamel hypoplasia, and distal limb segmentsanomalies. In addition to these cardinal features, facialdysmorphism, malformations of the kidney and respiratory systemand abnormal genitalia have been reported. Craniosynostosis andsevere syndactyly are not observed.

Defects in FGFR3 are a cause of keratinocytic non-epidermolytic nevus (KNEN) [MIM:162900], also known as pigmentedmoles. Epidermal nevi of the common, non-organoid and non-epidermolytic type are benign skin lesions and may vary in theirextent from a single (usually linear) lesion to widespread andsystematized involvement. They may be present at birth or developearly during childhood.

Defects in FGFR3 are a cause of Muenke syndrome (MNKS)[MIM:602849], also known as Muenke non-syndromic coronalcraniosynostosis. MNKS is a condition characterized by prematureclosure of coronal suture of skull during development (coronalcraniosynostosis), which affects the shape of the head and face.It may be uni- or bilateral. When bilateral, it is characterizedby a skull with a small antero-posterior diameter (brachycephaly),often with a decrease in the depth of the orbits and hypoplasia ofthe maxillae. Unilateral closure of the coronal sutures leads toflattening of the orbit on the involved side (plagiocephaly). Theintellect is normal. In addition to coronal craniosynostosis someaffected individuals show skeletal abnormalities of hands andfeet, sensorineural hearing loss, mental retardation andrespiratory insufficiency.

Defects in FGFR3 are a cause of keratosis seborrheic(KERSEB) [MIM:182000]. A common benign skin tumor. Seborrheickeratoses usually begin with the appearance of one or more sharplydefined, light brown, flat macules. The lesions may be sparse ornumerous. As they initially grow, they develop a velvety to finelyverrucous surface, followed by an uneven warty surface withmultiple plugged follicles and a dull or lackluster appearance.

Defects in FGGY are associated with sporadic amyotrophiclateral sclerosis (ALS) [MIM:105400]. Amyotrophic lateralsclerosis is a neurodegenerative disorder affecting upper andlower motor neurons and resulting in fatal paralysis. Sensoryabnormalities are absent. Death usually occurs within 2 to 5years. The etiology of amyotrophic lateral sclerosis is likely tobe multifactorial, involving both genetic and environmentalfactors.

Note=A chromosomal aberration involving FGFR1OP2 may be acause of stem cell myeloproliferative disorder (MPD). Insertionins(12,8)(p11,p11p22) with FGFR1. MPD is characterized by myeloidhyperplasia, eosinophilia and T-cell or B-cell lymphoblasticlymphoma. In general it progresses to acute myeloid leukemia. Thefusion protein FGFR1OP2-FGFR1 may exhibit constitutive kinaseactivity and be responsible for the transforming activity.

Note=A chromosomal aberration involving FHIT has beenfound in a lymphoblastoid cell line established from a family withrenal cell carcinoma and thyroid carcinoma. Translocationt(3,8)(p14.2,q24.1) with RNF139. Although the 3p14.2 breakpointhas been shown to interrupt FHIT in its 5-prime non-coding region,it is unlikely that FHIT is causally related to renal or othermalignancies.

Note=Associated with digestive tract cancers. Numeroustumor types are found to have aberrant forms of FHIT protein dueto deletions in a coding region of chromosome 3p14.2 including thefragile site locus FRA3B.

Defects in FHL1 are the cause of X-linked dominantscapuloperoneal myopathy (SPM) [MIM:300695]. Scapuloperonealsyndrome (SPS) was initially described more than 120 years ago byJules Broussard as 'une forme hereditaire d'atrophie musculaireprogressive' beginning in the lower legs and affecting theshoulder region earlier and more severely than distal arm. Theetiology of this condition remains unclear.

Defects in FHL1 are the cause of X-linked myopathy withpostural muscle atrophy (XMPMA) [MIM:300696]. Myopathies areinherited muscle disorders characterized by weakness and atrophyof voluntary skeletal muscle, and several types of myopathy alsoshow involvement of cardiac muscle. XMPMA is a distinct form ofadult-onset X-linked recessive myopathy with several features incommon with other myopathies, but the presentation of apseudoathletic phenotype, scapuloperoneal weakness, and bent spineis unique and might render the clinical phenotype distinguishablefrom other myopathies.

Defects in FHL1 are the cause of X-linked severe early-onset reducing body myopathy (RBM) [MIM:300717]. RBM is a raremuscle disorder causing progressive muscular weakness andcharacteristic intracytoplasmic inclusions in myofibers. Clinicalpresentations of RBM have ranged from early onset fatal tochildhood onset to adult onset cases.

Defects in FHL1 are the cause of X-linked childhood-onsetreducing body myopathy (CO-RBM) [MIM:300718]. This disorder isallelic to severe early-onset reducing body myopathy (RBM)[MIM:300717].

Note=Defects in CFHR5 have been found in patients withatypical hemolytic uremic syndrome and may contribute to thedisease. Atypical hemolytic uremic syndrome is a complex geneticdisease characterized by microangiopathic hemolytic anemia,thrombocytopenia, renal failure and absence of episodes ofenterocolitis and diarrhea. In contrast to typical hemolyticuremic syndrome, atypical forms have a poorer prognosis, withhigher death rates and frequent progression to end-stage renaldisease. Susceptibility to the development of atypical hemolyticuremic syndrome can be conferred by mutations in variouscomponents of or regulatory factors in the complement cascadesystem. Other genes may play a role in modifying the phenotype.

Defects in FGA are a cause of congenital afibrinogenemia(CAFBN) [MIM:202400]. This is a rare autosomal recessive disordercharacterized by bleeding that varies from mild to severe and bycomplete absence or extremely low levels of plasma and plateletfibrinogen. Note=The majority of cases of afibrinogenemia are dueto truncating mutations. Variations in position Arg-35 (the siteof cleavage of fibrinopeptide a by thrombin) leads to alpha-dysfibrinogenemias.

Defects in FGA are a cause of amyloidosis type 8 (AMYL8)[MIM:105200], also known as systemic non-neuropathic amyloidosisor Ostertag-type amyloidosis. AMYL8 is a hereditary generalizedamyloidosis due to deposition of apolipoprotein A1, fibrinogen andlysozyme amyloids. Viscera are particularly affected. There is noinvolvement of the nervous system. Clinical features include renalamyloidosis resulting in nephrotic syndrome, arterialhypertension, hepatosplenomegaly, cholestasis, petechial skinrash.

Defects in FGB are a cause of thrombophilia.

Defects in FGB are a cause of congenital afibrinogenemia(CAFBN) [MIM:202400]. This rare autosomal recessive disorder ischaracterized by bleeding that varies from mild to severe and bycomplete absence or extremely low levels of plasma and plateletfibrinogen.

Defects in FGG are a cause of thrombophilia.

Defects in FGG are a cause of congenital afibrinogenemia(CAFBN) [MIM:202400]. It is a rare autosomal recessive disordercharacterized by complete absence of detectable fibrinogen.

Defects in FIG4 are the cause of Charcot-Marie-Toothdisease type 4J (CMT4J) [MIM:611228]. CMT4J is a recessivedemyelinating, severe form of Charcot-Marie-Tooth disease, themost common inherited disorder of the peripheral nervous system.Charcot-Marie-Tooth disease is classified in two main groups onthe basis of electrophysiologic properties and histopathology:primary peripheral demyelinating neuropathies characterized byseverely reduced motor nerve conduction velocities (NCVs) (lessthan 38m/s) and segmental demyelination and remyelination, andprimary peripheral axonal neuropathies characterized by normal ormildly reduced NCVs and chronic axonal degeneration andregeneration on nerve biopsy.

Defects in FIG4 are the cause of amyotrophic lateralsclerosis type 11 (ALS11) [MIM:612577]. ALS is a neurodegenerativedisorder affecting upper motor neurons in the brain and lowermotor neurons in the brain stem and spinal cord, resulting infatal paralysis. Sensory abnormalities are absent. Death usuallyoccurs within 2 to 5 years. The etiology of amyotrophic lateralsclerosis is likely to be multifactorial, involving both geneticand environmental factors. The disease is inherited in 5-10%.

Defects in FIGLA are the cause of premature ovarianfailure type 6 (POF6) [MIM:612310]. An ovarian disorder defined asthe cessation of ovarian function under the age of 40 years. It ischaracterized by oligomenorrhea or amenorrhea, in the presence ofelevated levels of serum gonadotropins and low estradiol.

Defects in FLG are the cause of ichthyosis vulgaris (VI)[MIM:146700], also known as ichthyosis simplex. Ichthyosisvulgaris is the most common form of ichthyosis inherited as anautosomal dominant trait. It is characterized by palmarhyperlinearity, keratosis pilaris and a fine scale that is mostprominent over the lower abdomen, arms, and legs. Ichthyosisvulgaris is characterized histologically by absent or reducedkeratohyalin granules in the epidermis and mild hyperkeratosis.The disease can be associated with frequent asthma, eczema or hayfever.

Defects in FLG are a cause of susceptibility todermatitis atopic type 2 (ATOD2) [MIM:605803]. Atopic dermatitisis a complex, inflammatory disease with multiple alleles atseveral loci thought to be involved in the pathogenesis. Itcommonly begins in infancy or early childhood and is characterizedby a chronic relapsing form of skin inflammation, a disturbance ofepidermal barrier function that culminates in dry skin, and IgE-mediated sensitization to food and environmental allergens. It ismanifested by lichenification, excoriation, and crusting, mainlyon the flexural surfaces of the elbow and knee.

Defects in FN1 are the cause of glomerulopathy withfibronectin deposits type 2 (GFND2) [MIM:601894], also known asfamilial glomerular nephritis with fibronectin deposits orfibronectin glomerulopathy. GFND is a genetically heterogeneousautosomal dominant disorder characterized clinically byproteinuria, microscopic hematuria, and hypertension that leads toend-stage renal failure in the second to fifth decade of life.

Note=A chromosomal aberration involving FIP1L1 is foundin some cases of hypereosinophilic syndrome. Interstitialchromosomal deletion del(4)(q12q12) causes the fusion of FIP1L1and PDGFRA (FIP1L1-PDGFRA).

Defects in FKBP10 are the cause of osteogenesisimperfecta type 6 (OI6) [MIM:610968]. OI6 is a moderate to severe,autosomal recessive form of osteogenesis imperfecta characterizedby increased serum alkaline phosphatase levels and bone histologyexhibiting a fish scale-like lamellar pattern. Osteogenesisimperfecta defines a group of connective tissue disorderscharacterized by bone fragility and low bone mass.

Note=FKBP6 is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.Haploinsufficiency of FKBP6 may be the cause of certaincardiovascular and musculo-skeletal abnormalities observed in thedisease.

Defects in FKRP are the cause of muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies type A5(MDDGA5) [MIM:613153]. MDDGA5 is an autosomal recessive disordercharacterized by congenital muscular dystrophy associated withcobblestone lissencephaly and other brain anomalies, eyemalformations, profound mental retardation, and death usually inthe first years of life. Included diseases are the more severeWalker-Warburg syndrome and the slightly less severe muscle-eye-brain disease.

Defects in FKRP are the cause of muscular dystrophy-dystroglycanopathy congenital with or without mental retardationtype B5 (MDDGB5) [MIM:606612]. MDDGB5 is a congenital musculardystrophy characterized by a severe phenotype with inability towalk, muscle hypertrophy, marked elevation of serum creatinekinase, a secondary deficiency of laminin alpha2, and a markedreduction in alpha-dystroglycan expression. Only a subset ofMDDGB5 patients have brain involvements.

Defects in FKRP are the cause of muscular dystrophy-dystroglycanopathy limb-girdle type C5 (MDDGC5) [MIM:607155], alsoknown as limb-girdle muscular dystrophy type 2I. MDDGC5 is anautosomal recessive disorder with age of onset ranging fromchildhood to adult life, and variable severity. Clinical featuresinclude proximal muscle weakness, waddling gait, calf hypertrophy,cardiomyopathy and respiratory insufficiency. A reduction ofalpha-dystroglycan and laminin alpha-2 expression can be observedon skeletal muscle biopsy from MDDGC5 patients.

Defects in FKTN are the cause of muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies type A4(MDDGA4) [MIM:253800], also called congenital muscular dystrophyFukuyama type (FCMD) or Walker-Warburg syndrome FKTN-related.MDDGA4 is an autosomal recessive disorder characterized bycongenital muscular dystrophy associated with cobblestonelissencephaly and other brain anomalies. Patients suffer fromgeneralized skeletal muscle weakness and hypotonia from earlyinfancy, mental retardation and seizures. Occasional featuresinclude optic atrophy, retinal detachment, cardiomyopathy.

Defects in FKTN are the cause of muscular dystrophy-dystroglycanopathy congenital without mental retardation type B4(MDDGB4) [MIM:613152]. An autosomal recessive disordercharacterized by congenital muscular dystrophy and evidence ofdystroglycanopathy. Features included increased serum creatinekinase, generalized weakness, mild white matter changes on brainMRI in some cases, and absence of mental retardation.

Defects in FKTN are the cause of muscular dystrophy-dystroglycanopathy limb-girdle type C4 (MDDGC4) [MIM:611588].MDDGC4 is an autosomal recessive degenerative myopathycharacterized by progressive weakness of the pelvic and shouldergirdle muscles and elevated serum creatine kinase. The severity ofthe disease depends on age at onset which may vary from early tolate childhood or even adulthood. MDDGC4 is a novel form of LGMD2and has no brain involvement and a remarkable clinical response tocorticosteroids.

Defects in FKTN are the cause of cardiomyopathy dilatedtype 1X (CMD1X) [MIM:611615], also called dilated cardiomyopathywith mild or no proximal muscle weakness. Dilated cardiomyopathyis a disorder characterized by ventricular dilation and impairedsystolic function, resulting in congestive heart failure andarrhythmia. Patients are at risk of premature death.

Defects in FLCN are the cause of Birt-Hogg-Dube syndrome(BHD) [MIM:135150]. BHD is a rare autosomal dominantgenodermatosis characterized by hair follicle hamartomas(fibrofolliculomas), kidney tumors, and spontaneous pneumothorax.Fibrofolliculomas are part of the triad of BHD skin lesions thatalso includes trichodiscomas and acrochordons. Onset of thisdermatologic condition is invariably in adulthood. BHD isassociated with a variety of histologic types of renal tumors,including chromophobe renal cell carcinoma (RCC), benign renaloncocytoma, clear-cell RCC and papillary type I RCC. Multiplelipomas, angiolipomas, and parathyroid adenomas are also seen inpatients affected with this disease. The majority of mutations arepredicted to prematurely terminate the protein.

Defects in FLCN are in some cases a cause of primaryspontaneous pneumothorax (PSP) [MIM:173600]. PSP is a condition inwhich air is present in the pleural space in the absence of aprecipitating event, such as trauma or lung disease. This resultsin secondary collapse of the lung, either partially or completely,and some degree of hypoxia. PSP is relatively common, with anincidence between 7.4-18/100'000 for men and 1.2-6/100'000 forwomen and a dose-dependent, increased risk among smokers. Mostcases are sporadic, typically occurring in tall, thin men aged 10-30 years and generally while at rest. Familial PSP is rarer andusually is inherited as an autosomal dominant condition withreduced penetrance, although X-linked recessive and autosomalrecessive inheritance have also been suggested.

Note=Defects in FLCN may be involved in renal cellcarcinoma.

Defects in FLI1 are a cause of Ewing sarcoma (ES)[MIM:612219]. A highly malignant, metastatic, primitive smallround cell tumor of bone and soft tissue that affects children andadolescents. It belongs to the Ewing sarcoma family of tumors, agroup of morphologically heterogeneous neoplasms that share thesame cytogenetic features. They are considered neural tumorsderived from cells of the neural crest. Ewing sarcoma representsthe less differentiated form of the tumors. Note=A chromosomalaberration involving FLI1 is found in patients with Erwingsarcoma. Translocation t(11,22)(q24,q12) with EWSR1.

Deletion of the FLII gene may be a cause of Smith-Magenissyndrome (SMS) [MIM:182290]. It is a contiguous gene deletionsyndrome involving developmental abnormalities and mentalretardation. The spectrum of clinical findings includes shortstature, brachydactyly, developmental delay, dysmorphic features,sleep disturbances, and behavioral problems.

Defects in FLNA are the cause of periventricular nodularheterotopia type 1 (PVNH1) [MIM:300049], also called nodularheterotopia, bilateral periventricular (NHBP or BPNH). PVNH is adevelopmental disorder characterized by the presence ofperiventricular nodules of cerebral gray matter, resulting from afailure of neurons to migrate normally from the lateralventricular proliferative zone, where they are formed, to thecerebral cortex. PVNH1 is an X-linked dominant form. Heterozygousfemales have normal intelligence but suffer from seizures andvarious manifestations outside the central nervous system,especially related to the vascular system. Hemizygous affectedmales die in the prenatal or perinatal period.

Defects in FLNA are the cause of periventricular nodularheterotopia type 4 (PVNH4) [MIM:300537], also known asperiventricular heterotopia Ehlers-Danlos variant. PVNH4 ischaracterized by nodular brain heterotopia, joint hypermobilityand development of aortic dilation in early adulthood.

Defects in FLNA are the cause of otopalatodigitalsyndrome type 1 (OPD1) [MIM:311300]. OPD1 is an X-linked dominantmultiple congenital anomalies disease mainly characterized by ageneralized skeletal dysplasia, mild mental retardation, hearingloss, cleft palate, and typical facial anomalies. OPD1 belongs toa group of X-linked skeletal dysplasias known as oto-palato-digital syndrome spectrum disorders that also include OPD2,Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia(FMD). Remodeling of the cytoskeleton is central to the modulationof cell shape and migration. FLNA is a widely expressed proteinthat regulates re-organization of the actin cytoskeleton byinteracting with integrins, transmembrane receptor complexes andsecond messengers. Males with OPD1 have cleft palate,malformations of the ossicles causing deafness and milder bone andlimb defects than those associated with OPD2. Obligate femalecarriers of mutations causing both OPD1 and OPD2 have variable(often milder) expression of a similar phenotypic spectrum.

Defects in FLNA are the cause of otopalatodigitalsyndrome type 2 (OPD2) [MIM:304120], also known ascranioorodigital syndrome. OPD2 is a congenital bone disorder thatis characterized by abnormally modeled, bowed bones, small orabsent first digits and, more variably, cleft palate, posteriorfossa brain anomalies, omphalocele and cardiac defects.

Defects in FLNA are the cause of frontometaphysealdysplasia (FMD) [MIM:305620]. FMD is a congenital bone diseasecharacterized by supraorbital hyperostosis, deafness and digitalanomalies.

Defects in FLNA are the cause of Melnick-Needles syndrome(MNS) [MIM:309350]. MNS is a severe congenital bone disordercharacterized by typical facies (exophthalmos, full cheeks,micrognathia and malalignment of teeth), flaring of the metaphysesof long bones, s-like curvature of bones of legs, irregularconstrictions in the ribs, and sclerosis of base of skull.

Defects in FLNA are the cause of X-linked congenitalidiopathic intestinal pseudoobstruction (CIIPX) [MIM:300048].CIIPX is characterized by a severe abnormality of gastrointestinalmotility due to primary qualitative defects of enteric ganglia andnerve fibers. Affected individuals manifest recurrent signs ofintestinal obstruction in the absence of any mechanical lesion.

Defects in FLNA are the cause of FG syndrome type 2(FGS2) [MIM:300321]. FG syndrome (FGS) is an X-linked disordercharacterized by mental retardation, relative macrocephaly,hypotonia and constipation.

Defects in FLNA are the cause of terminal osseousdysplasia (TOD) [MIM:300244]. A rare X-linked dominant male-lethaldisease characterized by skeletal dysplasia of the limbs,pigmentary defects of the skin and recurrent digital fibromaduring infancy. A significant phenotypic variability is observedin affected females.

Defects in FLNA are the cause of cardiac valvulardysplasia X-linked (CVDX) [MIM:314400]. A rare X-linked heartdisease characterized by mitral and/or aortic valve regurgitation.The histologic features include fragmentation of collagenousbundles within the valve fibrosa and accumulation ofproteoglycans, which produces excessive valve tissue leading tobillowing of the valve leaflets.

Note=Interaction with FLNA may compensate fordysfunctional FLNA homodimer in the periventricular nodularheterotopia (PVNH) disorder.

Defects in FLNB are the cause of atelosteogenesis type 1(AO1) [MIM:108720], also known as giant cell chondrodysplasia orspondylohumerofemoral hypoplasia. Atelosteogenesis are lethalshort-limb skeletal dysplasias with vertebral abnormalities,disharmonious skeletal maturation, poorly modeled long bones andjoint dislocations.

Defects in FLNB are the cause of atelosteogenesis type 3(AO3) [MIM:108721]. Atelosteogenesis are short-limb lethalskeletal dysplasias with vertebral abnormalities, disharmoniousskeletal maturation, poorly modeled long bones and jointdislocations. In AO3 recurrent respiratory insufficiency and/orinfections usually result in early death.

Defects in FLNB are the cause of boomerang dysplasia(BOOMD) [MIM:112310]. This is a perinatal lethalosteochondrodysplasia characterized by absence orunderossification of the limb bones and vertebre. Boomerangdysplasia is distinguished from atelosteogenesis on the basis of amore severe defect in mineralisation, with complete absence ofossification in some limb elements and vertebral segments.

Defects in FLNB are the cause of autosomal dominantLarsen syndrome (LRS1) [MIM:150250]. LRS1 is a geneticallyheterogeneous disorder characterized by multiple jointdislocations, craniofacial abnormalities and accessory carpalbones.

Defects in FLNB are the cause of spondylocarpotarsalsynostosis syndrome (SCT) [MIM:272460], also known asspondylocarpotarsal syndrome (SCT) or congenital synspondylism orvertebral fusion with carpal coalition or congenital scoliosiswith unilateral unsegmented bar. The disorder is characterized byshort stature and vertebral, carpal and tarsal fusions.

Defects in FLNC are the cause of myopathy myofibrillarfilamin C-related (MFM-FLNC) [MIM:609524]. A neuromusculardisorder, usually with an adult onset, characterized by focalmyofibrillar destruction and pathological cytoplasmic proteinaggregations, and clinical features of a limb-girdle myopathy.

Defects in FLVCR1 are the cause of posterior columnataxia with retinitis pigmentosa (PCARP) [MIM:609033]. Aneurodegenerative syndrome beginning in infancy with areflexia andretinitis pigmentosa. Nyctalopia (night blindness) and peripheralvisual field loss are usually evident during late childhood orteenage years, with subsequent progressive constriction of thevisual fields and loss of central retinal function over time. Asensory ataxia caused by degeneration of the posterior columns ofthe spinal cord results in a loss of proprioceptive sensation thatis clinically evident in the second decade of life and graduallyprogresses. Scoliosis, camptodactyly, achalasia, gastrointestinaldysmotility, and a sensory peripheral neuropathy are variablefeatures of the disease. Affected individuals have no clinical orradiological evidence of cerebral or cerebellar involvement.Note=Defective neuronal heme transmembrane export due to FLVCR1mutations may abrogate the neuroprotective effects of neuroglobinand initiate an apoptotic cascade that results in the selectivedegeneration of photoreceptors in the neurosensory retina andsensory neurons in the posterior spinal cord.

Defects in FLVCR2 are the cause of proliferativevasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH)[MIM:225790]. It is a rare prenatally lethal disordercharacterized by hydranencephaly, a distinctive glomerularvasculopathy in the central nervous system and retina, and diffuseischemic lesions of the brain stem, basal ganglia, and spinal cordwith calcifications. Hydranencephaly is a condition where thegreater portions of the cerebral hemispheres and corpus striatumare replaced by cerebrospinal fluid and glial tissue.

Defects in FMO3 are the cause of trimethylaminuria (TMAU)[MIM:602079], also known as fish-odor syndrome. TMAU is an inbornerror of metabolism associated with an offensive body odor andcaused by deficiency of FMO-mediated N-oxidation of amino-trimethylamine (TMA) derived from foodstuffs. Such individualsexcrete relatively large amounts of TMA in their urine, sweat, andbreath, and exhibit a fishy body odor characteristic of themalodorous free amine.

Defects in FMR1 are the cause of fragile X syndrome(FRAX) [MIM:300624]. Fragile X syndrome is a common geneticdisease (has a prevalence of one in every 2000 children) which ischaracterized by moderate to severe mental retardation,macroorchidism (enlargement of the testicles), large ears,prominent jaw, and high-pitched, jocular speech. The defect inmost fragile X syndrome patients results from an amplification ofa CGG repeat region which is directly in front of the codingregion.

Defects in FMR1 are the cause of fragile X tremor/ataxiasyndrome (FXTAS) [MIM:300623]. In FXTAS, the expanded repeatsrange in size from 55 to 200 repeats and are referred to as'premutations'. Full repeat expansions with greater than 200repeats results in fragile X mental retardation syndrome[MIM:300624]. Carriers of the premutation typically do not showthe full fragile X syndrome phenotype, but comprise a subgroupthat may have some physical features of fragile X syndrome or mildcognitive and emotional problems.

Defects in FMR1 are the cause of premature ovarianfailure syndrome type 1 (POF1) [MIM:311360]. An ovarian disorderdefined as the cessation of ovarian function under the age of 40years. It is characterized by oligomenorrhea or amenorrhea, in thepresence of elevated levels of serum gonadotropins and lowestradiol.

Note=A chromosomal aberration involving FNBP1 is found inacute leukemias. Translocation t(9,11)(q34,q23) with MLL. Therelatively low incidence of the MLL-FNBP1 fusion protein in acuteleukemia may reflect the marginal capacity of this fusion proteinto induce cellular transformation.

Defects in ZFPM2 may be a cause of tetralogy of Fallot(TOF) [MIM:187500]. TOF is a congenital heart anomaly whichconsists of pulmonary stenosis, ventricular septal defect,dextroposition of the aorta (aorta is on the right side instead ofthe left) and hypertrophy of the right ventricle. This conditionresults in a blue baby at birth due to inadequate oxygenation.Surgical correction is emergent.

Defects in ZFPM2 are the cause of diaphragmatic hernia 3(DIH3) [MIM:610187], a form of congenital diaphragmatic hernia(CDH). CDH refers to a group of congenital defects in thestructural integrity of the diaphragm associated with often lethalpulmonary hypoplasia and pulmonary hypertension.

Defects in FOLR1 are the cause of neurodegeneration dueto cerebral folate transport deficiency (NCFTD) [MIM:613068].NCFTD is an autosomal recessive disorder resulting from brain-specific folate deficiency early in life. Onset is apparent inlate infancy with severe developmental regression, movementdisturbances, epilepsy, and leukodystrophy. Note=Recognition anddiagnosis of this disorder is critical because folinic acidtherapy can reverse the clinical symptoms and improve brainabnormalities and function.

Defects in FOXC2 are the cause of lymphedema hereditarytype 2 (LMPH2) [MIM:153200], also known as Meige lymphedema.Hereditary lymphedema is a chronic disabling condition whichresults in swelling of the extremities due to altered lymphaticflow. Patients with lymphedema suffer from recurrent localinfections, and physical impairment.

Defects in FOXC2 are a cause of lymphedema-yellow nails(LYYN) [MIM:153300]. LYYN is characterized by yellow, dystrophic,thick and slowly growing nails, associated with lymphedema andrespiratory involvement. Lymphedema occurs more often in the lowerlimbs. It can appear at birth or later in life. Onset generallyfollows the onset of ungual abnormalities.

Defects in FOXC2 are a cause of lymphedema-distichiasis(LYD) [MIM:153400]. LYD is characterized by primary limblymphedema usually starting at puberty (but in some cases later orat birth) and associated with distichiasis (double rows ofeyelashes, with extra eyelashes growing from the Meibomian glandorifices).

Defects in FOXD3 are associated with susceptibility toautoimmune disease type 1 (AIS1) [MIM:607836]. AIS1 is a disordercharacterized by the association of vitiligo with autoimmunethyroiditis (Hashimoto thyroiditis).

Defects in FOXE1 are the cause of Bamforth-Lazarussyndrome (BLS) [MIM:241850]. BLS is associated with thyroidagenesis, cleft palate and choanal atresia.

Defects in FOXE3 are a cause of anterior segmentmesenchymal dysgenesis (ASMD) [MIM:107250], also known as anteriorsegment ocular dysgenesis (ASOD). ASMD consists of a range ofdevelopmental defects in structures at the front of the eye,resulting from abnormal migration or differentiation of the neuralcrest derived mesenchymal cells that give rise to the cornea,iris, and other components of the anterior chamber during eyedevelopment. Mature anterior segment anomalies are associated withan increased risk of glaucoma and corneal opacity. Conditionsfalling within the phenotypic spectrum include aniridia, posteriorembryotoxon, Axenfeld anomaly, Reiger anomaly/syndrome, Petersanomaly, and iridogoniodysgenesis.

Defects in FOXE3 are a cause of congenital primaryaphakia (CPA) [MIM:610256]. Aphakia is a rare congenital eyedisorder in which the lens is missing. It has been histologicallysubdivided into primary and secondary forms, in accordance withthe severity of defects of the ocular tissues, whose developmentrequires the initial presence of a lens. CPA results from an earlydevelopmental arrest, around the 4th-5th week of gestation inhumans, that prevents the formation of any lens structure andleads to severe secondary ocular defects, including a completeaplasia of the anterior segment of the eye. In contrast, insecondary aphakic eyes, lens induction has occurred, and the lensvesicle has developed to some degree but finally has progressivelyresorbed perinatally, leading, therefore, to less-severe oculardefects.

Defects in FOXF1 are the cause of alveolar capillarydysplasia with misalignment of pulmonary veins (ACDMPV)[MIM:265380]. ACDMPV is a rare malformation due to abnormaldevelopment of the capillary vascular system in the lungs.Histologically, it is characterized by failure of formation andingrowth of alveolar capillaries, medial muscular thickening ofsmall pulmonary arterioles with muscularization of the intraacinararterioles, thickened alveolar walls, and anomalously situatedpulmonary veins running alongside pulmonary arterioles and sharingthe same adventitial sheath. Less common features include areduced number of alveoli and a patchy distribution of thehistopathologic changes. Affected infants present with respiratorydistress and the disease is fatal within the newborn period.Additional features include multiple congenital anomaliesaffecting the cardiovascular, gastrointestinal, genitourinary, andmusculoskeletal systems, as well as disruption of the normalright-left asymmetry of intrathoracic or intraabdominal organs.ACDMPV is a rare cause of persistent pulmonary hypertension of thenewborn, an abnormal physiologic state caused by failure oftransition of the pulmonary circulation from the high pulmonaryvascular resistance of the fetus to the low pulmonary vascularresistance of the newborn.

Defects in FOXG1 are the cause of congenital variant ofRett syndrome (RTTCV) [MIM:613454]. RTTCV is a severeneurodevelopmental disorder with features of classic Rett syndromebut earlier onset in the first months of life. Clinical featuresinclude progressive microcephaly, hypotonia, irresponsiveness andirritability in the neonatal period, mental retardation,psychomotor regression and stereotypical movements.

Genetic variations in FOXJ1 may be associated withsusceptibility to allergic rhinitis (ALRH) [MIM:607154]. Allergicrhinitis is a common disease of complex inheritance and ischaracterized by mucosal inflammation caused by allergen exposure.

Defects in FOXN1 are the cause of T-cell immunodeficiencycongenital alopecia and nail dystrophy (TIDAND) [MIM:601705]. Adisorder characterized by the association of congenital alopecia,severe T-cell immunodeficiency, and ridging and pitting of allnails.

Defects in FOXO1 are a cause of rhabdomyosarcoma type 2(RMS2) [MIM:268220]. It is a form of rhabdomyosarcoma, a highlymalignant tumor of striated muscle derived from primitivemesenchimal cells and exhibiting differentiation alongrhabdomyoblastic lines. Rhabdomyosarcoma is one of the mostfrequently occurring soft tissue sarcomas and the most common inchildren. It occurs in four forms: alveolar, pleomorphic,embryonal and botryoidal rhabdomyosarcomas. Note=Chromosomalaberrations involving FOXO1 are found in rhabdomyosarcoma.Translocation (2,13)(q35,q14) with PAX3, translocationt(1,13)(p36,q14) with PAX7. The resulting protein is atranscriptional activator.

Note=A chromosomal aberration involving FOXO3 is found insecondary acute leukemias. Translocation t(6,11)(q21,q23) withMLL/HRX.

Note=A chromosomal aberration involving FOXO4 is found inacute leukemias. Translocation t(X,11)(q13,q23) with MLL/HRX. Theresult is a rogue activator protein.

Note=A chromosomal aberration involving FOXP1 is found inacute lymphoblastic leukemia. Translocation t(9,3)(p13,p14.1) withPAX5.

Defects in FOXP1 are the cause of mental retardation withlanguage impairment and autistic features (MRLIAF) [MIM:613670].It is a developmental disorder characterized by mild to moderatemental retardation, language impairment, and autistic features.Patients show global delay, delayed walking, severely delayedspeech development, and behavioral abnormalities, includingirritability, hyperactivity, aggression, and stereotypical rigidbehaviors.

Defects in FOXP2 are the cause of speech-languagedisorder 1 (SPCH1) [MIM:602081], also known as autosomal dominantspeech and language disorder with orofacial dyspraxia. Affectedindividuals have a severe impairment in the selection andsequencing of fine orofacial movements, which are necessary forarticulation. They also show deficits in several facets oflanguage processing (such as the ability to break up words intotheir constituent phonemes) and grammatical skills.

Note=A chromosomal aberration involving FOXP2 is a causeof severe speech and language impairment. Translocationt(5,7)(q22,q31.2).

Defects in FOXP3 are the cause of immunodeficiencypolyendocrinopathy, enteropathy, X-linked syndrome (IPEX)[MIM:304790], also known as X-linked autoimmunity-immunodeficiencysyndrome. IPEX is characterized by neonatal onset insulin-dependent diabetes mellitus, infections, secretory diarrhea,trombocytopenia, anemia and eczema. It is usually lethal ininfancy.

Note=A chromosomal aberration involving FGFR1OP may be acause of stem cell myeloproliferative disorder (MPD).Translocation t(6,8)(q27,p11) with FGFR1. MPD is characterized bymyeloid hyperplasia, eosinophilia and T-cell or B-celllymphoblastic lymphoma. In general it progresses to acute myeloidleukemia. The fusion proteins FGFR1OP-FGFR1 or FGFR1-FGFR1OP mayexhibit constitutive kinase activity and be responsible for thetransforming activity.

Defects in FRAS1 are a cause of Fraser syndrome (FRASS)[MIM:219000]. Fraser syndrome is a multisystem malformationusually comprising cryptophthalmos, cutaneous syndactyly, earabnormalities, renal agenesis and congenital heart defects.

Defects in FXN are the cause of Friedreich ataxia (FRDA)[MIM:229300]. FRDA is an autosomal recessive, progressivedegenerative disease characterized by neurodegeneration andcardiomyopathy it is the most common inherited ataxia. Thedisorder is usually manifest before adolescence and is generallycharacterized by incoordination of limb movements, dysarthria,nystagmus, diminished or absent tendon reflexes, Babinski sign,impairment of position and vibratory senses, scoliosis, pes cavus,and hammer toe. In most patients, FRDA is due to GAA tripletrepeat expansions in the first intron of the frataxin gene. But insome cases the disease is due to mutations in the coding region.

Defects in FREM1 are the cause of bifid nose with orwithout anorectal and renal anomalies (BNAR) [MIM:608980]. A bifidnose is a rare congenital deformity due to failure of the pairednasal processes to fuse to a single midline organ during earlygestation. BNAR is an autosomal recessive disorder and patientsusually present a bifid nose associated with renal and anorectalmalformations.

Defects in FREM2 are a cause of Fraser syndrome (FRASS)[MIM:219000]. Fraser syndrome is a multisystem malformationusually comprising cryptophthalmos, cutaneous syndactyly, earabnormalities, renal agenesis and congenital heart defects.

Defects in FTL are the cause of hereditaryhyperferritinemia-cataract syndrome (HHCS) [MIM:600886]. It is anautosomal dominant disease characterized by early-onset bilateralcataract. Affected patients have elevated level of circulatingferritin. HHCS is caused by mutations in the iron responsiveelement (IRE) of the FTL gene.

Defects in FTL are the cause of neurodegeneration withbrain iron accumulation type 3 (NBIA3) [MIM:606159], also known asadult-onset basal ganglia disease. It is a movement disorder withheterogeneous presentations starting in the fourth to sixthdecade. It is characterized by a variety of neurological signsincluding parkinsonism, ataxia, corticospinal signs, mildnonprogressive cognitive deficit and episodic psychosis. It islinked with decreased serum ferritin levels.

Defects in WDPCP are the cause of Bardet-Biedl syndrometype 15 (BBS15) [MIM:209900]. Bardet-Biedl syndrome (BBS) is agenetically heterogeneous, autosomal recessive disordercharacterized by usually severe pigmentary retinopathy, earlyonset obesity, polydactyly, hypogenitalism, renal malformation andmental retardation. Secondary features include diabetes mellitus,hypertension and congenital heart disease. Bardet-Biedl syndromeinheritance is autosomal recessive, but three mutated alleles (twoat one locus, and a third at a second locus) may be required forclinical manifestation of some forms of the disease.

Note=Mutations in WDPCP may act as modifiers of thephenotypic expression of Bardet-Biedl syndrome and Meckel syndromeby interacting in trans with primary BBS and MKS loci.

Defects in FRMD7 are the cause of nystagmus congenital X-linked type 1 (NYS1) [MIM:310700]. NYS1 is a condition defined asconjugated, spontaneous and involuntary ocular oscillations thatappear at birth or during the first three months of life. Otherassociated features may include mildly decreased visual acuity,strabismus, astigmatism, and occasionally head nodding.

Note=A chromosomal aberration involving FRYL is found intreatment-related acute lymphoblastic leukemia (ALL).Translocation t(4,11)(p12,q23) that forms a MLL-FRYL fusionprotein.

Defects in FSCN2 are the cause of retinitis pigmentosatype 30 (RP30) [MIM:607921]. RP leads to degeneration of retinalphotoreceptor cells. Patients typically have night visionblindness and loss of midperipheral visual field. As theircondition progresses, they lose their far peripheral visual fieldand eventually central vision as well. RP30 inheritance isautosomal dominant.

Defects in FSHB are a cause of isolated follicle-stimulating hormone deficiency (IFSHD) [MIM:229070]. Selectivefollicle-stimulating hormone deficiency is an uncommon cause ofinfertility, producing amenorrhea and hypogonadism in women andoligo or azoospermia with normal testosterone levels in normallyvirilised men.

Defects in FSHR are a cause of ovarian dysgenesis type 1(ODG1) [MIM:233300], also known as premature ovarian failure orgonadal dysgenesis XX type or XX gonadal dysgenesis (XXGD) orhereditary hypergonadotropic ovarian failure or hypergonadotropicovarian dysgenesis with normal karyotype. ODG1 is an autosomalrecessive disease characterized by primary amenorrhea, variabledevelopment of secondary sex characteristics, and high serumlevels of follicle-stimulating hormone (FSH) and luteinizinghormone (LH).

Defects in FSHR are a cause of ovarian hyperstimulationsyndrome (OHSS) [MIM:608115]. OHSS is a disorder which occurseither spontaneously or most often as an iatrogenic complicationof ovarian stimulation treatments for in vitro fertilization. Theclinical manifestations vary from abdominal distention anddiscomfort to potentially life-threatening, massive ovarianenlargement and capillary leak with fluid sequestration.Pathologic features of this syndrome include the presence ofmultiple serous and hemorrhagic follicular cysts lined byluteinized cells, a condition called hyperreactio luteinalis.

Note=A chromosomal aberration involving FSTL3 is found ina case of B-cell chronic lymphocytic leukemia. Translocationt(11,19)(q13,p13) with CCDN1.

Defects in FTCD are the cause of glutamateformiminotransferase deficiency (GLUFORDE) [MIM:229100], alsoknown as formiminoglutamicaciduria (FIGLU-uria). It is anautosomal recessive disorder. Features of a severe phenotype,include elevated levels of formiminoglutamate (FIGLU) in the urinein response to histidine administration, megaloblastic anemia, andmental retardation. Features of a mild phenotype include highurinary excretion of FIGLU in the absence of histidineadministration, mild developmental delay, and no hematologicalabnormalities.

Defects in RPGRIP1L are the cause of Joubert syndrometype 7 (JBTS7) [MIM:611560]. JBTS is an autosomal recessivedisorder presenting with cerebellar ataxia, oculomotor apraxia,hypotonia, neonatal breathing abnormalities and psychomotor delay.Neuroradiologically, it is characterized by cerebellar vermishypoplasia/aplasia, thickened and reoriented superior cerebellarpeduncles, and an abnormally large interpeduncular fossa, givingthe appearance of a molar tooth on transaxial slices (molar toothsign). Additional variable features include retinal dystrophy andrenal disease.

Defects in RPGRIP1L are the cause of Meckel syndrome type5 (MKS5) [MIM:611561]. MKS is an autosomal recessive disordercharacterized by a combination of renal cysts and variablyassociated features including developmental anomalies of thecentral nervous system (typically encephalocele), hepatic ductaldysplasia and cysts, and polydactyly.

Defects in RPGRIP1L are a cause of COACH syndrome(COACHS) [MIM:216360]. It is a disorder characterized by mentalretardation, ataxia due to cerebellar hypoplasia, and hepaticfibrosis. Patients present the molar tooth sign, a midbrain-hindbrain malformation pathognomonic for Joubert syndrome andrelated disorders. Other features, such as coloboma and renalcysts, may be variable.

Defects in FTO are the cause of growth retardationdevelopmental delay coarse facies and early death (GRDDCFED)[MIM:612938]. The disease consists of a severe children multiplecongenital anomaly syndrome with death by the age of 3 years. Allaffected individuals had postnatal growth retardation,microcephaly, severe psychomotor delay, functional brain deficits,and characteristic facial dysmorphism. In some patients,structural brain malformations, cardiac defects, genitalanomalies, and cleft palate were also observed.

Defects in FUCA1 are the cause of fucosidosis (FUCA1D)[MIM:230000]. FUCA1D is an autosomal recessive lysosomal storagedisease characterized by accumulation of fucose-containingglycolipids and glycoproteins in various tissues. Clinical signsinclude facial dysmorphism, dysostosis multiplex, moderatehepatomegaly, severe intellectual deficit, deafness, and accordingto age, angiokeratomas.

Defects in SLC35C1 are the cause of congenital disorderof glycosylation type 2C (CDG2C) [MIM:266265], also known asleukocyte adhesion deficiency type II (LAD2). CDGs are a family ofsevere inherited diseases caused by a defect in protein N-glycosylation. They are characterized by under-glycosylated serumproteins. These multisystem disorders present with a wide varietyof clinical features, such as disorders of the nervous systemdevelopment, psychomotor retardation, dysmorphic features,hypotonia, coagulation disorders, and immunodeficiency. The broadspectrum of features reflects the critical role of N-glycoproteinsduring embryonic development, differentiation, and maintenance ofcell functions. The clinical features of CDG2C include mentalretardation, short stature, facial stigmata, and recurrentbacterial peripheral infections with persistently elevatedperipheral leukocytes. Biochemically, CDG2C is characterized by alack of fucosylated glycoconjugates, including selectin ligands.

Defects in FH are the cause of fumarase deficiency (FHD)[MIM:606812], also known as fumaricaciduria. FHD is characterizedby progressive encephalopathy, developmental delay, hypotonia,cerebral atrophy and lactic and pyruvic acidemia.

Defects in FH are the cause of multiple cutaneous anduterine leiomyomata (MCUL1) [MIM:150800]. MCUL1 is an autosomaldominant condition in which affected individuals develop benignsmooth muscle tumors (leiomyomata) of the skin. Affected femalesalso usually develop leiomyomata of the uterus (fibroids).

Defects in FH are the cause of hereditary leiomyomatosisand renal cell cancer (HLRCC) [MIM:605839].

Note=A chromosomal aberration involving FUS is found in apatient with malignant myxoid liposarcoma. Translocationt(12,16)(q13,p11) with DDIT3.

Note=A chromosomal aberration involving FUS is a cause ofacute myeloid leukemia (AML). Translocation t(16,21)(p11,q22) withERG.

Defects in FUS may be a cause of angiomatoid fibroushistiocytoma (AFH) [MIM:612160]. A distinct variant of malignantfibrous histiocytoma that typically occurs in children andadolescents and is manifest by nodular subcutaneous growth.Characteristic microscopic features include lobulated sheets ofhistiocyte-like cells intimately associated with areas ofhemorrhage and cystic pseudovascular spaces, as well as a strikingcuffing of inflammatory cells, mimicking a lymph node metastasis.Note=A chromosomal aberration involving FUS is found in a patientwith angiomatoid fibrous histiocytoma. Translocationt(12,16)(q13,p11.2) with ATF1 generates a chimeric FUS/ATF1protein.

Defects in FUS are the cause of amyotrophic lateralsclerosis type 6 (ALS6) [MIM:608030]. ALS6 is a familial form ofamyotrophic lateral sclerosis. ALS is a neurodegenerative disorderaffecting upper motor neurons in the brain and lower motor neuronsin the brain stem and spinal cord, resulting in fatal paralysis.Sensory abnormalities are absent. Death usually occurs within 2 to5 years. The etiology of amyotrophic lateral sclerosis is likelyto be multifactorial, involving both genetic and environmentalfactors. The disease is inherited in 5-10%.

Defects in FOXRED1 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinicalmanifestations from lethal neonatal disease to adult-onsetneurodegenerative disorders. Phenotypes include macrocephaly withprogressive leukodystrophy, non-specific encephalopathy,cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leberhereditary optic neuropathy, and some forms of Parkinson disease.

Genetic variations in FXYD6 are associated withsusceptibility to schizophrenia type 2 (SCZD2) [MIM:603342]. Acomplex, multifactorial psychotic disorder or group of disorderscharacterized by disturbances in the form and content of thought(e.g. delusions, hallucinations), in mood (e.g. inappropriateaffect), in sense of self and relationship to the external world(e.g. loss of ego boundaries, withdrawal), and in behavior (e.gbizarre or apparently purposeless behavior). Although it affectsemotions, it is distinguished from mood disorders in which suchdisturbances are primary. Similarly, there may be mild impairmentof cognitive function, and it is distinguished from the dementiasin which disturbed cognitive function is considered primary. Somepatients manifest schizophrenic as well as bipolar disordersymptoms and are often given the diagnosis of schizoaffectivedisorder.

Defects in PIKFYVE are the cause of corneal fleckdystrophy (CFD) [MIM:121850]. CFD is an autosomal dominantdisorder of the cornea characterized by numerous small whiteflecks scattered in all levels of the stroma. Although CFD mayoccasionally cause mild photophobia, patients are typicallyasymptomatic and have normal vision.

Defects in FZD4 are the cause of vitreoretinopathyexudative type 1 (EVR1) [MIM:133780], also known as autosomaldominant familial exudative vitreoretinopathy (FEVR) or Criswick-Schepens syndrome. EVR1 is a disorder of the retinal vasculaturecharacterized by an abrupt cessation of growth of peripheralcapillaries, leading to an avascular peripheral retina. This maylead to compensatory retinal neovascularization, which is thoughtto be induced by hypoxia from the initial avascular insult. Newvessels are prone to leakage and rupture causing exudates andbleeding, followed by scarring, retinal detachment and blindness.Clinical features can be highly variable, even within the samefamily. Patients with mild forms of the disease are asymptomatic,and their only disease-related abnormality is an arc of avascularretina in the extreme temporal periphery.

Defects in G6PC3 are the cause of neutropenia severecongenital autosomal recessive type 4 (SCN4) [MIM:612541].Autosomal recessive SCN constitutes a primary immunodeficiencysyndrome associated with increased apoptosis in myeloid cells.Individuals show a paucity of mature neutrophils in peripheralblood and bone marrow and develop life-threatening bacterialinfections. SCN4 is a severe congenital neutropenia syndromeassociated with cardiac and urogenital malformations.

Defects in G6PC3 are the cause of Dursun syndrome (DURSS)[MIM:612541]. A disease characterized by pulmonary arterialhypertension, cardiac abnormalities including secundum-type atrialseptal defect, intermittent neutropenia, lymphopenia, monocytosisand anemia.

Defects in G6PC are the cause of glycogen storage diseasetype 1A (GSD1A) [MIM:232200]. A metabolic disorder characterizedby impairment of terminal steps of glycogenolysis andgluconeogenesis. Patients manifest a wide range of clinicalsymptoms and biochemical abnormalities, including hypoglycemia,severe hepatomegaly due to excessive accumulation of glycogen,kidney enlargement, growth retardation, lactic acidemia,hyperlipidemia, and hyperuricemia.

Defects in G6PD are the cause of chronic non-spherocytichemolytic anemia (CNSHA) [MIM:305900]. Deficiency of G6PD isassociated with hemolytic anemia in two different situations.First, in areas in which malaria has been endemic, G6PD-deficiencyalleles have reached high frequencies (1% to 50%) and deficientindividuals, though essentially asymptomatic in the steady state,have a high risk of acute hemolytic attacks. Secondly, sporadiccases of G6PD deficiency occur at a very low frequencies, and theyusually present a more severe phenotype. Several types of CNSHAare recognized. Class-I variants are associated with severe NSHA,class-II have an activity <10% of normal, class-III have anactivity of 10% to 60% of normal, class-IV have near normalactivity.

Defects in H6PD are a cause of cortisone reductasedeficiency (CRD) [MIM:604931]. In CRD, activation of cortisone tocortisol does not occur, resulting in adrenocorticotropin-mediatedandrogen excess and a phenotype resembling polycystic ovarysyndrome (PCOS).

Defects in GPI are the cause of hemolytic anemia non-spherocytic due to glucose phosphate isomerase deficiency (HA-GPID) [MIM:613470]. It is a form of anemia in which there is noabnormal hemoglobin or spherocytosis. It is caused by glucosephosphate isomerase deficiency. Severe GPI deficiency can beassociated with hydrops fetalis, immediate neonatal death andneurological impairment.

Defects in SLC37A4 are the cause of glycogen storagedisease type 1B (GSD1B) [MIM:232220]. GSD1B is a metabolicdisorder characterized by impairment of terminal steps ofglycogenolysis and gluconeogenesis. GSD1 patients manifest a widerange of clinical symptoms and biochemical abnormalities,including hypoglycemia, severe hepatomegaly due to excessiveaccumulation of glycogen, kidney enlargement, growth retardation,lactic acidemia, hyperlipidemia, and hyperuricemia. GSD1B patientsalso present a tendency towards infections associated withneutropenia, relapsing aphthous gingivostomatitis, andinflammatory bowel disease.

Defects in SLC37A4 are the cause of glycogen storagedisease type 1C (GSD1C) [MIM:232240].

Defects in SLC37A4 are the cause of glycogen storagedisease type 1D (GSD1D) [MIM:232240].

Defects in GALC are the cause of leukodystrophy globoidcell (GLD) [MIM:245200], also known as Krabbe disease. Thisautosomal recessive disorder results in the insufficientcatabolism of several galactolipids that are important in theproduction of normal myelin. Clinically, the most frequent form isthe infantile form. Most patients (90%) present before six monthsof age with irritability, spasticity, arrest of motor and mentaldevelopment, and bouts of temperature elevation without infection.This is followed by myoclonic jerks of arms and legs,oposthotonus, hypertonic fits, and mental regression, whichprogresses to a severe decerebrate condition with no voluntarymovements and death from respiratory infections or cerebralhyperpyrexia before 2 years of age. However, a significant numberof cases with later onset, presenting with unexplained blindness,weakness and/or progressive motor, and sensory neuropathy that canprogress to severe mental incapacity and death, have beenidentified.

Defects in GALE are the cause of epimerase-deficiencygalactosemia (EDG) [MIM:230350], also known as galactosemia type3. Clinical features include early-onset cataracts, liver damage,deafness and mental retardation. There are two clinically distinctforms of EDG. (1) A benign, or 'peripheral' form with nodetectable GALE activity in red blood cells and characterized bymild symptoms. Some patients may suffer no symptoms beyond raisedlevels of galactose-1-phosphate in the blood. (2) A much rarer'generalized' form with undetectable levels of GALE activity inall tissues and resulting in severe features such as restrictedgrowth and mental development.

Defects in GALK1 are the cause of galactosemia II(GALCT2) [MIM:230200]. Galactosemia II is an autosomal recessivedeficiency characterized by congenital cataracts during infancyand presenile cataracts in the adult population. The cataracts aresecondary to accumulation of galactitol in the lenses.

Defects in GALNS are the cause of mucopolysaccharidosistype 4A (MPS4A) [MIM:253000], also known as Morquio A syndrome.MPS4A is a form of mucopolysaccharidosis type 4, an autosomalrecessive lysosomal storage disease characterized by intracellularaccumulation of keratan sulfate and chondroitin-6-sulfate. Keyclinical features include short stature, skeletal dysplasia,dental anomalies, and corneal clouding. Intelligence is normal andthere is no direct central nervous system involvement, althoughthe skeletal changes may result in neurologic complications. Thereis variable severity, but patients with the severe phenotypeusually do not survive past the second or third decade of life.

Defects in GALNT3 are a cause of hyperphosphatemicfamilial tumoral calcinosis (HFTC) [MIM:211900]. HFTC is a severeautosomal recessive metabolic disorder that manifests withhyperphosphatemia and massive calcium deposits in the skin andsubcutaneous tissues. Some patients manifest recurrent, transient,painful swellings of the long bones associated with theradiographic findings of periosteal reaction and corticalhyperostosis and absence of skin involvement.

Defects in GALT are the cause of galactosemia (GALCT)[MIM:230400]. Galactosemia is an inherited disorder of galactosemetabolism that causes jaundice, cataracts, and mentalretardation.

Defects in GAMT are the cause of guanidinoacetatemethyltransferase deficiency (GAMT deficiency) [MIM:612736]. GAMTdeficiency is an autosomal recessive disorder characterized bydevelopmental delay/regression, mental retardation, severedisturbance of expressive and cognitive speech, intractableseizures and movement disturbances, severe depletion ofcreatine/phosphocreatine in the brain, and accumulation ofguanidinoacetic acid (GAA) in brain and body fluids.

Defects in GAN are the cause of giant axonal neuropathy(GAN) [MIM:256850]. GAN is a severe autosomal recessivesensorimotor neuropathy affecting both the peripheral nerves andthe central nervous system. It is characterized by neurofilamentaccumulation, leading to segmental distention of axons.

Note=A chromosomal aberration involving GAS7 is found inacute myeloid leukemia. Translocation t(11,17)(q23,p13) withMLL/HRX.

Defects in GATA1 are the cause of X-linkeddyserythropoietic anemia and thrombocytopenia (XDAT) [MIM:300367].XDAT is a disorder characterized by erythrocytes with abnormalsize and shape, and paucity of platelets in peripheral blood. Thebone marrow contains abundant and abnormally small megakaryocytes.

Defects in GATA1 are the cause of X-linkedthrombocytopenia with beta-thalassemia (XLTT) [MIM:314050], alsoknwon as thrombocytopenia, platelet dysfunction, hemolysis, andimbalanced globin synthesis. XLTT consists of an unusual form ofthrombocytopenia with beta-thalassemia. Patients have splenomegalyand petechiae, moderate thrombocytopenia, prolonged bleeding timedue to platelet dysfunction, reticulocytosis and unbalancedhemoglobin chain synthesis resembling that of beta-thalassemiaminor.

Defects in GATA3 are the cause of hypoparathyroidism withsensorineural deafness and renal dysplasia (HDR) [MIM:146255],also known as Barakat syndrome.

Defects in GATA4 are the cause of atrial septal defecttype 2 (ASD2) [MIM:607941]. ASD2 is a congenital heartmalformation characterized by incomplete closure of the wallbetween the atria resulting in blood flow from the left to theright atria. ASD2 patients show other heart abnormalitiesincluding ventricular and atrioventricular septal defects,pulmonary valve thickening or insufficiency of the cardiac valves.ASD2 is not associated with defects in the cardiac conductionsystem or non-cardiac abnormalities.

Defects in GATM are the cause of arginine:glycineamidinotransferase deficiency (AGAT deficiency) [MIM:612718]. AGATdeficiency is an autosomal recessive disorder characterized bydevelopmental delay/regression, mental retardation, severedisturbance of expressive and cognitive speech, and severedepletion of creatine/phosphocreatine in the brain.

Defects in GABRA1 are a cause of juvenile myoclonicepilepsy type 5 (EJM5) [MIM:611136], also known as childhoodabsence epilepsy type 4 (ECA4). EJM5 is a subtype of idiopathicgeneralized epilepsy (IGE) characterized by onset at age 6-7years, frequent absence seizures (several per day) and bilateral,synchronous, symmetric 3-Hz spike waves on EEG. Duringadolescence, tonic-clonic and myoclonic seizures develop. Absenceseizures may either remit or persist into adulthood.

Note=Defects in GABRB3 are associated with chronicinsomnia, a condition of inability to initiate or maintain sleep.This may occur as a primary disorder or in association withanother medical or psychiatric condition.

Defects in GABRB3 are the cause of childhood absenceepilepsy type 5 (ECA5) [MIM:612269]. ECA5 is a subtype ofidiopathic generalized epilepsy (IGE) characterized by an onset atage 6-7 years, frequent absence seizures (several per day) andbilateral, synchronous, symmetric 3-Hz spike waves on EEG. Duringadolescence, tonic-clonic and myoclonic seizures develop. Absenceseizures may either remit or persist into adulthood.

Defects in GABRD are the cause of susceptibility togeneralized epilepsy with febrile seizures plus type 5 (GEFS+5)[MIM:604233]. Generalized epilepsy with febrile seizures-plusrefers to a rare familial condition with incomplete penetrance andlarge intrafamilial variability. Patients display febrile seizurespersisting sometimes beyond the age of 6 years and/or a variety ofafebrile seizure types. GEFS+ is a disease combining febrileseizures, generalized seizures often precipitated by fever at age6 years or more, and partial seizures, with a variable degree ofseverity.

Defects in GABRD are the cause of susceptibility toidiopathic generalized epilepsy type 10 (IGE10) [MIM:613060]. Adisorder characterized by recurring generalized seizures in theabsence of detectable brain lesions and/or metabolicabnormalities. Generalized seizures arise diffusely andsimultaneously from both hemispheres of the brain.

Defects in GABRD are the cause of susceptibility tojuvenile myoclonic epilepsy type 7 (EJM7) [MIM:613060]. A subtypeof idiopathic generalized epilepsy. Patients have afebrileseizures only, with onset in adolescence (rather than inchildhood) and myoclonic jerks which usually occur after awakeningand are triggered by sleep deprivation and fatigue.

Defects in GABRG2 are the cause of childhood absenceepilepsy type 2 (ECA2) [MIM:607681]. ECA2 is a subtype ofidiopathic generalized epilepsy (IGE) characterized by an onset atage 6-7 years, frequent absence seizures (several per day) andbilateral, synchronous, symmetric 3-Hz spike waves on EEG. Duringadolescence, tonic-clonic and myoclonic seizures develop. Someindividuals manifest ECA2 occurring in combination with febrileconvulsions.

Defects in GABRG2 are the cause of familial febrileconvulsions type 8 (FEB8) [MIM:611277]. A febrile convulsion isdefined as a seizure event in infancy or childhood, usuallyoccurring between 6 months and 6 years of age, associated withfever but without any evidence of intracranial infection ordefined pathologic or traumatic cause. Febrile convulsions affect5-12% of infants and children up to 6 years of age. There isepidemiological evidence that febrile seizures are associated withsubsequent afebrile and unprovoked seizures in 2% to 7% ofpatients.

Defects in GABRG2 are the cause of generalized epilepsywith febrile seizures plus type 3 (GEFS+3) [MIM:604233].Generalized epilepsy with febrile seizures-plus refers to a rareautosomal dominant, familial condition with incomplete penetranceand large intrafamilial variability. Patients display febrileseizures persisting sometimes beyond the age of 6 years and/or avariety of afebrile seizure types. GEFS+ is a disease combiningfebrile seizures, generalized seizures often precipitated by feverat age 6 years or more, and partial seizures, with a variabledegree of severity.

Defects in GABRG2 are a cause of severe myoclonicepilepsy in infancy (SMEI) [MIM:607208], also called Dravetsyndrome. SMEI is a rare disorder characterized by generalizedtonic, clonic, and tonic-clonic seizures that are initiallyinduced by fever and begin during the first year of life. Later,patients also manifest other seizure types, including absence,myoclonic, and simple and complex partial seizures. Psychomotordevelopment delay is observed around the second year of life. SMEIis considered to be the most severe phenotype within the spectrumof generalized epilepsies with febrile seizures-plus.

Defects in GCDH are the cause of glutaric aciduria type 1(GA1) [MIM:231670]. GA1 is an autosomal recessive metabolicdisorder characterized by progressive dystonia and athetosis dueto gliosis and neuronal loss in the basal ganglia.

Defects in GCH1 are the cause of GTP cyclohydrolase 1deficiency (GCH1D) [MIM:233910], also known as atypical severephenylketonuria due to GTP cyclohydrolase I deficiency,. GCH1D isone of the causes of malignant hyperphenylalaninemia due totetrahydrobiopterin deficiency. It is also responsible fordefective neurotransmission due to depletion of theneurotransmitters dopamine and serotonin. The principal symptomsinclude: psychomotor retardation, tonicity disorders, convulsions,drowsiness, irritability, abnormal movements, hyperthermia,hypersalivation, and difficulty swallowing. Some patients maypresent a phenotype of intermediate severity between severehyperphenylalaninemia and mild dystonia type 5 (dystonia-parkinsonism with diurnal fluctuation). In this intermediatephenotype, there is marked motor delay, but no mental retardationand only minimal, if any, hyperphenylalaninemia.

Defects in GCH1 are the cause of dystonia type 5 (DYT5)[MIM:128230], also known as progressive dystonia with diurnalfluctuation, autosomal dominant Segawa syndrome or dystonia-parkinsonism with diurnal fluctuation. DYT5 is a DOPA-responsivedystonia. Dystonia is defined by the presence of sustainedinvoluntary muscle contractions, often leading to abnormalpostures. DYT5 typically presents in childhood with walkingproblems due to dystonia of the lower limbs and worsening of thedystonia towards the evening. It is characterized by postural andmotor disturbances showing marked diurnal fluctuation. Torsion ofthe trunk is unusual. Symptoms are alleviated after sleep andaggravated by fatigue and excercise. There is a favorable responseto L-DOPA without side effects.

Defects in GCM2 are a cause of familial isolatedhypoparathyroidism (FIH) [MIM:146200], also known as autosomaldominant hypoparathyroidism or autosomal dominant hypocalcemia.FIH is characterized by hypocalcemia and hyperphosphatemia due toinadequate secretion of parathyroid hormone. Symptoms areseizures, tetany and cramps. An autosomal recessive form of FIHalso exists.

Defects in NR3C1 are a cause of glucocorticoid resistance(GCRES) [MIM:138040], also known as cortisol resistance. It is ahypertensive, hyperandrogenic disorder characterized by increasedserum cortisol concentrations. Inheritance is autosomal dominant.

Defects in GCSH are a cause of non-ketotichyperglycinemia (NKH) [MIM:605899], also known as glycineencephalopathy (GCE). NKH is an autosomal recessive diseasecharacterized by accumulation of a large amount of glycine in bodyfluid and by severe neurological symptoms.

Defects in GLDC are a cause of non-ketotichyperglycinemia (NKH) [MIM:605899], also known as glycineencephalopathy (GCE). NKH is an autosomal recessive diseasecharacterized by accumulation of a large amount of glycine in bodyfluid and by severe neurological symptoms.

Defects in AMT are a cause of non-ketotic hyperglycinemia(NKH) [MIM:605899], also known as glycine encephalopathy (GCE).NKH is an autosomal recessive disease characterized byaccumulation of a large amount of glycine in body fluid and bysevere neurological symptoms.

Defects in GDAP1 are the cause of Charcot-Marie-Toothdisease type 4A (CMT4A) [MIM:214400]. CMT4A is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of theperipheral nervous system. Charcot-Marie-Tooth disease isclassified in two main groups on the basis of electrophysiologicproperties and histopathology: primary peripheral demyelinatingneuropathy or CMT1, and primary peripheral axonal neuropathy orCMT2. Demyelinating CMT neuropathies are characterized by severelyreduced nerve conduction velocities (less than 38 m/sec),segmental demyelination and remyelination with onion bulbformations on nerve biopsy, slowly progressive distal muscleatrophy and weakness, absent deep tendon reflexes, and hollowfeet. Autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are by convention designated CMT4. CMT4A is a severeform characterized by early age of onset and rapid progressionleading to inability to walk in late childhood or adolescence.

Defects in GDAP1 are the cause of Charcot-Marie-Toothdisease axonal recessive with vocal cord paresis (CMT2RV)[MIM:607706]. CMT2RV is a form of Charcot-Marie-Tooth diseasecharacterized by the association of axonal neuropathy with vocalcord paresis.

Defects in GDAP1 are the cause of Charcot-Marie-Toothdisease type 2K (CMT2K) [MIM:607831]. CMT2K is an axonal form ofCharcot-Marie-Tooth disease. Axonal CMT neuropathies arecharacterized by signs of axonal regeneration in the absence ofobvious myelin alterations, normal or slightly reduced nerveconduction velocities, and progressive distal muscle weakness andatrophy. CMT2K onset is in early childhood (younger than 3 years).This phenotype is characterized by foot deformities,kyphoscoliosis, distal limb muscle weakness and atrophy,areflexia, and diminished sensation in the lower limbs. Weaknessin the upper limbs is observed in the first decade, with clawingof the fingers. Inheritance can be autosomal dominant orrecessive.

Defects in GDAP1 are the cause of Charcot-Marie-Toothdisease recessive intermediate type A (CMTRIA) [MIM:608340].CMTRIA is a form of Charcot-Marie-Tooth disease characterized byclinical and pathologic features intermediate betweendemyelinating and axonal peripheral neuropathies, and motor mediannerve conduction velocities ranging from 25 to 45 m/sec.

Defects in AGL are the cause of glycogen storage diseasetype 3 (GSD3) [MIM:232400], also known as Forbes disease. GSD3 isa metabolic disorder associated with an accumulation of abnormalglycogen with short outer chains. Three GSD3 types are recognized:GSD type 3A patients lack glycogen debrancher enzyme activity inboth liver and muscle, while GSD type 3B patients are enzyme-deficient in liver only. In rare cases, selective loss of only 1of the 2 debranching activities, glucosidase or transferase,results in GSD type 3C or type 3D, respectively. GSD3 isclinically characterized by hepatomegaly, hypoglycemia, shortstature, and variable myopathy.

Defects in GDF3 are the cause of Klippel-Feil syndrometype 3 (KFS3) [MIM:613702], also called Klippel-Feil syndromeautosomal dominant 3. KFS3 is a skeletal disorder characterized bycongenital fusion of cervical vertebrae. It is due to a failure inthe normal segmentation of vertebrae during the early weeks offetal development. The clinical triad consists of short neck, lowposterior hairline, and limited neck movement.

Defects in GDF3 are the cause of microphthalmia isolatedwith coloboma type 6 (MCOPCB6) [MIM:613703], also called isolatedcolobomatous microphthalmia 6. MCOPCB6 is a disorder of eyeformation, ranging from small size of a single eye to completebilateral absence of ocular tissues. Ocular abnormalities likeopacities of the cornea and lens, scaring of the retina andchoroid, cataract and other abnormalities like cataract may alsobe present. Ocular colobomas are a set of malformations resultingfrom abnormal morphogenesis of the optic cup and stalk, and thefusion of the fetal fissure (optic fissure).

Defects in GDF3 are a cause of microphthalmia isolatedtype 7 (MCOP7) [MIM:613704]. MCOP7 is a disorder of eye formation,ranging from small size of a single eye to complete bilateralabsence of ocular tissues. Ocular abnormalities like opacities ofthe cornea and lens, scaring of the retina and choroid, cataractand other abnormalities like cataract may also be present.

Defects in GDF5 are the cause of acromesomelicchondrodysplasia Grebe type (AMDG) [MIM:200700]. Acromesomelicchondrodysplasias are rare hereditary skeletal disorderscharacterized by short stature, very short limbs, and hand/footmalformations. The severity of limb abnormalities increases fromproximal to distal with profoundly affected hands and feet showingbrachydactyly and/or rudimentary fingers (knob-like fingers). AMDGis an autosomal recessive form characterized by normal axialskeletons and missing or fused skeletal elements within the handsand feet.

Defects in GDF5 are the cause of acromesomelicchondrodysplasia Hunter-Thompson type (AMDH) [MIM:201250]. AMDH isan autosomal recessive form of dwarfism. Patients have limbabnormalities, with the middle and distal segments being mostaffected and the lower limbs more affected than the upper. AMDH ischaracterized by normal axial skeletons and missing or fusedskeletal elements within the hands and feet.

Defects in GDF5 are the cause of brachydactyly type C(BDC) [MIM:113100]. BDC is an autosomal dominant disordercharacterized by an abnormal shortness of the fingers and toes.

Defects in GDF5 are the cause of Du Pan syndrome (DPS)[MIM:228900], also known as fibular hypoplasia and complexbrachydactyly. Du Pan syndrome is a rare autosomal recessivecondition characterized by absence of the fibulae and severeacromesomelic limb shortening with small, non-functional toes.Although milder, the phenotype resembles the autosomal recessiveHunter-Thompson [MIM:201250] and Grebe types [MIM:200700] ofacromesomelic chondrodysplasia.

Defects in GDF5 are a cause of symphalangism proximalsyndrome (SYM1) [MIM:185800]. SYM1 is characterized by thehereditary absence of the proximal interphalangeal (PIP) joints(Cushing symphalangism). Severity of PIP joint involvementdiminishes towards the radial side. Distal interphalangeal jointsare less frequently involved and metacarpophalangeal joints arerarely affected whereas carpal bone malformation and fusion arecommon. In the lower extremities, tarsal bone coalition is common.Conducive hearing loss is seen and is due to fusion of the stapesto the petrous part of the temporal bone.

Defects in GDF5 are the cause of multiple synostosessyndrome type 2 (SYNS2) [MIM:610017]. Multiple synostoses syndromeis an autosomal dominant condition characterized by progressivejoint fusions of the fingers, wrists, ankles and cervical spine,characteristic facies and progressive conductive deafness.

Defects in GDF5 are a cause of brachydactyly type A2(BDA2) [MIM:112600]. Brachydactylies (BDs) are a group ofinherited malformations characterized by shortening of the digitsdue to abnormal development of the phalanges and/or themetacarpals. They have been classified on an anatomic and geneticbasis into five groups, A to E, including three subgroups (A1 toA3) that usually manifest as autosomal dominant traits.

Genetic variations in GDF5 are associated withsusceptibility to osteoarthritis type 5 (OS5) [MIM:612400].Osteoarthritis is a degenerative disease of the jointscharacterized by degradation of the hyaline articular cartilageand remodeling of the subchondral bone with sclerosis. Clinicalsymptoms include pain and joint stiffness often leading tosignificant disability and joint replacement.

Defects in GDF5 may be a cause of brachydactyly type A1(BDA1) [MIM:112500]. Brachydactylies (BDs) are a group ofinherited malformations characterized by shortening of the digitsdue to abnormal development of the phalanges and/or themetacarpals. They have been classified on an anatomic and geneticbasis into five groups, A to E, including three subgroups (A1 toA3) that usually manifest as autosomal dominant traits.

Defects in GDF6 are the cause of Klippel-Feil syndrometype 1 (KFS1) [MIM:118100]. A skeletal disorder characterized bycongenital fusion of cervical vertebrae. It is due to a failure inthe normal segmentation of vertebrae during the early weeks offetal development. The clinical triad consists of short neck, lowposterior hairline, and limited neck movement. Deafness is a well-known feature of KFS and may be of sensorineural, conductive, ormixed type.

Note=A chromosomal aberration involving GDF6 has beenfound in a patient with Klippel-Feil syndrome (KFS). Paracentricinv(8)(q22,2q23.3).

Defects in GDF6 are the cause of microphthalmia isolatedtype 4 (MCOP4) [MIM:613094]. A disorder of eye formation, rangingfrom small size of a single eye to complete bilateral absence ofocular tissues. Ocular abnormalities like opacities of the corneaand lens, scaring of the retina and choroid, cataract and otherabnormalities like cataract may also be present.

Defects in GDI1 are the cause of mental retardation X-linked type 41 (MRX41) [MIM:300104]. Mental retardation ischaracterized by significantly sub-average general intellectualfunctioning associated with impairments in adaptative behavior andmanifested during the developmental period. Non-syndromic mentalretardation patients do not manifest other clinical signs.

Defects in GDI1 are the cause of mental retardation X-linked type 48 (MRX48) [MIM:300104], also known as MRX3.

Defects in GDNF may be a cause of Hirschsprung diseasetype 3 (HSCR3) [MIM:613711]. In association with mutations of RETgene, defects in GDNF may be involved in Hirschsprung disease.This genetic disorder of neural crest development is characterizedby the absence of intramural ganglion cells in the hindgut, oftenresulting in intestinal obstruction.

Defects in GDNF are a cause of congenital centralhypoventilation syndrome (CCHS) [MIM:209880], also known ascongenital failure of autonomic control or Ondine curse. CCHS is arare disorder characterized by abnormal control of respiration inthe absence of neuromuscular or lung disease, or an identifiablebrain stem lesion. A deficiency in autonomic control ofrespiration results in inadequate or negligible ventilatory andarousal responses to hypercapnia and hypoxemia.

Defects in GSN are the cause of amyloidosis type 5(AMYL5) [MIM:105120], also known as familial amyloidosis Finnishtype. AMYL5 is a hereditary generalized amyloidosis due togelsolin amyloid deposition. It is typically characterized bycranial neuropathy and lattice corneal dystrophy. Most patientshave modest involvement of internal organs, but severe systemicdisease can develop in some individuals causing peripheralpolyneuropathy, amyloid cardiomyopathy, and nephrotic syndromeleading to renal failure.

Defects in GPHN are the cause of molybdenum cofactordeficiency type C (MOCOD type C) [MIM:252150]. MOCOD type C is anautosomal recessive disease which leads to the pleiotropic loss ofall molybdoenzyme activities and is characterized by severeneurological damage, neonatal seizures and early childhood death.

Defects in GPHN are a cause of startle disease (STHE)[MIM:149400], also known as hyperekplexia. STHE is a geneticallyheterogeneous neurologic disorder characterized by muscularrigidity of central nervous system origin, particularly in theneonatal period, and by an exaggerated startle response tounexpected acoustic or tactile stimuli.

Defects in GFAP are a cause of Alexander disease (ALEXD)[MIM:203450]. Alexander disease is a rare disorder of the centralnervous system. It is a progressive leukoencephalopathy whosehallmark is the widespread accumulation of Rosenthal fibers whichare cytoplasmic inclusions in astrocytes. The most common formaffects infants and young children, and is characterized byprogressive failure of central myelination, usually leading todeath usually within the first decade. Infants with Alexanderdisease develop a leukoencephalopathy with macrocephaly, seizures,and psychomotor retardation. Patients with juvenile or adult formstypically experience ataxia, bulbar signs and spasticity, and amore slowly progressive course.

Defects in GFI1 are a cause of neutropenia severecongenital autosomal dominant type 2 (SCN2) [MIM:613107]. SCN2 isa disorder of hematopoiesis characterized by a maturation arrestof granulopoiesis at the level of promyelocytes with peripheralblood absolute neutrophil counts below 0.5 x 10(9)/l and earlyonset of severe bacterial infections.

Defects in GFI1 are a cause of dominant nonimmune chronicidiopathic neutropenia of adults (NI-CINA) [MIM:607847]. NI-CINAis a relatively mild form of neutropenia diagnosed in adults, butpredisposing to leukemia in a subset of patients.

Defects in GGT1 are a cause of glutathionuria (GLUTH)[MIM:231950], also known as gamma-glutamyltranspeptidasedeficiency. It is an autosomal recessive disease.

Defects in SLC25A22 are the cause of epilepticencephalopathy early infantile type 3 (EIEE3) [MIM:609304], alsoknown as early myoclonic encephalopathy (EME) or neonatal epilepsywith suppression-burst pattern. Severe neonatal epilepsies withsuppression-burst pattern are early-onset epileptic syndromescharacterized by a typical EEG pattern. The suppression-burstpattern of the EEG is characterized by higher-voltage bursts ofslow waves mixed with multifocal spikes alternating withisoelectric suppression phases. EME is characterized by a veryearly onset, erratic and fragmentary myoclonus, massive myoclonus,partial motor seizures and late tonic spasms. The prognosis of EMEis poor, with no effective treatment, and children with thecondition either die within 1 to 2 years after birth or survive ina persistent vegetative state. EME inheritance is autosomalrecessive.

Defects in GHRHR are a cause of growth hormone deficiencyisolated type 1B (IGHD1B) [MIM:612781], also known as dwarfism ofSindh. IGHD1B is an autosomal recessive deficiency of GH whichcauses short stature. IGHD1B patients have low but detectablelevels of GH.

Defects in GHR are a cause of Laron syndrome (LARS)[MIM:262500]. A severe form of growth hormone insensitivitycharacterized by growth impairment, short stature, dysfunctionalgrowth hormone receptor, and failure to generate insulin-likegrowth factor I in response to growth hormone.

Defects in GHR may be a cause of idiopathic short statureautosomal (ISSA) [MIM:604271]. Short stature is defined by asubnormal rate of growth.

Defects in GHSR may be a cause of idiopathic shortstature autosomal (ISSA) [MIM:604271]. Short stature is defined bya subnormal rate of growth.

Defects in GBA are the cause of Gaucher disease (GD)[MIM:230800], also known as glucocerebrosidase deficiency. GD isthe most prevalent lysosomal storage disease, characterized byaccumulation of glucosylceramide in the reticulo-endothelialsystem. Different clinical forms are recognized depending on thepresence (neuronopathic forms) or absence of central nervoussystem involvement, severity and age of onset.

Defects in GBA are the cause of Gaucher disease type 1(GD1) [MIM:230800], also known as adult non-neuronopathic Gaucherdisease. GD1 is characterized by hepatosplenomegaly withconsequent anemia and thrombopenia, and bone involvement. Thecentral nervous system is not involved.

Defects in GBA are the cause of Gaucher disease type 2(GD2) [MIM:230900], also known as acute neuronopathic Gaucherdisease. GD2 is the most severe form and is universallyprogressive and fatal. It manifests soon after birth, with deathgenerally occurring before patients reach two years of age.

Defects in GBA are the cause of Gaucher disease type 3(GD3) [MIM:231000], also known as subacute neuronopathic Gaucherdisease. GD3 has central nervous manifestations.

Defects in GBA are the cause of Gaucher disease type 3C(GD3C) [MIM:231005], also known as pseudo-Gaucher disease orGaucher-like disease.

Defects in GBA are the cause of Gaucher disease perinatallethal (GDPL) [MIM:608013]. It is a distinct form of Gaucherdisease type 2, characterized by fetal onset. Hydrops fetalis, inutero fetal death and neonatal distress are prominent features.When hydrops is absent, neurologic involvement begins in the firstweek and leads to death within 3 months. Hepatosplenomegaly is amajor sign, and is associated with ichthyosis, arthrogryposis, andfacial dysmorphism.

Note=Perinatal lethal Gaucher disease is associated withnon-immune hydrops fetalis, a generalized edema of the fetus withfluid accumulation in the body cavities due to non-immune causes.Non-immune hydrops fetalis is not a diagnosis in itself but asymptom, a feature of many genetic disorders, and the end-stage ofa wide variety of disorders.

Defects in GBA contribute to susceptibility to Parkinsondisease (PARK) [MIM:168600]. A complex neurodegenerative disordercharacterized by bradykinesia, resting tremor, muscular rigidityand postural instability. Additional features are characteristicpostural abnormalities, dysautonomia, dystonic cramps, anddementia. The pathology of Parkinson disease involves the loss ofdopaminergic neurons in the substantia nigra and the presence ofLewy bodies (intraneuronal accumulations of aggregated proteins),in surviving neurons in various areas of the brain. The disease isprogressive and usually manifests after the age of 50 years,although early-onset cases (before 50 years) are known. Themajority of the cases are sporadic suggesting a multifactorialetiology based on environmental and genetic factors. However, somepatients present with a positive family history for the disease.Familial forms of the disease usually begin at earlier ages andare associated with atypical clinical features.

Defects in GNE are a cause of sialuria (SIALURIA)[MIM:269921], also known as sialuria French type. In sialuria,free sialic acid accumulates in the cytoplasm and gram quantitiesof neuraminic acid are secreted in the urine. The metabolic defectinvolves lack of feedback inhibition of UDP-GlcNAc 2-epimerase byCMP-Neu5Ac, resulting in constitutive overproduction of freeNeu5Ac. Clinical features include variable degrees ofdevelopmental delay, coarse facial features and hepatomegaly.Sialuria inheritance is autosomal dominant.

Defects in GNE are the cause of inclusion body myopathytype 2 (IBM2) [MIM:600737]. Hereditary inclusion body myopathiesare a group of neuromuscular disorders characterized by adultonset, slowly progressive distal and proximal weakness and atypical muscle pathology including rimmed vacuoles and filamentousinclusions. IBM2 is an autosomal recessive disorder affectingmainly leg muscles, but with an unusual distribution that sparesthe quadriceps as also observed in Nonaka myopathy.

Defects in GNE are the cause of Nonaka myopathy (NM)[MIM:605820], also known as distal myopathy with rimmed vacuoles(DMRV). NM is an autosomal recessive muscular disorder, allelic toinclusion body myopathy 2. It is characterized by weakness of theanterior compartment of the lower limbs with onset in earlyadulthood, and sparing of the quadriceps muscles. As the inclusionbody myopathy, NM is histologically characterized by the presenceof numerous rimmed vacuoles without inflammatory changes in musclespecimens.

Note=Glycerate kinase activity has been found to bereduced in the liver of a patient with D-glyceric acidemia.

Defects in GLE1 are the cause of lethal congenitalcontracture syndrome type 1 (LCCS1) [MIM:253310], also known asmultiple contracture syndrome type Finnish. LCCS is an autosomalrecessive disorder characterized by early fetal hydrops andakinesia, micrognatia, pulmonary hypoplasia, pterygia, multiplejoint contractures, specific neuropathology with degeneration ofanterior horn neurons and extreme skeletal muscle atrophy. LCCS1leads to prenatal death.

Defects in GLE1 are the cause of lethal arthrogryposiswith anterior horn cell disease (LAAHD) [MIM:611890]. LAAHD ischaracterized by fetal akinesia, arthrogryposis and motor neuronloss. LAADH fetus often survive delivery, but die early as aresult of respiratory failure. Neuropathological findings resemblethose of LCCS1, but are less severe.

Defects in GBE1 are the cause of glycogen storage diseasetype 4 (GSD4) [MIM:232500], also known as Andersen disease. GSD4is a metabolic disorder characterized by the accumulation of anamylopectin-like polysaccharide. The typical clinicalmanifestation is liver disease of childhood, progressing to lethalhepatic cirrhosis. Most children with this condition die beforetwo years of age. However, the liver disease is not alwaysprogressive. No treatment apart from liver transplantation hasbeen found to prevent progression of the disease. There is also aneuromuscular form of GSD4 that varies in onset (perinatal,congenital, juvenile, or adult) and severity.

Note=Neuromuscular perinatal glycogen storage diseasetype 4 is associated with non-immune hydrops fetalis, ageneralized edema of the fetus with fluid accumulation in the bodycavities due to non-immune causes. Non-immune hydrops fetalis isnot a diagnosis in itself but a symptom, a feature of many geneticdisorders, and the end-stage of a wide variety of disorders.

Defects in GBE1 are the cause of adult polyglucosan bodydisease (APBD) [MIM:263570]. APBD is a late-onset, slowlyprogressive disorder affecting the central and peripheral nervoussystems. Patients typically present after age 40 years with avariable combination of cognitive impairment, pyramidaltetraparesis, peripheral neuropathy, and neurogenic bladder. Othermanifestations include cerebellar dysfunction and extrapyramidalsigns. The pathologic hallmark of APBD is the widespreadaccumulation of round, intracellular polyglucosan bodiesthroughout the nervous system, which are confined to neuronal andastrocytic processes.

Defects in GLI2 are the cause of holoprosencephaly type 9(HPE9) [MIM:610829], also called pituitary anomalies withholoprosencephaly-like features. The primary features of thisdisease include defective anterior pituitary formation and pan-hypopituitarism, with or without overt forebrain cleavageabnormalities, and holoprosencephaly-like midfacial hypoplasia.Holoprosencephaly is the most common structural anomaly of thebrain, in which the developing forebrain fails to correctlyseparate into right and left hemispheres. Holoprosencephaly isgenetically heterogeneous and associated with several distinctfacies and phenotypic variability.

Defects in GLI3 are the cause of Greig cephalo-poly-syndactyly syndrome (GCPS) [MIM:175700]. GCPS is an autosomaldominant disorder affecting limb and craniofacial development. Itis characterized by pre- and postaxial polydactyly, syndactyly offingers and toes, macrocephaly and hypertelorism.

Defects in GLI3 are a cause of Pallister-Hall syndrome(PHS) [MIM:146510]. PHS is characterized by a wide range ofclinical manifestations. It mainly associates central or postaxialpolydactyly, syndactyly, and hypothalamic hamartoma. Malformationsare frequent in the viscera, e.g. anal atresia, bifid uvula,congenital heart malformations, pulmonary or renal dysplasia. Itis an autosomal dominant disorder.

Defects in GLI3 are a cause of type A1/B postaxialpolydactyly (PAPA1/PAPB) [MIM:174200, 603596]. PAPA in humans isan autosomal dominant trait characterized by an extra digit in theulnar and/or fibular side of the upper and/or lower extremities.The extra digit is well formed and articulates with the fifth, orextra, metacarpal/metatarsal, and thus it is usually functional.

Defects in GLI3 are a cause of polydactyly preaxial type4 (POP4) [MIM:174700]. Polydactyly preaxial type 4 (i.e.,polydactyly on the radial/tibial side of the hand/foot) covers aheterogeneous group of entities. In preaxial polydactyly type IV,the thumb shows only the mildest degree of duplication, andsyndactyly of various degrees affects fingers 3 and 4.

Defects in GLI3 are the cause of acrocallosal syndrome(ACS) [MIM:200990], also abbreviated ACLS. ACS is characterized bypostaxial polydactyly, hallux duplication, macrocephaly, andabsence of the corpus callosum, usually with severe developmentaldelay.

Defects in GLIS2 are the cause of nephronophthisis type 7(NPHP7) [MIM:611498]. NPHP7 is an autosomal recessive disorderresulting in end-stage renal disease during childhood oradolescence. It is a progressive tubulo-interstitial kidneydisorder histologically characterized by modifications of thetubules with thickening of the basement membrane, interstitialfibrosis and, in the advanced stages, medullary cysts.

Defects in GLIS3 are a cause of diabetes mellitusneonatal with congenital hypothyroidism (NDH) [MIM:610199]. NDH isa neonatal diabetes syndrome associated with congenitalhypothyroidism, congenital glaucoma, hepatic fibrosis andpolycystic kidneys.

Defects in GLMN are the cause of glomuvenousmalformations (GVMs) [MIM:138000]. GVMs are characterized by thepresence of smooth-muscle-like glomus cells in the mediasurrounding distended vascular lumens.

Defects in GLUL are the cause of congenital systemicglutamine deficiency (CSGD) [MIM:610015]. CSGD is a raredevelopmental disorder with severe brain malformation resulting inmulti-organ failure and neonatal death. Glutamine is largelyabsent from affected patients serum, urine and cerebrospinalfluid.

Defects in GK are the cause of GK deficiency (GKD)[MIM:307030]. This disease can be either symptomatic with episodicmetabolic and CNS decompensation or asymptomatic withhyperglycerolemia and hyperglyceroluria only.

Defects in GLRA1 are a cause of startle disease (STHE)[MIM:149400], also known as hereditary hyperekplexia or congenitalstiff-person syndrome. STHE is a genetically heterogeneousneurologic disorder characterized by muscular rigidity of centralnervous system origin, particularly in the neonatal period, and byan exaggerated startle response to unexpected acoustic or tactilestimuli. Inheritance can be autosomal dominant or recessive.

Defects in GLRB are a cause of startle disease (STHE)[MIM:149400], also known as hereditary hyperekplexia or congenitalstiff-person syndrome. STHE is a genetically heterogeneousneurologic disorder characterized by muscular rigidity of centralnervous system origin, particularly in the neonatal period, and byan exaggerated startle response to unexpected acoustic or tactilestimuli. Inheritance can be autosomal dominant or recessive.

Defects in GLRX5 are a cause of anemia sideroblasticpyridoxine-refractory autosomal recessive (PRARSA) [MIM:205950]. Aform of sideroblastic anemia not responsive to pyridoxine.Sideroblastic anemia is characterized by anemia of varyingseverity, hypochromic peripheral erythrocytes, systemic ironoverload secondary to chronic ineffective erythropoiesis, and thepresence of bone marrow ringed sideroblasts. Sideroblasts arecharacterized by iron-loaded mitochondria clustered around thenucleus.

Defects in GALNT12 are a cause of susceptibility tocolorectal cancer type 1 (CRCS1) [MIM:608812]. Colorectal canceris a malignancy originating either in the colon or rectum or both.

Note=WBSCR17 is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.

Defects in GYG1 are the cause of glycogen storage diseasetype 15 (GSD15) [MIM:613507]. It is a metabolic disorder resultingin muscle weakness, associated with the glycogen depletion inskeletal muscle, and cardiac arrhythmia, associated with theaccumulation of abnormal storage material in the heart. Theskeletal muscle shows a marked predominance of slow-twitch,oxidative muscle fibers and mitochondrial proliferation.

Defects in GNAS are the cause of GNAS hyperfunction(GNASHYP) [MIM:139320]. This condition is characterized byincreased trauma-related bleeding tendency, prolonged bleedingtime, brachydactyly and mental retardation. Both the XLas isoformsand the ALEX protein are mutated which strongly reduces theinteraction between them and this may allow unimpeded activationof the XLas isoforms.

Defects in GNAS are a cause of ACTH-independentmacronodular adrenal hyperplasia (AIMAH) [MIM:219080], also knownas adrenal Cushing syndrome due to AIMAH. A rare adrenal defectcharacterized by multiple, bilateral, non-pigmented, benign,adrenocortical nodules. It results in excessive production ofcortisol leading to ACTH-independent Cushing syndrome. Clinicalmanifestations of Cushing syndrome include facial and trunkalobesity, abdominal striae, muscular weakness, osteoporosis,arterial hypertension, diabetes.

Genetic variations in GNAS are the cause ofpseudohypoparathyroidism type 1B (PHP1B) [MIM:603233]. PHP1B ischaracterized by parathyroid hormone (PTH)-resistant hypocalcemiaand hyperphosphatemia. Patients affected with PHP1B have normalactivity of the product of GNAS, lack developmental defectscharacteristic of AHO, and typically show no other endocrineabnormalities besides resistance to PTH. Most affected individualshave defects in methylation of the gene. In some casesmicrodeletions involving the STX16 appear to cause loss ofmethylation at exon A/B of GNAS, resulting in PHP1B. Paternaluniparental isodisomy have also been observed.

Defects in GNAS are the cause of pseudohypoparathyroidismtype 1C (PHP1C) [MIM:612462]. It is a disorder characterized byend-organ resistance to parathyroid hormone, hypocalcemia andhyperphosphatemia. It is commonly associated with Albrighthereditary osteodystrophy whose features are short stature,obesity, round facies, short metacarpals and ectopiccalcification.

Defects in GNAS are the cause of Albright hereditaryosteodystrophy (AHO) [MIM:103580]. AHO is an autosomal dominantdisorder characterized by a short stature, brachydactyly,subcutaneous ossifications. AHO is often associated withpseudohypoparathyoidism, hypocalcemia, and elevated PTH levels.The expression or the activity of GNAS is reduced in AHO.

Defects in GNAS are the cause of pseudohypoparathyroidismtype 1A (PHP1A) [MIM:103580]. Pseudohypoparathyroidism is a termapplied to a heterogeneous group of disorders whose common featureis resistance to parathyroid hormone.

Defects in GNAS are the cause of McCune-Albright syndrome(MAS) [MIM:174800]. MAS is characterized by polyostotic fibrousdysplasia, cafe-au-lait lesions, and a variety of endocrinedisorders, including precocious puberty, hyperthyroidism,hypercortisolism, growth hormone excess, and hyperprolactinemia.The mutations producing MAS lead to constitutive activation of GSalpha.

Defects in GNAS are the cause of growth hormone-secretingpituitary adenoma (GHSPA) [MIM:102200].

Defects in GNAS are the cause of progressive osseousheteroplasia (POH) [MIM:166350]. POH is a rare autosomal dominantdisorder characterized by extensive dermal ossification duringchildhood, followed by disabling and widespread heterotopicossification of skeletal muscle and deep connective tissue.

Defects in GNAS are a cause of ACTH-independentmacronodular adrenal hyperplasia (AIMAH) [MIM:219080], also knownas adrenal Cushing syndrome due to AIMAH. A rare adrenal defectcharacterized by multiple, bilateral, non-pigmented, benign,adrenocortical nodules. It results in excessive production ofcortisol leading to ACTH-independent Cushing syndrome. Clinicalmanifestations of Cushing syndrome include facial and trunkalobesity, abdominal striae, muscular weakness, osteoporosis,arterial hypertension, diabetes.

Genetic variations in GNAS are the cause ofpseudohypoparathyroidism type 1B (PHP1B) [MIM:603233]. PHP1B ischaracterized by parathyroid hormone (PTH)-resistant hypocalcemiaand hyperphosphatemia. Patients affected with PHP1B have normalactivity of the product of GNAS, lack developmental defectscharacteristic of AHO, and typically show no other endocrineabnormalities besides resistance to PTH. Most affected individualshave defects in methylation of the gene. In some casesmicrodeletions involving the STX16 appear to cause loss ofmethylation at exon A/B of GNAS, resulting in PHP1B. Paternaluniparental isodisomy have also been observed.

Defects in GNAS are the cause of GNAS hyperfunction(GNASHYP) [MIM:139320]. This condition is characterized byincreased trauma-related bleeding tendency, prolonged bleedingtime, brachydactyly and mental retardation. Both the XLas isoformsand the ALEX protein are mutated which strongly reduces theinteraction between them and this may allow unimpeded activationof the XLas isoforms.

Defects in GNAS are a cause of ACTH-independentmacronodular adrenal hyperplasia (AIMAH) [MIM:219080], also knownas adrenal Cushing syndrome due to AIMAH. A rare adrenal defectcharacterized by multiple, bilateral, non-pigmented, benign,adrenocortical nodules. It results in excessive production ofcortisol leading to ACTH-independent Cushing syndrome. Clinicalmanifestations of Cushing syndrome include facial and trunkalobesity, abdominal striae, muscular weakness, osteoporosis,arterial hypertension, diabetes.

Genetic variations in GNAS are the cause ofpseudohypoparathyroidism type 1B (PHP1B) [MIM:603233]. PHP1B ischaracterized by parathyroid hormone (PTH)-resistant hypocalcemiaand hyperphosphatemia. Patients affected with PHP1B have normalactivity of the product of GNAS, lack developmental defectscharacteristic of AHO, and typically show no other endocrineabnormalities besides resistance to PTH. Most affected individualshave defects in methylation of the gene. In some casesmicrodeletions involving the STX16 appear to cause loss ofmethylation at exon A/B of GNAS, resulting in PHP1B. Paternaluniparental isodisomy have also been observed.

Defects in GNAS are the cause of GNAS hyperfunction(GNASHYP) [MIM:139320]. This condition is characterized byincreased trauma-related bleeding tendency, prolonged bleedingtime, brachydactyly and mental retardation. Both the XLas isoformsand the ALEX protein are mutated which strongly reduces theinteraction between them and this may allow unimpeded activationof the XLas isoforms.

Defects in GNAT1 are the cause of congenital stationarynight blindness autosomal dominant type 3 (CSNBAD3) [MIM:610444],also known as congenital stationary night blindness Nougaret type.Congenital stationary night blindness is a non-progressive retinaldisorder characterized by impaired night vision.

Defects in GNAT2 are the cause of achromatopsia type 4(ACHM4) [MIM:139340]. Achromatopsia is an autosomal recessivelyinherited visual disorder that is present from birth and thatfeatures the absence of color discrimination.

Defects in GNMT are the cause of glycine N-methyltransferase deficiency (GNMT deficiency) [MIM:606664], alsoknown as hypermethioninemia. The only clinical abnormalities inpatients with this deficiency are mild hepatomegaly and chronicelevation of serum transaminases.

Defects in GNPAT are the cause of rhizomelicchondrodysplasia punctata type 2 (RCDP2) [MIM:222765]. RDCP2 ischaracterized by rhizomelic shortening of femur and humerus,vertebral disorders, cataract, cutaneous lesions and severe mentalretardation.

Defects in GNPTAB are the cause of mucolipidosis type II(MLII) [MIM:252500], also known as inclusion cell disease or I-cell disease (ICD). MLII is a fatal, autosomal recessive,lysosomal storage disorder characterized by severe clinical andradiologic features, peculiar fibroblast inclusions, and noexcessive mucopolysacchariduria. Congenital dislocation of thehip, thoracic deformities, hernia, and hyperplastic gums areevident soon after birth.

Defects in GNPTAB are the cause of mucolipidosis type IIIcomplementation group A (MLIIIA) [MIM:252600], also known asvariant pseudo-Hurler polydystrophy. MLIIIA is an autosomalrecessive disease of lysosomal enzyme targeting. Clinically MLIIIis characterized by restricted joint mobility, skeletal dysplasia,and short stature. Mildly coarsened facial features and thickeningof the skin have been described. Cardiac valvular disease andcorneal clouding may also occur. Half of the reported patientsshow learning disabilities or mental retardation.

Defects in GNPTG are the cause of mucolipidosis type IIIcomplementation group C (MLIIIC) [MIM:252605], also known asvariant pseudo-Hurler polydystrophy. MLIIIC is an autosomalrecessive disease of lysosomal hydrolase trafficking. Unlike therelated diseases, mucolipidosis II and IIIA, the enzyme affectedin mucolipidosis IIIC (GlcNAc-phosphotransferase) retains fulltransferase activity on synthetic substrates but lacks activity onlysosomal hydrolases. Typical clinical findings include stiffnessof the hands and shoulders, claw-hand deformity, scoliosis, shortstature, coarse facies, and mild mental retardation.Radiographically, severe dysostosis multiplex of the hip ischaracteristic and frequently disabling. The clinical diagnosiscan be confirmed by finding elevated serum lysosomal enzyme levelsand/or decreased lysosomal enzyme levels in cultured fibroblasts.

Defects in GNRHR are a cause of idiopathichypogonadotropic hypogonadism (IHH) [MIM:146110]. IHH is definedas a deficiency of the pituitary secretion of follicle-stimulatinghormone and luteinizing hormone, which results in the impairmentof pubertal maturation and of reproductive function.

Defects in GNRHR are a cause of fertile eunuch syndrome(FEUNS) [MIM:228300]. Fertile eunuch syndrome is a mild phenotypicform of HH going with the presence of normal testicular size andsome degree of spermatogenesis.

Defects in GNS are the cause of mucopolysaccharidosistype 3D (MPS3D) [MIM:252940], also known as Sanfilippo D syndrome.MPS3D is a form of mucopolysaccharidosis type 3, an autosomalrecessive lysosomal storage disease due to impaired degradation ofheparan sulfate. MPS3 is characterized by severe central nervoussystem degeneration, but only mild somatic disease. Onset ofclinical features usually occurs between 2 and 6 years, severeneurologic degeneration occurs in most patients between 6 and 10years of age, and death occurs typically during the second orthird decade of life.

Defects in GOLGA5 are a cause of thyroid papillarycarcinoma (TPC) [MIM:188550]. TPC is a common tumor of the thyroidthat typically arises as an irregular, solid or cystic mass fromotherwise normal thyroid tissue. Papillary carcinomas aremalignant neoplasm characterized by the formation of numerous,irregular, finger-like projections of fibrous stroma that iscovered with a surface layer of neoplastic epithelial cells.Note=A chromosomal aberration involving GOLGA5 is found in thyroidpapillary carcinomas. Translocation t(10,14)(q11,q32) with RET.The translocation generates the RET/GOLGA5 (PTC5) oncogene whichwas found in 2 cases of PACT in children exposed to radioactivefallout after Chernobyl.

Note=A chromosomal aberration involving GOPC is found ina glioblastoma multiforme sample. An intra-chromosomal deletiondel(6)(q21q21) is responsible for the formation of GOPC-ROS1chimeric protein which has a constitutive receptor tyrosine kinaseactivity.

Defects in GORAB are the cause of gerodermaosteodysplasticum (GO) [MIM:231070], also known as gerodermiaosteodysplastica or Walt Disney dwarfism. GO is a rare autosomalrecessive disorder characterized by lax, wrinkled skin, jointlaxity and a typical face with a prematurely aged appearance.Skeletal signs include severe osteoporosis leading to frequentfractures, malar and mandibular hypoplasia and a variable degreeof growth retardation.

Defects in GPR143 are the cause of albinism ocular type 1(OA1) [MIM:300500], also known as Nettleship-Falls type ocularalbinism. Form of albinism affecting only the eye. Pigment of thehair and skin is normal or only slightly diluted. Eyes may beseverely affected with photophobia and reduced visual acuity.Nystagmus or strabismus are often associated. The irides andfundus are depigmented.

Defects in GPR143 are the cause of Nystagmus congenitalX-linked type 6 (NYS6) [MIM:300814]. It is a condition defined asconjugated, spontaneous and involuntary ocular oscillations thatappear at birth or during the first three months of life. Otherassociated features may include mildly decreased visual acuity,strabismus, astigmatism, and occasionally head nodding.

Genetic variations in GP1BA may be a cause ofsusceptibility to non-arteritic anterior ischemic optic neuropathy(NAION) [MIM:258660]. NAION is an ocular disease due to ischemicinjury to the optic nerve. It usually affects the optic disk andleads to visual loss and optic disk swelling of a pallid nature.Visual loss is usually sudden, or over a few days at most and isusually permanent, with some recovery possibly occurring withinthe first weeks or months. Patients with small disks havingsmaller or non-existent cups have an anatomical predisposition fornon-arteritic anterior ischemic optic neuropathy. As an ischemicepisode evolves, the swelling compromises circulation, with aspiral of ischemia resulting in further neuronal damage.

Defects in GP1BA are a cause of Bernard-Soulier syndrome(BSS) [MIM:231200], also known as giant platelet disease (GPD).BSS patients have unusually large platelets and have a clinicalbleeding tendency.

Defects in GP1BA are the cause of benign mediterraneanmacrothrombocytopenia (BMM) [MIM:153670], also known as autosomaldominant benign Bernard-Soulier syndrome. BMM is characterized bymild or no clinical symptoms, normal platelet function, and normalmegakaryocyte count.

Defects in GP1BA are the cause of von Willebrand diseaseplatelet-type (PVWD) [MIM:177820], also known as pseudo-vonWillebrand disease (pseudo-vWD). This autosomal dominant bleedingdisorder is caused by an increased affinity of GP-Ib for solublevWF resulting in impaired hemostatic function due to the removalof vWF from the circulation.

Defects in GP1BB are a cause of Bernard-Soulier syndrome(BSS) [MIM:231200], also known as giant platelet disease (GPD).BSS patients have unusually large platelets and have a clinicalbleeding tendency.

Defects in GPC3 are the cause of Simpson-Golabi-Behmelsyndrome type 1 (SGBS1) [MIM:312870], also known as Simpsondysmorphia syndrome (SDYS). SGBS is a condition characterized bypre- and postnatal overgrowth (gigantism) with visceral andskeletal anomalies.

Defects in GPC6 are a cause of omodysplasia type 1(OMOD1) [MIM:258315]. OMOD1 is a rare autosomal recessive skeletaldysplasia characterized by severe congenital micromelia withshortening and distal tapering of the humeri and femora to give aclub-like appearance. Typical facial features include a prominentforehead, frontal bossing, short nose with a depressed broadbridge, short columella, anteverted nostrils, long philtrum, andsmall chin. Note=Point mutations leading to protein truncation, aswell as larger genomic rearrangements resulting in exon deletions,have been found in family segregating omodysplasia type 1. Allmutations identified in individuals affected by omodysplasia couldlead to the absence of a functional protein, the mutant RNAs beingsuspected to be nonsense-mediated mRNA decay (NMD) targets. Evenif the mRNA escapes NMD and is translated, all mutations areexpected to disrupt the three-dimensional protein structure andoften to abolish multiple highly conserved cysteine residues.

Defects in GPD1L are the cause of Brugada syndrome type 2(BRS2) [MIM:611777]. BRS2 is an autosomal dominant tachyarrhythmiacharacterized by right bundle branch block and ST segmentelevation on an electrocardiogram (ECG). It can cause theventricles to beat so fast that the blood is prevented fromcirculating efficiently in the body. When this situation occurs(called ventricular fibrillation), the individual will faint andmay die in a few minutes if the heart is not reset.

Defects in GPD1L are a cause of sudden infant deathsyndrome (SIDS) [MIM:272120]. SIDS is the sudden death of aninfant younger than 1 year that remains unexplained after athorough case investigation, including performance of a completeautopsy, examination of the death scene, and review of clinicalhistory. Pathophysiologic mechanisms for SIDS may includerespiratory dysfunction, cardiac dysrhythmias, cardiorespiratoryinstability, and inborn errors of metabolism, but definitivepathogenic mechanisms precipitating an infant sudden death remainelusive.

Defects in GP9 are a cause of Bernard-Soulier syndrome(BSS) [MIM:231200], also known as giant platelet disease (GPD).BSS patients have unusually large platelets and have a clinicalbleeding tendency.

Defects in GPR56 are the cause of bilateralfrontoparietal polymicrogyria (BFPP) [MIM:606854]. BFPP ischaracterized by disorganized cortical lamination that is mostsevere in frontal cortex.

Defects in GPR98 are the cause of Usher syndrome type 2C(USH2C) [MIM:605472]. USH is a genetically heterogeneous conditioncharacterized by the association of retinitis pigmentosa withsensorineural deafness. Age at onset and differences in auditoryand vestibular function distinguish Usher syndrome type 1 (USH1),Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3).USH2 is characterized by congenital mild hearing impairment withnormal vestibular responses.

Defects in GPR98 may be a cause of familial febrileconvulsions type 4 (FEB4) [MIM:604352], also known as familialfebrile seizures 4. Febrile convulsions are seizures associatedwith febrile episodes in childhood without any evidence ofintracranial infection or defined pathologic or traumatic cause.It is a common condition, affecting 2-5% of children aged 3 monthsto 5 years. The majority are simple febrile seizures (generallydefined as generalized onset, single seizures with a duration ofless than 30 minutes). Complex febrile seizures are characterizedby focal onset, duration greater than 30 minutes, and/or more thanone seizure in a 24 hour period. The likelihood of developingepilepsy following simple febrile seizures is low. Complex febrileseizures are associated with a moderately increased incidence ofepilepsy.

Defects in GPSM2 are the cause of deafness autosomalrecessive type 82 (DFNB82) [MIM:613557]. DFNB82 is a form of non-syndromic deafness characterized by prelingual, bilateral, severe,sensorineural hearing loss. There are no symptoms of vestibulardysfunction.

Defects in DPAGT1 are the cause of congenital disorder ofglycosylation type 1J (CDG1J) [MIM:608093]. CDGs are a family ofsevere inherited diseases caused by a defect in protein N-glycosylation. They are characterized by under-glycosylated serumproteins. These multisystem disorders present with a wide varietyof clinical features, such as disorders of the nervous systemdevelopment, psychomotor retardation, dysmorphic features,hypotonia, coagulation disorders, and immunodeficiency. The broadspectrum of features reflects the critical role of N-glycoproteinsduring embryonic development, differentiation, and maintenance ofcell functions.

Defects in GRXCR1 are the cause of deafness autosomalrecessive type 25 (DFNB25) [MIM:613285]. DFNB25 is characterizedby moderate to severe or profound hearing loss which isprogressive in some individuals but not in others. Speechdevelopment is impaired in some but not all affected individualsand vestibular dysfunction is observed in some affectedindividuals.

Defects in GRHL2 are the cause of deafness autosomaldominant type 28 (DFNA28) [MIM:608641]. DFNA28 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information. DFNA28 is characterized by mild to moderatehearing loss across most frequencies that progressed to severeloss in the higher frequencies by the fifth decade. Age at onsetvaried, with the earliest case documented at 7 years of age.

Defects in GRHPR are the cause of hyperoxaluria primarytype 2 (HP2) [MIM:260000], also known as primary hyperoxaluriatype II (PH2). HP2 is a disorder where the main clinicalmanifestation is calcium oxalate nephrolithiasis though chronic aswell as terminal renal insufficiency has been described. It ischaracterized by an elevated urinary excretion of oxalate and L-glycerate.

Defects in GRIA3 are the cause of mental retardation X-linked type 94 (MRX94) [MIM:300699]. Mental retardation ischaracterized by significantly sub-average general intellectualfunctioning associated with impairments in adaptative behavior andmanifested during the developmental period. MRX94 patients havemoderate mental retardation. Other variable features aremacrocephaly, seizures, myoclonic jerks, autistic behavior,asthenic body habitus, distal muscle weakness and hyporeflexia.

Defects in GRIK2 are the cause of mental retardationautosomal recessive type 6 (MRT6) [MIM:611092]. It ischaracterized by significantly sub-average general intellectualfunctioning associated with impairments in adaptative behavior andmanifested during the developmental period. In contrast tosyndromic or specific mental retardation which also present withassociated physical, neurological and/or psychiatricmanifestations, intellectual deficiency is the only primarysymptom of non-syndromic mental retardation. MRT6 patients displaymild to severe mental retardation and psychomotor developmentdelay in early childhood. Patients do not have neurologicproblems, congenital malformations, or facial dysmorphism. Bodyheight, weight, and head circumference are normal.

Defects in GRM6 are the cause of congenital stationarynight blindness type 1B (CSNB1B) [MIM:257270]. This disorderconsits of a previously unrecognized, autosomal recessive form ofcongenital night blindness associated with a negativeelectroretinogram waveform. Patients are night blind from an earlyage, and when maximally dark-adapted, they could perceive lightsonly with an intensity equal to or slightly dimmer than thatnormally detected by the cone system. ERGs in response to singlebrief flashes of light have clearly detectable a-waves, which arederived from photoreceptors, and greatly reduced b-waves, whichare derived from the second-order inner retinal neurons. ERGs inresponse to sawtooth flickering light indicate a markedly reducedON response and a nearly normal OFF response. There is nosubjective delay in the perception of suddenly appearing white vsblack objects on a gray background.

Defects in GRN are the cause of ubiquitin-positivefrontotemporal dementia (UP-FTD) [MIM:607485], also known as tau-negative frontotemporal dementia linked to chromosome 17.Frontotemporal dementia (FTD) is the second most common cause ofdementia in people under the age of 65 years. It is an autosomaldominant neurodegenerative disease.

Defects in RASGRP1 may contribute to susceptibility tosystemic lupus erythematosus (SLE) [MIM:152700]. SLE is a chronic,inflammatory and often febrile multisystemic disorder ofconnective tissue. It affects principally the skin, joints,kidneys and serosal membranes. SLE is thought to represent afailure of the regulatory mechanisms of the autoimmune system.Note=Aberrantly spliced isoforms and/or diminished levels ofRASGRP1 are found in a cohort of SLE patients raising thepossibility that dysregulation of this signaling proteincontributes to the development of autoimmunity in a subset of SLEpatients.

Note=Autoantigen in rheumatoid arthritis.

Defects in GCLC are the cause of hemolytic anemia(HAGGSD) [MIM:230450].

Defects in GSS are the cause of glutathione synthetasedeficiency (GSS deficiency) [MIM:266130], also known as 5-oxoprolinuria or pyroglutamic aciduria. It is a severe formcharacterized by an increased rate of hemolysis and defectivefunction of the central nervous system.

Defects in GSS are the cause of glutathione synthetasedeficiency of erythrocytes (GLUSYNDE)[MIM:231900]. Glutathionesynthetase deficiency of erythrocytes is a mild form causinghemolytic anemia.

Note=GTF2IRD1 is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.Haploinsufficiency of GTF2IRD1 may be the cause of certaincardiovascular and musculo-skeletal abnormalities observed in thedisease.

Note=GTF2IRD2 is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.

Note=GTF2IRD2B is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.

Note=GTF2I is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.Haploinsufficiency of GTF2I may be the cause of certaincardiovascular and musculo-skeletal abnormalities observed in thedisease.

Defects in SLC2A10 are the cause of arterial tortuositysyndrome (ATS) [MIM:208050]. ATS is an autosomal recessivedisorder characterized by tortuosity and elongation of majorarteries, often resulting in death at young age. Other typicalfeatures include aneurysms of large arteries and stenosis of thepulmonary artery, in association with facial features and severalconnective tissue manifestations such as soft skin and jointlaxity. Histopathological findings include fragmentation ofelastic fibers in the tunica media of large arteries.

Defects in SLC2A1 are the cause of GLUT1 deficiencysyndrome type 1 (GLUT1DS1) [MIM:606777], also known as blood-brainbarrier glucose transport defect. A neurologic disorder showingwide phenotypic variability. The most severe 'classic' phenotypecomprises infantile-onset epileptic encephalopathy associated withdelayed development, acquired microcephaly, motor incoordination,and spasticity. Onset of seizures, usually characterized by apneicepisodes, staring spells, and episodic eye movements, occurswithin the first 4 months of life. Other paroxysmal findingsinclude intermittent ataxia, confusion, lethargy, sleepdisturbance, and headache. Varying degrees of cognitive impairmentcan occur, ranging from learning disabilities to severe mentalretardation.

Defects in SLC2A1 are the cause of GLUT1 deficiencysyndrome type 2 (GLUT1DS2) [MIM:612126]. A clinically variabledisorder characterized primarily by onset in childhood ofparoxysmal exercise-induced dyskinesia. The dyskinesia involvestransient abnormal involuntary movements, such as dystonia andchoreoathetosis, induced by exercise or exertion, and affectingthe exercised limbs. Some patients may also have epilepsy, mostcommonly childhood absence epilepsy. Mild mental retardation mayalso occur. In some patients involuntary exertion-induceddystonic, choreoathetotic, and ballistic movements may beassociated with macrocytic hemolytic anemia.

Defects in SLC2A2 are the cause of Fanconi-Bickelsyndrome (FBS) [MIM:227810]. FBS is a rare, well-defined clinicalentity, inherited in an autosomal recessive mode and characterizedby hepatorenal glycogen accumulation, proximal renal tubulardysfunction, and impaired utilization of glucose and galactose.

Defects in SLC2A4 may be a cause of noninsulin-dependentdiabetes mellitus (NIDDM) [MIM:125853]. Defects in SLC2A4 may be acause of certain post-receptor defects in NIDDM. The variant inposition Ile-383 is found in a small number of NIDDM patients, butseems not to be found in nondiabetic subjects.

Note=A chromosomal aberration involving GMPS is found inacute myeloid leukemias. Translocation t(3,11)(q25,q23) with MLL.

Defects in GUCA1A are the cause of cone dystrophy type 3(COD3) [MIM:602093]. COD3 is an autosomal dominant cone dystrophy.Cone dystrophies are retinal dystrophies characterized byprogressive degeneration of the cone photoreceptors withpreservation of rod function, as indicated by electroretinogram.However, some rod involvement may be present in some conedystrophies, particularly at late stage. Affected individualssuffer from photophobia, loss of visual acuity, color vision andcentral visual field. Another sign is the absence of macularlesions for many years. Cone dystrophies are distinguished fromthe cone-rod dystrophies, in which some loss of peripheral visionalso occurs.

Defects in GUCY2D are the cause of Leber congenitalamaurosis type 1 (LCA1) [MIM:204000]. LCA designates a clinicallyand genetically heterogeneous group of childhood retinaldegenerations, generally inherited in an autosomal recessivemanner. Affected infants have little or no retinal photoreceptorfunction as tested by electroretinography. LCA represents the mostcommon genetic cause of congenital visual impairment in infantsand children.

Defects in GUCY2D are the cause of cone-rod dystrophytype 6 (CORD6) [MIM:601777]. CORDs are inherited retinaldystrophies belonging to the group of pigmentary retinopathies.CORDs are characterized by retinal pigment deposits visible onfundus examination, predominantly in the macular region, andinitial loss of cone photoreceptors followed by rod degeneration.This leads to decreased visual acuity and sensitivity in thecentral visual field, followed by loss of peripheral vision.Severe loss of vision occurs earlier than in retinitis pigmentosa.

Defects in MASTL are the cause of thrombocytopenia type 2(THC2) [MIM:188000]. Thrombocytopenia is defined by a decrease inthe number of platelets in circulating blood, resulting in thepotential for increased bleeding and decreased ability forclotting.

Defects in GYS1 are the cause of muscle glycogen storagedisease type 0 (GSD0b) [MIM:611556], also known as muscle glycogensynthase deficiency. GSD0b is a metabolic disorder characterizedby fasting hypoglycemia presenting in infancy or early childhood.The role of muscle glycogen is to provide critical energy duringbursts of activity and sustained muscle work.

Defects in GYS2 are the cause of glycogen storage diseasetype 0 (GSD0) [MIM:240600], also known as liver glycogen synthasedeficiency. GSD0 is a metabolic disorder characterized by fastinghypoglycemia presenting in infancy or early childhood andaccompanied by high blood ketones and low alanine and lactateconcentrations. Although feeding relieves symptoms, it oftenresults in postprandial hyperglycemia and hyperlactatemia.

Defects in HR are the cause of alopecia universaliscongenita (ALUNC) [MIM:203655]. ALUNC is a rare autosomalrecessive form of hair loss characterized by hair follicleswithout hair.

Defects in HR are the cause of atrichia with papularlesions (APL) [MIM:209500], also known as congenital atrichia. APLis an autosomal recessive disease characterized by papillarylesions over most of the body and almost complete absence of hair.

Defects in HR are the cause of hypotrichosis Marie Unnatype 1 (MUHH1) [MIM:146550]. An autosomal dominant conditioncharacterized by reduced amount of hair, alopecia, little or noeyebrows, eyelashes or body hair, and coarse, wiry, twisted hairin early childhood.

Note=A chromosomal aberration involving HAS2 may be acause of lipoblastomas, which are benign tumors resulting fromtransformation of adipocytes, usually diagnosed in children.8q12.1 to 8q24.1 intrachromosomal rearrangement with PLAG1.

Defects in HAX1 are the cause of neutropenia severecongenital autosomal recessive type 3 (SCN3) [MIM:610738], alsoknown as Kostmann disease. A disorder of hematopoiesischaracterized by maturation arrest of granulopoiesis at the levelof promyelocytes with peripheral blood absolute neutrophil countsbelow 0.5 x 10(9)/l and early onset of severe bacterialinfections. Some patients affected by severe congenitalneutropenia type 3 have neurological manifestations such aspsychomotor retardation and seizures. Note=The clinical phenotypedue to HAX1 deficiency appears to depend on the localization ofthe mutations and their influence on the transcript variants.Mutations affecting exclusively isoform 1 are associated withisolated congenital neutropenia, whereas mutations affecting bothisoform 1 and isoform 5 are associated with additional neurologicsymptoms.

Note=A chromosomal aberration involving HSPBAP1 has beenfound in a family with renal carcinoma. Translocationt(2,3)(q35,q21) with the putative pseudogene DIRC3. Produces anhybrid mRNA encoding a truncated HSPBAP1 lacking the first 36amino acids.

Defects in HBA1/HBA2 may be a cause of Heinz body anemias(HEIBAN) [MIM:140700]. This is a form of non-spherocytic hemolyticanemia of Dacie type 1. After splenectomy, which has littlebenefit, basophilic inclusions called Heinz bodies aredemonstrable in the erythrocytes. Before splenectomy, diffuse orpunctate basophilia may be evident. Most of these cases areprobably instances of hemoglobinopathy. The hemoglobindemonstrates heat lability. Heinz bodies are observed also withthe Ivemark syndrome (asplenia with cardiovascular anomalies) andwith glutathione peroxidase deficiency.

Defects in HBA1/HBA2 are the cause of alpha-thalassemia(A-THAL) [MIM:604131]. The thalassemias are the most commonmonogenic diseases and occur mostly in Mediterranean and SoutheastAsian populations. The hallmark of alpha-thalassemia is animbalance in globin-chain production in the adult HbA molecule.The level of alpha chain production can range from none to verynearly normal levels. Deletion of both copies of each of the twoalpha-globin genes causes alpha(0)-thalassemia, also known ashomozygous alpha thalassemia. Due to the complete absence of alphachains, the predominant fetal hemoglobin is a tetramer of gamma-chains (Bart hemoglobin) that has essentially no oxygen carryingcapacity. This causes oxygen starvation in the fetal tissuesleading to prenatal lethality or early neonatal death. The loss ofthree alpha genes results in high levels of a tetramer of fourbeta chains (hemoglobin H), causing a severe and life-threateninganemia known as hemoglobin H disease. Untreated, most patients diein childhood or early adolescence. The loss of two alpha genesresults in mild alpha-thalassemia, also known as heterozygousalpha-thalassemia. Affected individuals have small red cells and amild anemia (microcytosis). If three of the four alpha-globingenes are functional, individuals are completely asymptomatic.Some rare forms of alpha-thalassemia are due to point mutations(non-deletional alpha-thalassemia). The thalassemic phenotype isdue to unstable globin alpha chains that are rapidly catabolizedprior to formation of the alpha-beta heterotetramers.

Note=Alpha(0)-thalassemia is associated with non-immunehydrops fetalis, a generalized edema of the fetus with fluidaccumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom,a feature of many genetic disorders, and the end-stage of a widevariety of disorders.

Defects in HBB may be a cause of Heinz body anemias(HEIBAN) [MIM:140700]. This is a form of non-spherocytic hemolyticanemia of Dacie type 1. After splenectomy, which has littlebenefit, basophilic inclusions called Heinz bodies aredemonstrable in the erythrocytes. Before splenectomy, diffuse orpunctate basophilia may be evident. Most of these cases areprobably instances of hemoglobinopathy. The hemoglobindemonstrates heat lability. Heinz bodies are observed also withthe Ivemark syndrome (asplenia with cardiovascular anomalies) andwith glutathione peroxidase deficiency.

Defects in HBB are the cause of beta-thalassemia (B-THAL)[MIM:604131]. A form of thalassemia. Thalassemias are commonmonogenic diseases occurring mostly in Mediterranean and SoutheastAsian populations. The hallmark of beta-thalassemia is animbalance in globin-chain production in the adult HbA molecule.Absence of beta chain causes beta(0)-thalassemia, while reducedamounts of detectable beta globin causes beta(+)-thalassemia. Inthe severe forms of beta-thalassemia, the excess alpha globinchains accumulate in the developing erythroid precursors in themarrow. Their deposition leads to a vast increase in erythroidapoptosis that in turn causes ineffective erythropoiesis andsevere microcytic hypochromic anemia. Clinically, beta-thalassemiais divided into thalassemia major which is transfusion dependent,thalassemia intermedia (of intermediate severity), and thalassemiaminor that is asymptomatic.

Defects in HBB are the cause of sickle cell anemia (SKCA)[MIM:603903], also known as sickle cell disease. Sickle cellanemia is characterized by abnormally shaped red cells resultingin chronic anemia and periodic episodes of pain, seriousinfections and damage to vital organs. Normal red blood cells areround and flexible and flow easily through blood vessels, but insickle cell anemia, the abnormal hemoglobin (called Hb S) causesred blood cells to become stiff. They are C-shaped and resembles asickle. These stiffer red blood cells can led to microvascularocclusion thus cutting off the blood supply to nearby tissues.

Defects in HBB are the cause of beta-thalassemia dominantinclusion body type (B-THALIB) [MIM:603902]. An autosomal dominantform of beta thalassemia characterized by moderate anemia,lifelong jaundice, cholelithiasis and splenomegaly, markedmorphologic changes in the red cells, erythroid hyperplasia of thebone marrow with increased numbers of multinucleate red cellprecursors, and the presence of large inclusion bodies in thenormoblasts, both in the marrow and in the peripheral blood aftersplenectomy.

Defects in HSD17B10 are the cause of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (MHBD deficiency)[MIM:300438]. MHBD deficiency leads to neurological abnormalities,including psychomotor retardation, and, in virtually all patients,loss of mental and motor skills.

Defects in HSD17B10 are the cause of mental retardationsyndromic X-linked type 10 (MRXS10) [MIM:300220]. MRXS10 ischaracterized by mild mental retardation, choreoathetosis andabnormal behavior.

A chromosomal microduplication involving HSD17B10 andHUWE1 is the cause of mental retardation X-linked type 17 (MRX17)[MIM:300705], also known as mental retardation X-linked type 31(MRX31). Mental retardation is characterized by significantly sub-average general intellectual functioning associated withimpairments in adaptative behavior and manifested during thedevelopmental period. In contrast to syndromic or specific X-linked mental retardation which also present with associatedphysical, neurological and/or psychiatric manifestations,intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation.

Defects in HADH are the cause of 3-alpha-hydroxyacyl-CoAdehydrogenase deficiency (HADH deficiency) [MIM:231530]. HADHdeficiency is a metabolic disorder with various clinicalpresentations including hypoglycemia, hepatoencephalopathy,myopathy or cardiomyopathy, and in some cases sudden death.

Defects in HADH are the cause of familialhyperinsulinemic hypoglycemia type 4 (HHF4) [MIM:609975], alsoknown as persistent hyperinsulinemic hypoglycemia of infancy(PHHI) or congenital hyperinsulinism. HHF is the most common causeof persistent hypoglycemia in infancy and is due to defectivenegative feedback regulation of insulin secretion by low glucoselevels. It causes nesidioblastosis, a diffuse abnormality of thepancreas in which there is extensive, often disorganized formationof new islets. Unless early and aggressive intervention isundertaken, brain damage from recurrent episodes of hypoglycemiamay occur. HHF4 should be easily recognizable by analysis ofacylcarnitine species and that this disorder responds well totreatment with diazoxide. It provides the first 'experiment ofnature' that links impaired fatty acid oxidation tohyperinsulinism and that provides support for the concept that alipid signaling pathway is implicated in the control of insulinsecretion.

Defects in HCN4 are a cause of sick sinus syndrome type 2(SSS2) [MIM:163800], also known as atrial fibrillation withbradyarrhythmia or familial sinus bradycardia. The term 'sicksinus syndrome' encompasses a variety of conditions caused bysinus node dysfunction. The most common clinical manifestationsare syncope, presyncope, dizziness, and fatigue. Electrocardiogramtypically shows sinus bradycardia, sinus arrest, and/or sinoatrialblock. Episodes of atrial tachycardias coexisting with sinusbradycardia ('tachycardia-bradycardia syndrome') are also commonin this disorder. SSS occurs most often in the elderly associatedwith underlying heart disease or previous cardiac surgery, but canalso occur in the fetus, infant, or child without heart disease orother contributing factors, in which case it is considered to be acongenital disorder.

Defects in HCN4 are the cause of Brugada syndrome type 8(BRS8) [MIM:613123]. A tachyarrhythmia characterized by rightbundle branch block and ST segment elevation on anelectrocardiogram (ECG). It can cause the ventricles to beat sofast that the blood is prevented from circulating efficiently inthe body. When this situation occurs (called ventricularfibrillation), the individual will faint and may die in a fewminutes if the heart is not reset.

Defects in HDAC4 are the cause of brachydactyly-mentalretardation syndrome (BDMR) [MIM:600430]. A syndrome resemblingthe physical anomalies found in Albright hereditaryosteodystrophy. Common features are mild facial dysmorphism,congenital heart defects, distinct brachydactyly type E, mentalretardation, developmental delay, seizures, autism spectrumdisorder, and stocky build. Soft tissue ossification is absent,and there are no abnormalities in parathyroid hormone or calciummetabolism.

Note=A chromosomal aberration involving HDAC9 is found ina family with Peters anomaly. Translocation t(1,7)(q41,p21) withTGFB2 resulting in lack of HDAC9 protein.

Defects in HTT are the cause of Huntington disease (HD)[MIM:143100]. HD is an autosomal dominant neurodegenerativedisorder characterized by involuntary movements (chorea), generalmotor impairment, psychiatric disorders and dementia. Onset of thedisease occurs usually in the third or fourth decade of life andsymptoms progressively worsen leading to death in 10 to 20 years.Onset and clinical course depend on the degree of poly-Gln repeatexpansion, longer expansions resulting in earlier onset and moresevere clinical manifestations. HD affects 1 in 10,000 individualsof European origin. Neuropathology of Huntington disease displaysa distinctive pattern with loss of neurons, especially in thecaudate and putamen (striatum).

Defects in ALAS2 are a cause of anemia sideroblastic X-linked (XLSA) [MIM:300751]. Sideroblastic anemia is characterizedby anemia of varying severity, hypochromic peripheralerythrocytes, systemic iron overload secondary to chronicineffective erythropoiesis, and the presence of bone marrow ringedsideroblasts. Sideroblasts are characterized by iron-loadedmitochondria clustered around the nucleus. XLSA shows a variablehematologic response to pharmacologic doses of pyridoxine.

Defects in ALAS2 are the cause of erythropoieticprotoporphyria X-linked dominant (XLDPT) [MIM:300752]. Porphyriasare inherited defects in the biosynthesis of heme, resulting inthe accumulation and increased excretion of porphyrins orporphyrin precursors. They are classified as erythropoietic orhepatic, depending on whether the enzyme deficiency occurs in redblood cells or in the liver. XLDPT is a form of porphyriacharacterized biochemically by a high proportion of zinc-protoporphyrin in erythrocytes, in which a mismatch betweenprotoporphyrin production and the heme requirement ofdifferentiating erythroid cells leads to overproduction ofprotoporphyrin in amounts sufficient to cause photosensitivity andliver disease.

Defects in ALAD are the cause of acute hepatic porphyria(AHP) [MIM:612740]. AHP is a form of porphyria. Porphyrias areinherited defects in the biosynthesis of heme, resulting in theaccumulation and increased excretion of porphyrins or porphyrinprecursors. They are classified as erythropoietic or hepatic,depending on whether the enzyme deficiency occurs in red bloodcells or in the liver. AHP is characterized by attacks ofgastrointestinal disturbances, abdominal colic, paralysis, andperipheral neuropathy. Most attacks are precipitated by drugs,alcohol, caloric deprivation, infections, or endocrine factors.

Defects in HMBS are the cause of acute intermittentporphyria (AIP) [MIM:176000]. AIP is a form of porphyria.Porphyrias are inherited defects in the biosynthesis of heme,resulting in the accumulation and increased excretion ofporphyrins or porphyrin precursors. They are classified aserythropoietic or hepatic, depending on whether the enzymedeficiency occurs in red blood cells or in the liver. AIP is anautosomal dominant form of hepatic porphyria characterized byacute attacks of neurological dysfunctions with abdominal pain,hypertension, tachycardia, and peripheral neuropathy. Most attacksare precipitated by drugs, alcohol, caloric deprivation,infections, or endocrine factors.

Defects in UROS are the cause of congenitalerythropoietic porphyria (CEP) [MIM:263700], also known as Guntherdisease. Porphyrias are inherited defects in the biosynthesis ofheme, resulting in the accumulation and increased excretion ofporphyrins or porphyrin precursors. They are classified aserythropoietic or hepatic, depending on whether the enzymedeficiency occurs in red blood cells or in the liver. Themanifestations of CEP are heterogeneous, ranging from nonimmunehydrops fetalis due to severe hemolytic anemia in utero to milder,later onset forms, which have only skin lesions due to cutaneousphotosensitivity in adult life. The deficiency in UROS activityresults in the non-enzymatic conversion of hydroxymethylbilane(HMB) into the uroporphyrinogen-I isomer.

Note=Severe congenital erythropoietic porphyria isassociated with non-immune hydrops fetalis, a generalized edema ofthe fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis initself but a symptom, a feature of many genetic disorders, and theend-stage of a wide variety of disorders.

Defects in CPOX are the cause of hereditarycoproporphyria (HCP) [MIM:121300]. HCP is an acute hepaticporphyria and an autosomal dominant disease characterized byneuropsychiatric disturbances and skin photosensitivity.Biochemically, there is an overexcretion of coproporphyrin III inthe urine and in the feces. HCP is clinically characterized byattacks of abdominal pain, neurological disturbances, andpsychiatric symptoms. The symptoms are generally manifested withrapid onset, and can be precipitated by drugs, alcohol, caloricdeprivation, infection, endocrine factors or stress. A severevariant form is harderoporphyria, which is characterized byearlier onset attacks, massive excretion of harderoporphyrin inthe feces, and a marked decrease of coproporphyrinogen IX oxidaseactivity.

Defects in FECH are the cause of erythropoieticprotoporphyria (EPP) [MIM:177000]. Porphyrias are inheriteddefects in the biosynthesis of heme, resulting in the accumulationand increased excretion of porphyrins or porphyrin precursors.They are classified as erythropoietic or hepatic, depending onwhether the enzyme deficiency occurs in red blood cells or in theliver. EPP is a form of porphyria marked by excessiveprotoporphyrin in erythrocytes, plasma, liver and feces, and bywidely varying photosensitive skin changes ranging from a burningor pruritic sensation to erythema, edema and wheals.

Defects in SERPIND1 are the cause of heparin cofactor 2deficiency (HCF2D) [MIM:612356]. HCF2D is an important risk factorfor hereditary thrombophilia, a hemostatic disorder characterizedby a tendency to recurrent thrombosis.

Defects in HAMP are the cause of hemochromatosis type 2B(HFE2B) [MIM:613313], also known as juvenile hemochromatosis (JH).HFE2B is a disorder of iron metabolism with excess deposition ofiron in the tissues, bronze skin pigmentation, hepatic cirrhosis,arthropathy and diabetes. The most common symptoms ofhemochromatosis type 2 at presentation are hypogonadism andcardiomyopathy.

Defects in HES7 are the cause of spondylocostaldysostosis type 4 (SCDO4) [MIM:613686]. A rare condition ofvariable severity characterized by vertebral and costal anomalies.The main feature include dwarfism, vertebral fusion,hemivertebrae, posterior rib fusion, reduced rib number, and otherrib malformations.

Defects in HESX1 are a cause of septooptic dysplasia(SOD) [MIM:182230], also known as de Morsier syndrome. SOD is arare autosomal recessive disease. SOD is characterized by opticnerve hypoplasia, absence of the corpus callosum and hypoplasia ofthe pituitary gland with panhypopopituitarism.

Defects in HESX1 are a cause of growth hormone deficiencywith pituitary anomalies (GHDPA) [MIM:182230].

Defects in HESX1 are the cause of pituitary hormonedeficiency combined type 5 (CPHD5) [MIM:182230]. This disorder ismanifested by deficiencies in anterior pituitary tropic hormones.week-old embryo.

Defects in HEXB are the cause of GM2-gangliosidosis type2 (GM2G2) [MIM:268800], also known as Sandhoff disease. GM2-gangliosidosis is an autosomal recessive lysosomal storage diseasemarked by the accumulation of GM2 gangliosides in the neuronalcells. GM2G2 is clinically indistinguishable from GM2-gangliosidosis type 1, presenting startle reactions, earlyblindness, progressive motor and mental deterioration,macrocephaly and cherry-red spots on the macula.

Defects in HFE are a cause of hemochromatosis (HFE)[MIM:235200]. A disorder of iron metabolism characterized by ironoverload. Excess iron is deposited in a variety of organs leadingto their failure, and resulting in serious illnesses includingcirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis, andhypogonadotropic hypogonadism. Severe effects of the diseaseusually do not appear until after decades of progressive ironloading.

Defects in HFE are associated with variegate porphyria(VP) [MIM:176200]. Porphyrias are inherited defects in thebiosynthesis of heme, resulting in the accumulation and increasedexcretion of porphyrins or porphyrin precursors. They areclassified as erythropoietic or hepatic, depending on whether theenzyme deficiency occurs in red blood cells or in the liver. VP isthe most common form of porphyria in South Africa. It ischaracterized by skin hyperpigmentation and hypertrichosis,abdominal pain, tachycardia, hypertension and neuromusculardisturbances. High fecal levels of protoporphyrin andcoproporphyrin, increased urine uroporphyrins and iron overloadare typical markers of the disease. Note=Iron overload due to HFEmutations is a precipitating or exacerbating factor in variegateporphyria.

Defects in HFE are associated with susceptibility tomicrovascular complications of diabetes type 7 (MVCD7)[MIM:612635]. These are pathological conditions that develop innumerous tissues and organs as a consequence of diabetes mellitus.They include diabetic retinopathy, diabetic nephropathy leading toend-stage renal disease, and diabetic neuropathy. Diabeticretinopathy remains the major cause of new-onset blindness amongdiabetic adults. It is characterized by vascular permeability andincreased tissue ischemia and angiogenesis.

Defects in HGD are the cause of alkaptonuria (AKU)[MIM:203500]. AKU is an autosomal recessive error of metabolismcharacterized by an increase in the level of homogentisic acid.The clinical manifestations of AKU are urine that turns dark onstanding and alkalinization, black ochronotic pigmentation ofcartilage and collagenous tissues, and spine arthritis.

Defects in HGF are the cause of deafness autosomalrecessive type 39 (DFNB39) [MIM:608265]. A form of profoundprelingual sensorineural hearing loss. Sensorineural deafnessresults from damage to the neural receptors of the inner ear, thenerve pathways to the brain, or the area of the brain thatreceives sound information.

Defects in HGSNAT are the cause of mucopolysaccharidosistype 3C (MPS3C) [MIM:252930], also known as Sanfilippo C syndrome.MPS3C is a form of mucopolysaccharidosis type 3, an autosomalrecessive lysosomal storage disease due to impaired degradation ofheparan sulfate. MPS3 is characterized by severe central nervoussystem degeneration, but only mild somatic disease. Onset ofclinical features usually occurs between 2 and 6 years, severeneurologic degeneration occurs in most patients between 6 and 10years of age, and death occurs typically during the second orthird decade of life.

Defects in HIBCH are the cause of HIBCH deficiency(HIBCHD) [MIM:250620], also known as deficiency of beta-hydroxyisobutyryl CoA deacylase or methacrylic aciduria. Theenzyme defect results in accumulation of methacrylyl-CoA, a highlyreactive compound, which readily undergoes addition reactions withfree sulfhydryl groups. Affected individuals showed delayeddevelopment of motor skills, hypotonia, initial poor feeding, anda deterioration in neurological function during first stages oflife.

Note=A chromosomal aberration involving HIP1 is found ina form of chronic myelomonocytic leukemia (CMML). Translocationt(5,7)(q33,q11.2) with PDGFRB. The chimeric HIP1-PDGFRB transcriptresults from an in-frame fusion of the two genes. The reciprocalPDGFRB-HIP1 transcript is not expressed.

Note=A chromosomal aberration involving HLF is a cause ofpre-B-cell acute lymphoblastic leukemia (B-ALL). Translocationt(17,19)(q22,p13.3) with TCF3.

Defects in HMCN1 are a cause of age-related maculardegeneration type 1 (ARMD1) [MIM:603075]. ARMD is a multifactorialeye disease and the most common cause of irreversible vision lossin the developed world. In most patients, the disease is manifestas ophthalmoscopically visible yellowish accumulations of proteinand lipid (known as drusen) that lie beneath the retinal pigmentepithelium and within an elastin-containing structure known asBruch membrane.

Defects in HMGCS2 are the cause of HMG-CoA synthasedeficiency (HMGCS deficiency) [MIM:605911], also known asdeficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoAsynthase 2. Affected individuals present with severe hypoketotichypoglycemia, mild hepatomegaly, or fatty liver, and anondiagnostic pattern of urinary organic acids with increase ofmedium and short chain dicarboxylic acids.

Note=Genetic variations in EN2 may be associated withsusceptibility to autism.

Note=A chromosomal aberration involving HMGA1 is found inpulmonary chondroid hamartoma. Translocation t(6,14)(p21,q23-24)with RAD51L1.

Note=A chromosomal aberration involving HMGA2 isassociated with a subclass of benign mesenchymal tumors known aslipomas. Translocation t(3,12)(q27-q28,q13-q15) with LPP is shownin lipomas. HMGA2 is also fused with a number of other genes inlipomas.

Note=A chromosomal aberration involving HMGA2 isassociated with pulmonary chondroid hamartomas. Translocationt(3,12)(q27-q28,q14-q15) with LPP is detected in pulmonarychondroid hamartomas.

Note=A chromosomal aberration involving HMGA2 isassociated with parosteal lipomas. Translocation t(3,12)(q28,q14)with LPP is also shown in one parosteal lipoma.

Note=A chromosomal aberration involving HMGA2 is found inuterine leiomyoma. Translocation t(12,14)(q15,q23-24) withRAD51L1. Chromosomal rearrangements involving HMGA2 do not seem tobe the principle pathobiological mechanism in uterine leiomyoma.

Defects in HMGCL are the cause of 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) [MIM:246450], alsoknown as hydroxymethylglutaricaciduria or HL deficiency. Anautosomal recessive disease affecting ketogenesis and L-leucinecatabolism. The disease usually appears in the first year of lifeafter a fasting period and its clinical acute symptoms includevomiting, seizures, metabolic acidosis, hypoketotic hypoglycemiaand lethargy. These symptoms sometimes progress to coma, withfatal outcome in some cases.

Defects in HMX1 are the cause of oculoauricular syndrome(OCLAUS) [MIM:612109], also known as microphthalmia, microcornea,anterior segment dysgenesis, cataract, ocular coloboma, retinalpigment epithelium abnormalities, rod-cone dystrophy, andanomalies of the external ear.

Defects in HNF1A are a cause of hepatic adenomas familial(HEPAF) [MIM:142330]. Hepatic adenomas are rare benign livertumors of presumable epithelial origin that develop in anotherwise normal liver. Hepatic adenomas may be single ormultiple. They consist of sheets of well-differentiatedhepatocytes that contain fat and glycogen and can produce bile.Bile ducts or portal areas are absent. Kupffer cells, if present,are reduced in number and are non-functional. Conditionsassociated with adenomas are insulin-dependent diabetes mellitusand glycogen storage diseases (types 1 and 3). Note=Bi-allelicinactivation of HNF1A, whether sporadic or associated with MODY3,may be an early step in the developmant of some hepatocellularcarcinomas.

Defects in HNF1A are the cause of maturity-onset diabetesof the young type 3 (MODY3) [MIM:600496], also symbolized MODY-3.MODY is a form of diabetes that is characterized by an autosomaldominant mode of inheritance, onset in childhood or earlyadulthood (usually before 25 years of age), a primary defect ininsulin secretion and frequent insulin-independence at thebeginning of the disease.

Defects in HNF1A are the cause of susceptibility todiabetes mellitus insulin-dependent type 20 (IDDM20) [MIM:612520].IDDM20 is a multifactorial disorder of glucose homeostasis that ischaracterized by susceptibility to ketoacidosis in the absence ofinsulin therapy. Clinical fetaures are polydipsia, polyphagia andpolyuria which result from hyperglycemia-induced osmotic diuresisand secondary thirst. These features can result in long-termcomplications that affect the eyes, kidneys, nerves, and bloodvessels.

Defects in HNF1B are the cause of renal cysts anddiabetes syndrome (RCAD) [MIM:137920], also called maturity-onsetdiabetes of the young type 5 (MODY5) or familial hypoplasticglomerulocystic kidney disease (GCKD). RCAD is an autosomaldominant disorder comprising non-diabetic renal disease resultingfrom abnormal renal development, and diabetes, which in some casesoccurs earlier than age 25 years and is thus consistent with adiagnosis of maturity-onset diabetes of the young (MODY5). Therenal disease is highly variable and includes renal cysts,glomerular tufts, aberrant nephrogenesis, primitive tubules,irregular collecting systems, oligomeganephronia, enlarged renalpelves, abnormal calyces, small kidney, single kidney, horseshoekidney, and hyperuricemic nephropathy.

Defects in HNF1B may be rare genetic risk factorcontributing to the development of non-insulin-dependent diabetesmellitus (NIDDM) [MIM:125853]. NIDDM is characterized by anautosomal dominant mode of inheritance, onset during adulthood andinsulin resistance.

Defects in HNF1B may be a cause of susceptibility toprostate cancer hereditary type 11 (HPC11) [MIM:611955]. It is acondition associated with familial predisposition to cancer of theprostate. Most prostate cancers are adenocarcinomas that developin the acini of the prostatic ducts. Other rare histopathologictypes of prostate cancer that occur in approximately 5% ofpatients include small cell carcinoma, mucinous carcinoma,prostatic ductal carcinoma, transitional cell carcinoma, squamouscell carcinoma, basal cell carcinoma, adenoid cystic carcinoma(basaloid), signet-ring cell carcinoma and neuroendocrinecarcinoma.

Defects in HNF4A are the cause of maturity-onset diabetesof the young type 1 (MODY1) [MIM:125850], also symbolized MODY-1.MODY is a form of diabetes that is characterized by an autosomaldominant mode of inheritance, onset in childhood or earlyadulthood (usually before 25 years of age), a primary defect ininsulin secretion and frequent insulin-independence at thebeginning of the disease.

Defects in HOGA1 are the cause of hyperoxaluria primarytype 3 (HP3) [MIM:613616], also known as primary hyperoxaluriatype III (PH3). HP3 is a disorder where the main clinicalmanifestation is calcium oxalate nephrolithiasis though chronic aswell as terminal renal insufficiency has been described. It ischaracterized by an elevated urinary excretion of oxalate and L-glycerate.

Defects in HPD are the cause of tyrosinemia type 3(TYRO3) [MIM:276710]. TYRO3 is an inborn error of metabolismcharacterized by elevations of tyrosine in the blood and urine,seizures and mild mental retardation.

Defects in HPD are a cause of hawkinsinuria (HAWK)[MIM:140350]. HAWK is an inborn error of tyrosine metabolismcharacterized by failure to thrive, persistent metabolic acidosis,fine and sparse hair, and excretion of the unusual cyclic aminoacid metabolite, hawkinsin, in the urine.

Defects in HPRT1 are the cause of Lesch-Nyhan syndrome(LNS) [MIM:300322]. LNS is characterized by complete lack ofenzymatic activity that results in hyperuricemia, choreoathetosis,mental retardation, and compulsive self-mutilation.

Defects in HPRT1 are the cause of gout HPRT-related(GOUT-HPRT) [MIM:300323], also known as HPRT-related gout orKelley-Seegmiller syndrome. Gout is characterized by partialenzyme activity and hyperuricemia.

Defects in HPS1 are the cause of Hermansky-Pudlaksyndrome type 1 (HPS1) [MIM:203300]. Hermansky-Pudlak syndrome(HPS) is a genetically heterogeneous, rare, autosomal recessivedisorder characterized by oculocutaneous albinism, bleeding due toplatelet storage pool deficiency, and lysosomal storage defects.This syndrome results from defects of diverse cytoplasmicorganelles including melanosomes, platelet dense granules andlysosomes. Ceroid storage in the lungs is associated withpulmonary fibrosis, a common cause of premature death inindividuals with HPS.

Defects in HPS3 are the cause of Hermansky-Pudlaksyndrome type 3 (HPS3) [MIM:203300]. Hermansky-Pudlak syndrome(HPS) is a genetically heterogeneous, rare, autosomal recessivedisorder characterized by oculocutaneous albinism, bleeding due toplatelet storage pool deficiency, and lysosomal storage defects.This syndrome results from defects of diverse cytoplasmicorganelles including melanosomes, platelet dense granules andlysosomes. Ceroid storage in the lungs is associated withpulmonary fibrosis, a common cause of premature death inindividuals with HPS.

Defects in HPS4 are the cause of Hermansky-Pudlaksyndrome type 4 (HPS4) [MIM:203300]. Hermansky-Pudlak syndrome(HPS) is a genetically heterogeneous, rare, autosomal recessivedisorder characterized by oculocutaneous albinism, bleeding due toplatelet storage pool deficiency, and lysosomal storage defects.This syndrome results from defects of diverse cytoplasmicorganelles including melanosomes, platelet dense granules andlysosomes. Ceroid storage in the lungs is associated withpulmonary fibrosis, a common cause of premature death inindividuals with HPS.

Defects in HPS5 are the cause of Hermansky-Pudlaksyndrome type 5 (HPS5) [MIM:203300]. Hermansky-Pudlak syndrome(HPS) is a genetically heterogeneous, rare, autosomal recessivedisorder characterized by oculocutaneous albinism, bleeding due toplatelet storage pool deficiency, and lysosomal storage defects.This syndrome results from defects of diverse cytoplasmicorganelles including melanosomes, platelet dense granules andlysosomes. Ceroid storage in the lungs is associated withpulmonary fibrosis, a common cause of premature death inindividuals with HPS.

Defects in HPS6 are the cause of Hermansky-Pudlaksyndrome type 6 (HPS6) [MIM:203300]. Hermansky-Pudlak syndrome(HPS) is a genetically heterogeneous, rare, autosomal recessivedisorder characterized by oculocutaneous albinism, bleeding due toplatelet storage pool deficiency, and lysosomal storage defects.This syndrome results from defects of diverse cytoplasmicorganelles including melanosomes, platelet dense granules andlysosomes. Ceroid storage in the lungs is associated withpulmonary fibrosis, a common cause of premature death inindividuals with HPS.

Defects in HPSE2 are the cause of urofacial syndrome(UFS) [MIM:236730]. A rare autosomal recessive characterized byfacial grimacing when attempting to smile and failure of theurinary bladder to void completely despite a lack of anatomicalbladder outflow obstruction or overt neurological damage. Affectedindividuals often have reflux of infected urine from the bladderto the upper renal tract, with a risk of kidney damage and renalfailure.

Defects in HRG are the cause of thrombophilia due tohistidine-rich glycoprotein deficiency (THR-HRG) [MIM:613116]. Ahemostatic disorder characterized by a tendency to thrombosis.

Defects in HSF4 are the cause of cataract zonular HSF4-related (CZ-HSF4) [MIM:116800]. A form of zonular cataract.Zonular or lamellar cataracts are opacities, broad or narrow,usually consisting of powdery white dots affecting only certainlayers or zones between the cortex and nucleus of an otherwiseclear lens. The opacity may be so dense as to render the entirecentral region of the lens completely opaque, or so translucentthat vision is hardly if at all impeded. Zonular cataractsgenerally do not involve the embryonic nucleus, though sometimesthey involve the fetal nucleus. Usually sharply separated from aclear cortex outside them, they may have projections from theirouter edges known as riders or spokes.

Defects in HSF4 are the cause of cataract Marner type(CAM) [MIM:116800]. A form of cataract with variable andprogressive opacities. Affected individuals present with zonularcataract, although some have nuclear, anterior polar, or stellatecataract. Finger malformation is observed in some kindreds.

Defects in HSPB1 are the cause of Charcot-Marie-Toothdisease type 2F (CMT2F) [MIM:606595]. CMT2F is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of theperipheral nervous system. Charcot-Marie-Tooth disease isclassified in two main groups on the basis of electrophysiologicproperties and histopathology: primary peripheral demyelinatingneuropathy or CMT1, and primary peripheral axonal neuropathy orCMT2. Neuropathies of the CMT2 group are characterized by signs ofaxonal regeneration in the absence of obvious myelin alterations,normal or slightly reduced nerve conduction velocities, andprogressive distal muscle weakness and atrophy. Nerve conductionvelocities are normal or slightly reduced. CMT2F onset is between15 and 25 years with muscle weakness and atrophy usually beginningin feet and legs (peroneal distribution). Upper limb involvementoccurs later. CMT2F inheritance is autosomal dominant.

Defects in HSPB1 are a cause of distal hereditary motorneuronopathy type 2B (HMN2B) [MIM:608634]. Distal hereditary motorneuronopathies constitute a heterogeneous group of neuromusculardisorders caused by selective impairment of motor neurons in theanterior horn of the spinal cord, without sensory deficit in theposterior horn. The overall clinical picture consists of aclassical distal muscular atrophy syndrome in the legs withoutclinical sensory loss. The disease starts with weakness andwasting of distal muscles of the anterior tibial and peronealcompartments of the legs. Later on, weakness and atrophy mayexpand to the proximal muscles of the lower limbs and/or to thedistal upper limbs.

Defects in HSPB3 are the cause of distal hereditary motorneuronopathy type 2C (HMN2C) [MIM:613376]. It is a neuromusculardisorder. Distal hereditary motor neuronopathies constitute aheterogeneous group of neuromuscular disorders caused by selectivedegeneration of motor neurons in the anterior horn of the spinalcord, without sensory deficit in the posterior horn. The overallclinical picture consists of a classical distal muscular atrophysyndrome in the legs without clinical sensory loss. The diseasestarts with weakness and wasting of distal muscles of the anteriortibial and peroneal compartments of the legs. Later on, weaknessand atrophy may expand to the proximal muscles of the lower limbsand/or to the distal upper limbs.

Defects in HSPB8 are the cause of distal hereditary motorneuronopathy type 2A (HMN2A) [MIM:158590], also known as distalhereditary motor neuropathy type IIA or spinal Charcot-Marie-Toothdisease IIA. Distal hereditary motor neuronopathies constitute aheterogeneous group of neuromuscular disorders caused by selectiveimpairment of motor neurons in the anterior horn of the spinalcord, without sensory deficit in the posterior horn. The overallclinical picture consists of a classical distal muscular atrophysyndrome in the legs without clinical sensory loss. The diseasestarts with weakness and wasting of distal muscles of the anteriortibial and peroneal compartments of the legs. Later on, weaknessand atrophy may expand to the proximal muscles of the lower limbsand/or to the distal upper limbs.

Defects in HSPB8 are the cause of Charcot-Marie-Toothdisease type 2L (CMT2L) [MIM:608673]. CMT2L is an axonal form ofCharcot-Marie-Tooth disease. Axonal CMT neuropathies arecharacterized by signs of axonal regeneration in the absence ofobvious myelin alterations, normal or slightly reduced nerveconduction velocities, and progressive distal muscle weakness andatrophy.

Variations in the promoter region of HTRA1 are the causeof susceptibility to age-related macular degeneration type 7(ARMD7) [MIM:610149]. ARMD is the leading cause of vision loss andblindness among older individuals in the developed word. It isclassified as either dry (nonneovascular) or wet (neovascular).ARMD7 is a wet form, in which new blood vessels form and breakbeneath the retina. This leakage causes permanent damage tosurrounding retinal tissue, distorting and destroying centralvision. Wet ARMD is more prevalent among Asians than Caucasians.

Defects in HTRA1 are the cause of cerebral autosomalrecessive arteriopathy with subcortical infarcts andleukoencephalopathy (CARASIL) [MIM:600142]. CARASIL ischaracterized by nonhypertensive cerebral small-vesselarteriopathy with subcortical infarcts, alopecia, and spondylosis,with an onset in early adulthood. On neuropathologicalexamination, arteriosclerosis associated with intimal thickeningand dense collagen fibers, loss of vascular smooth-muscle cells,and hyaline degeneration of the tunica media has been observed incerebral small arteries.

Defects in HTRA2 are the cause of Parkinson disease type13 (PARK13) [MIM:610297]. A complex neurodegenerative disordercharacterized by bradykinesia, resting tremor, muscular rigidityand postural instability, as well as by a clinically significantresponse to treatment with levodopa. The pathology involves theloss of dopaminergic neurons in the substantia nigra and thepresence of Lewy bodies (intraneuronal accumulations of aggregatedproteins), in surviving neurons in various areas of the brain.

Defects in HAL are the cause of histidinemia (HISTID)[MIM:235800]. It is an autosomal recessive disease characterizedby increased histidine and histamine as well as decreased urocanicacid in body fluids.

Defects in UROC1 are a cause of urocanase deficiency(UROD) [MIM:276880]. An inborn error of histidine metabolismresulting in urocanic aciduria and neurological manifestationsincluding mental retardation, ataxia, episodic aggressive behavioror exaggerated affection-seeking.

Defects in HUWE1 are the cause of mental retardationsyndromic X-linked Turner type (MRXST) [MIM:300706], also known asmental retardation and macrocephaly syndrome. MRXST shows clinicalvariability. Associated phenotypes include macrocephaly andvariable contractures.

A chromosomal microduplication involving HUWE1 andHSD17B10 is the cause of mental retardation X-linked type 17(MRX17) [MIM:300705], also known as mental retardation X-linkedtype 31 (MRX31). Mental retardation is characterized bysignificantly sub-average general intellectual functioningassociated with impairments in adaptative behavior and manifestedduring the developmental period. In contrast to syndromic orspecific X-linked mental retardation which also present withassociated physical, neurological and/or psychiatricmanifestations, intellectual deficiency is the only primarysymptom of non-syndromic X-linked mental retardation.

Defects in HOXA11 are the cause of radioulnar synostosiswith amegakaryocytic thrombocytopenia (RSAT) [MIM:605432]. Thesyndrome consists of an unusual association of bone marrow failureand skeletal defects. Patients have the same skeletal defects, theproximal fusion of the radius and ulna, resulting in extremelylimited pronation and supination of the forearm. Some patientshave also symptomatic thrombocytopenia, with bruising and bleedingproblems since birth, necessitating correction by bone marrow orumbilical-cord stem-cell transplantation.

Defects in HOXA13 are the cause of hand-foot-genitalsyndrome (HFGS) [MIM:140000], also known as hand-foot-uterussyndrome. The clinical features include small feet with unusuallyshort great toes and abnormal thumbs. Females with the disorderhave duplication of the genital tract.

Defects in HOXA13 are the cause of Guttmacher syndrome(GUTTS) [MIM:176305]. Guttmacher syndrome is a dominantlyinherited combination of distal limb and genital tractabnormalities. It has several features in common with hand-foot-genital syndrome, including hypoplastic first digits andhypospadias. Typical features not seen in hand-foot-genitalsyndrome include postaxial polydactyly of the hands anduniphalangeal second toes with absent nails.

Defects in HOXA1 are the cause of Athabaskan brainstemdysgenesis syndrome (ABSD) [MIM:601536], also known as Narvajobrainstem syndrome. This syndrome is characterized by horizontalgaze palsy, sensorineural deafness, central hypoventilation, anddevelopmental delay. Some patients had swallowing dysfunction,vocal cord paralysis, facial paresis, seizures, and cardiacoutflow tract anomalies.

Defects in HOXA1 are the cause of Bosley-Salih-Alorainysyndrome (BSAS) [MIM:601536]. Affected individuals show horizontalgaze abnormalities, deafness, facial weakness, vascularmalformations of the internal carotid arteries and cardiac outflowtrac. Some patients manifest mental retardation and autismspectrum disorder. In contrast to individuals with ABSD, centralhypoventilation is not observed in individuals with BSAS.

Defects in HOXA2 are a cause of microtia hearingimpairment and cleft palate (MHICP) [MIM:612290]. Microtia is acongenital deformity of the outer ear and occurs in approximatelyone in 8'000-10'000 births. It is characterized by a small,abnormally shaped outer ear. It can be unilateral or bilateral.Syndromic forms of microtia occur in conjunction with otherabnormalities. The most common associated malformations is thecleft palate, a congenital fissure of the soft and/or hard palatedue to faulty fusion. Defects in HOXA2 are a cause of autosomal-recessive bilateral microtia, mixed symmetrical severe to profoundhearing impairment and partial cleft palate.

Note=A chromosomal aberration involving HOXA9 is found ina form of acute myeloid leukemia. Translocation t(7,11)(p15,p15)with NUP98.

Note=A chromosomal aberration involving HOXA9 maycontribute to disease progression in chronic myeloid leukemia.Translocation t(7,17)(p15,q23) with MSI2.

Defects in HOXD10 are a cause of congenital verticaltalus (CVT) [MIM:192950], also known as rocker-bottom footdeformity or congenital convex pes valgus. CVT is a dislocation ofthe talonavicular joint, with rigid dorsal dislocation of thenavicular over the neck of the talus. This condition is usuallyassociated with multiple other congenital deformities and onlyrarely is an isolated deformity.

Defects in HOXD13 are the cause of synpolydactyly 1(SPD1) [MIM:186000], also known as syndactyly type 2 (SDTY2). SPD1is a limb malformation that shows a characteristic manifestationin both hands and feet. This condition is inherited as anautosomal dominant trait with reduced penetrance.

Defects in HOXD13 are the cause of brachydactyly type D(BDD) [MIM:113200]. BDD is characterized by short and broadterminal phalanges of the thumbs and big toes. Inheritance isautosomal dominant.

Defects in HOXD13 are the cause of syndactyly type 5[MIM:186300], also known as syndactyly with metacarpal andmetatarsal fusion. The metacarpals and metatarsals most commonlyfused are the 4th and 5th or the 3rd and 4th. Soft tissuesyndactyly usually affects the 3rd and 4th fingers and the 2nd and3rd toes. Inheritance is autosomal dominant.

Defects in HOXD13 are the cause of brachydactyly-syndactyly syndrome (BDSD) [MIM:610713]. Most of affectedindividuals exhibit generalized shortening of the hands and feet,broad and short distal phalanges of the thumbs, and cutaneoussyndactyly of toes 2 and 3. The limb phenotypes observed in thissyndrome overlap those of brachydactyly types A4, D, E andsyndactyly type 1.

Defects in HOXD13 are the cause of brachydactyly type E(BDE) [MIM:113300]. BDE is characterized by shortening of thefingers mainly in the metacarpals and metatarsals. Inheritance isautosomal dominant.

Defects in HOXD13 are a cause of VACTERL association(VACTERL) [MIM:192350], which includes also VATER association.VACTERL is an acronym for vertebral anomalies, anal atresia,congenital cardiac disease, tracheoesophageal fistula, renalanomalies, radial dysplasia, and other limb defects.

Defects in HK1 are the cause of hexokinase deficiency (HKdeficiency) [MIM:235700]. HK deficiency is a rare autosomalrecessive disease with nonspherocytic hemolytic anemia as thepredominant clinical feature.

Defects in GCK are the cause of maturity-onset diabetesof the young type 2 (MODY2) [MIM:125851], also shortened MODY-2.MODY is a form of diabetes that is characterized by an autosomaldominant mode of inheritance, onset in childhood or earlyadulthood (usually before 25 years of age), a primary defect ininsulin secretion and frequent insulin-independence at thebeginning of the disease.

Defects in GCK are the cause of familial hyperinsulinemichypoglycemia type 3 (HHF3) [MIM:602485], also known as persistenthyperinsulinemic hypoglycemia of infancy (PHHI) or congenitalhyperinsulinism. HHF is the most common cause of persistenthypoglycemia in infancy. Unless early and aggressive interventionis undertaken, brain damage from recurrent episodes ofhypoglycemia may occur.

Defects in HYAL1 are the cause of mucopolysaccharidosistype 9 (MPS9) [MIM:601492], also called hyaluronidase deficiency.MPS9 is a lysosomal storage disease characterized by highhyaluronan (HA) concentration in the serum. The clinical featuresare periarticular soft tissue masses, mild short stature andacetabular erosions, and absence of neurological or visceralinvolvement.

Defects in FAM126A are the cause of leukodystrophyhypomyelinating type 5 (HLD5) [MIM:610532]. This disorder ischaracterized by congenital cataract, progressive neurologicimpairment, and diffuse myelin deficiency. Affected individualsexperience progressive pyramidal and cerebellar dysfunction,muscle weakness and wasting prevailingly in the lower limbs.Mental deficiency ranges from mild to moderate.

Note=In some populations, the high activity haplotypetyr113/his139 is overrepresented among women suffering frompregnancy-induced hypertension (pre-eclampsia) when compared withhealthy controls.

Defects in EPHX1 are a cause of familial hypercholanemia(FHCA) [MIM:607748]. FHCA is a disorder characterized by elevatedserum bile acid concentrations, itching, and fat malabsorption.

Defects in HYLS1 are the cause of hydrolethalus syndrometype 1 (HLS1) [MIM:236680]. HLS1 is a lethal malformation syndromeleading to stillbirth or death shortly after birth. It ischaracterized by hydrocephaly with absent upper midline structuresof the brain, micrognathia and polydactyly.

Defects in IL10RA are the cause of inflammatory boweldisease type 28 (IBD28) [MIM:613148]. It is a chronic, relapsinginflammation of the gastrointestinal tract with a complexetiology. It is subdivided into Crohn disease and ulcerativecolitis phenotypes. Crohn disease may affect any part of thegastrointestinal tract from the mouth to the anus, but mostfrequently it involves the terminal ileum and colon. Bowelinflammation is transmural and discontinuous, it may containgranulomas or be associated with intestinal or perianal fistulas.In contrast, in ulcerative colitis, the inflammation is continuousand limited to rectal and colonic mucosal layers, fistulas andgranulomas are not observed. Both diseases include extraintestinalinflammation of the skin, eyes, or joints.

Defects in IL12RB1 are a cause of mendeliansusceptibility to mycobacterial disease (MSMD) [MIM:209950], alsoknown as familial disseminated atypical mycobacterial infection.This rare condition confers predisposition to illness caused bymoderately virulent mycobacterial species, such as BacillusCalmette-Guerin (BCG) vaccine and environmental non-tuberculousmycobacteria, and by the more virulent Mycobacterium tuberculosis.Other microorganisms rarely cause severe clinical disease inindividuals with susceptibility to mycobacterial infections, withthe exception of Salmonella which infects less than 50% of theseindividuals. The pathogenic mechanism underlying MSMD is theimpairment of interferon-gamma mediated immunity, whose severitydetermines the clinical outcome. Some patients die of overwhelmingmycobacterial disease with lepromatous-like lesions in earlychildhood, whereas others develop, later in life, disseminated butcurable infections with tuberculoid granulomas. MSMD is agenetically heterogeneous disease with autosomal recessive,autosomal dominant or X-linked inheritance.

Defects in SERPING1 are the cause of hereditaryangioedema (HAE) [MIM:106100], also called hereditaryangioneurotic edema (HANE). HAE is an autosomal dominant disordercharacterized by episodic local subcutaneous edema and submucosaledema involving the upper respiratory and gastrointestinal tracts.HAE due to C1 esterase inhibitor deficiency is comprised of twoclinically indistinguishable forms. In HAE type 1, representing85% of patients, serum levels of C1 esterase inhibitor are lessthan 35% of normal. In HAE type 2, the levels are normal orelevated, but the protein is non-functional.

Defects in ICK are the cause of endocrine-cerebroosteodysplasia (ECO) [MIM:612651]. ECO is a previouslyunidentified neonatal lethal recessive disorder with multipleanomalies involving the endocrine, cerebral, and skeletal systems.

Defects in ICOS are the cause of immunodeficiency commonvariable type 1 (CVID1) [MIM:607594]. CVID1 is a primaryimmunodeficiency characterized by antibody deficiency,hypogammaglobulinemia, recurrent bacterial infections and aninability to mount an antibody response to antigen. The defectresults from a failure of B-cell differentiation and impairedsecretion of immunoglobulins, the numbers of circulating B cellsis usually in the normal range, but can be lo.

Defects in IDH3B are the cause of retinitis pigmentosatype 46 (RP46) [MIM:612572]. RP is a retinal dystrophy belongingto the group of pigmentary retinopathies. RP is characterized byretinal pigment deposits visible on fundus examination and primaryloss of rod photoreceptor cells followed by secondary loss of conephotoreceptors. Patients typically have night vision blindness andloss of midperipheral visual field. As their condition progresses,they lose their far peripheral visual field and eventually centralvision as well.

Defects in IDH1 are involved in the development of glioma(GLM) [MIM:137800]. Gliomas are central nervous system neoplasmsderived from glial cells and comprise astrocytomas, glioblastomamultiforme, oligodendrogliomas, and ependymomas. Note=Mutationsaffecting Arg-132 are tissue-specific, and suggest that thisresidue plays a unique role in the development of high-gradegliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolishmagnesium binding and abolish the conversion of isocitrate toalpha-ketoglutarate. Instead, alpha-ketoglutarate is converted toR(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-hydroxyglutarate are correlated with an elevated risk of malignantbrain tumors.

Defects in IDH2 are the cause of D-2-hydroxyglutaricaciduria type 2 (D2HGA2) [MIM:613657]. D2HGA2 is a neurometabolicdisorder causing developmental delay, epilepsy, hypotonia, anddysmorphic features. Both a mild and a severe phenotype exist. Thesevere phenotype is homogeneous and is characterized by earlyinfantile-onset epileptic encephalopathy and cardiomyopathy. Themild phenotype has a more variable clinical presentation.Diagnosis is based on the presence of an excess of D-2-hydroxyglutaric acid in the urine.

Defects in IDS are the cause of mucopolysaccharidosistype 2 (MPS2) [MIM:309900], also known as Hunter syndrome. MPS2 isan X-linked lysosomal storage disease characterized byintracellular accumulation of heparan sulfate and dermatan sulfateand their excretion in urine. Most children with MPS2 have asevere form with early somatic abnormalities including skeletaldeformities, hepatosplenomegaly, and progressive cardiopulmonarydeterioration. A prominent feature is neurological damage thatpresents as developmental delay and hyperactivity but progressesto mental retardation and dementia. They die before 15 years ofage, usually as a result of obstructive airway disease or cardiacfailure. In contrast, those with a mild form of MPS2 may surviveinto adulthood, with attenuated somatic complications and oftenwithout mental retardation.

Defects in IDUA are the cause of mucopolysaccharidosistype 1H (MPS1H) [MIM:607014], also known as Hurler syndrome. MPS1His a severe form of mucopolysaccharidosis type 1, a rare lysosomalstorage disease characterized by progressive physicaldeterioration with urinary excretion of dermatan sulfate andheparan sulfate. Patients with MPS1H usually present, within thefirst year of life, a combination of hepatosplenomegaly, skeletaldeformities, corneal clouding and severe mental retardation.Obstructive airways disease, respiratory infection and cardiaccomplications usually result in death before 10 years of age.

Defects in IDUA are the cause of mucopolysaccharidosistype 1H/S (MPS1H/S) [MIM:607015], also known as Hurler-Scheiesyndrome. MPS1H/S is a form of mucopolysaccharidosis type 1, arare lysosomal storage disease characterized by progressivephysical deterioration with urinary excretion of dermatan sulfateand heparan sulfate. MPS1H/S represents an intermediate phenotypeof the MPS1 clinical spectrum. It is characterized by relativelylittle neurological involvement, but most of the somatic symptomsdescribed for severe MPS1 develop in the early to mid-teens,causing considerable loss of mobility.

Defects in IDUA are the cause of mucopolysaccharidosistype 1S (MPS1S) [MIM:607016], also known as Scheie syndrome. MPS1Sis a mild form of mucopolysaccharidosis type 1, a rare lysosomalstorage disease characterized by progressive physicaldeterioration with urinary excretion of dermatan sulfate andheparan sulfate. Patients with MPS1S may have little or noneurological involvement, normal stature and life span, butpresent development of joints stiffness, mild hepatosplenomegaly,aortic valve disease and corneal clouding.

Defects in IFT122 are a cause of cranioectodermaldysplasia type 1 (CED1) [MIM:218330]. CED1 is a disordercharacterized by craniofacial, skeletal and ectodermalabnormalities. Clinical features include dolichocephaly (with orwithout sagittal suture synostosis), scaphocephaly, short stature,limb shortening, short ribs, narrow chest, brachydactyly, renalfailure and hepatic fibrosis, small and abnormally shaped teeth,sparse hair, skin laxity and abnormal nails.

Note=EIF4H is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.Haploinsufficiency of EIF4H may be the cause of certaincardiovascular and musculo-skeletal abnormalities observed in thedisease.

Genetic variation in IFIH1 is associated with diabetesmellitus insulin-dependent type 19 (IDDM19) [MIM:610155]. Amultifactorial disorder of glucose homeostasis that ischaracterized by susceptibility to ketoacidosis in the absence ofinsulin therapy. Clinical fetaures are polydipsia, polyphagia andpolyuria which result from hyperglycemia-induced osmotic diuresisand secondary thirst. These derangements result in long-termcomplications that affect the eyes, kidneys, nerves, and bloodvessels.

Note=IFIH1 is the CADM-140 autoantigen, involved inclinically amyopathic dermatomyositis (CADM). This is a chronicinflammatory disorder that shows typical skin manifestations ofdermatomyositis but has no or little evidence of clinicalmyositis. Anti-CADM-140 antibodies appear to be specific todermatomyositis, especially CADM. Patients with anti-CADM-140antibodies frequently develop life-threatening acute progressiveinterstitial lung disease (ILD).

In Caucasians, genetic variation in IFNG is associatedwith the risk of aplastic anemia (AA) [MIM:609135]. AA is a raredisease in which the reduction of the circulating blood cellsresults from damage to the stem cell pool in bone marrow. In mostpatients, the stem cell lesion is caused by an autoimmune attack.T-lymphocytes, activated by an endogenous or exogenous, and mostoften unknown antigenic stimulus, secrete cytokines, includingIFN-gamma, which would in turn be able to suppress hematopoiesis.

Defects in IFT43 are a cause of cranioectodermaldysplasia type 1 (CED1) [MIM:218330]. CED1 is a disordercharacterized by craniofacial, skeletal and ectodermalabnormalities. Clinical features include dolichocephaly (with orwithout sagittal suture synostosis), scaphocephaly, short stature,limb shortening, short ribs, narrow chest, brachydactyly, renalfailure and hepatic fibrosis, small and abnormally shaped teeth,sparse hair, skin laxity and abnormal nails.

Defects in IFT80 are the cause of asphyxiating thoracicdystrophy 2 (ATD2) [MIM:611263]. ATD2 is an autosomal recessivechondrodysplasia which often leads to death in infancy because ofa severely constricted thoracic cage and respiratoryinsufficiency. Retinal degeneration, cystic renal disease andpolydactyly may be complicating features.

Defects in GIF are the cause of hereditary intrinsicfactor deficiency (IFD) [MIM:261000], also known as congenitalpernicious anemia. IFD is an autosomal recessive disordercharacterized by megaloblastic anemia.

Defects in IGBP1 are the cause of agenesis of the corpuscallosum with mental retardation-ocular coloboma-micrognathia(ACCMRCM) [MIM:300472].

Defects in IGF1R are a cause of insulin-like growthfactor 1 resistance (IGF1RES) [MIM:270450]. It is a disordercharacterized by intrauterine growth retardation and poorpostnatal growth accompanied with increased plasma IGF1.

Defects in IGF1 are the cause of insulin-like growthfactor I deficiency (IGF1 deficiency) [MIM:608747]. IGF1deficiency is an autosomal recessive disorder characterized bygrowth retardation, sensorineural deafness and mental retardation.

Epigenetic changes of DNA hypomethylation in IGF2 are acause of Silver-Russell syndrome (SIRS) [MIM:180860]. SIRS is aclinically heterogeneous condition characterized by severeintrauterine growth retardation, poor postnatal growth,craniofacial features such as a triangular shaped face and a broadforehead, body asymmetry, and a variety of minor malformations.

Defects in IGHM are the cause of agammaglobulinemia type1 (AGM1) [MIM:601495]. It is a primary immunodeficiencycharacterized by profoundly low or absent serum antibodies and lowor absent circulating B cells due to an early block of B-celldevelopment. Affected individuals develop severe infections in thefirst years of life.

Defects in IGLL1 are the cause of agammaglobulinemia type2 (AGM2) [MIM:613500]. It is a primary immunodeficiencycharacterized by profoundly low or absent serum antibodies and lowor absent circulating B cells due to an early block of B-celldevelopment. Affected individuals develop severe infections in thefirst years of life.

Defects in IHH are the cause of brachydactyly type A1(BDA1) [MIM:112500]. BDA1 is an autosomal dominant disordercharacterized by middle phalanges of all the digits rudimentary orfused with the terminal phalanges. The proximal phalanges of thethumbs and big toes are short.

Defects in IHH are a cause of acrocapitofemoral dysplasia(ACFD) [MIM:607778]. ACFD is a disorder characterized by shortstature of variable severity with postnatal onset. The mostconstant radiographic abnormalities are observed in the tubularbones of the hands and in the proximal part of the femur. Cone-shaped epiphyses or a similar epiphyseal configuration withpremature epimetaphyseal fusion result in shortening of theskeletal components involved. Cone-shaped epiphyses were alsopresent to a variable extent at the shoulders, knees, and ankles.

Defects in NFKBIA are the cause of ectodermal dysplasiaanhidrotic with T-cell immunodeficiency autosomal dominant(ADEDAID) [MIM:612132]. Ectodermal dysplasia defines aheterogeneous group of disorders due to abnormal development oftwo or more ectodermal structures. ADEDAID is an ectodermaldysplasia associated with decreased production of pro-inflammatorycytokines and certain interferons, rendering patients susceptibleto infection.

Defects in NFKBIL1 are a cause of susceptibility torheumatoid arthritis (RA) [MIM:180300]. It is a systemicinflammatory disease with autoimmune features and a complexgenetic component. It primarily affects the joints and ischaracterized by inflammatory changes in the synovial membranesand articular structures, widespread fibrinoid degeneration of thecollagen fibers in mesenchymal tissues, and by atrophy andrarefaction of bony structures.

Defects in CHUK are the cause of cocoon syndrome (COCOS)[MIM:613630], also known as fetal encasement syndrome. COCOS is alethal syndrome characterized by multiple fetal malformationsincluding defective face and seemingly absent limbs, which arebound to the trunk and encased under the skin.

Note=Defects in IKZF1 are frequent occurrences (28.6%) inacute lymphoblasic leukemia (ALL). Such alterations or deletionslead to poor prognosis for ALL.

Defects in IL12B are a cause of mendelian susceptibilityto mycobacterial disease (MSMD) [MIM:209950], also known asfamilial disseminated atypical mycobacterial infection. This rarecondition confers predisposition to illness caused by moderatelyvirulent mycobacterial species, such as Bacillus Calmette-Guerin(BCG) vaccine and environmental non-tuberculous mycobacteria, andby the more virulent Mycobacterium tuberculosis. Othermicroorganisms rarely cause severe clinical disease in individualswith susceptibility to mycobacterial infections, with theexception of Salmonella which infects less than 50% of theseindividuals. The pathogenic mechanism underlying MSMD is theimpairment of interferon-gamma mediated immunity, whose severitydetermines the clinical outcome. Some patients die of overwhelmingmycobacterial disease with lepromatous-like lesions in earlychildhood, whereas others develop, later in life, disseminated butcurable infections with tuberculoid granulomas. MSMD is agenetically heterogeneous disease with autosomal recessive,autosomal dominant or X-linked inheritance.

Genetic variations in IL12B are a cause of susceptibilityto psoriasis type 11 (PSORS11) [MIM:612599]. Psoriasis is acommon, chronic inflammatory disease of the skin withmultifactorial etiology. It is characterized by red, scaly plaquesusually found on the scalp, elbows and knees. These lesions arecaused by abnormal keratinocyte proliferation and infiltration ofinflammatory cells into the dermis and epidermis.

Defects in IL13 may be a cause of susceptibility toallergic rhinitis (ALRH) [MIM:607154]. Allergic rhinitis is acommon disease of complex inheritance and is characterized bymucosal inflammation caused by allergen exposure.

Genetic variation in IL1RN is associated withsusceptibility to microvascular complications of diabetes type 4(MVCD4) [MIM:612628]. These are pathological conditions thatdevelop in numerous tissues and organs as a consequence ofdiabetes mellitus. They include diabetic retinopathy, diabeticnephropathy leading to end-stage renal disease, and diabeticneuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized byvascular permeability and increased tissue ischemia andangiogenesis.

Defects in IL1RN are the cause of interleukin 1 receptorantagonist deficiency (DIRA) [MIM:612852], also known asdeficiency of interleukin 1 receptor antagonist. Autoinflammatorydiseases manifest inflammation without evidence of infection,high-titer autoantibodies, or autoreactive T-cells. DIRA is arare, autosomal recessive, genetic autoinflammatory disease thatresults in sterile multifocal osteomyelitis (bone inflammation inmultiple places), periostitis (inflammation of the membranesurrounding the bones), and pustulosis (due to skin inflammation)from birth.

Genetic variations in IL23R are associated withinflammatory bowel disease type 17 (IBD17) [MIM:612261]. IBD17 isa chronic, relapsing inflammation of the gastrointestinal tractwith a complex etiology. It is subdivided into Crohn disease andulcerative colitis phenotypes. Crohn disease may affect any partof the gastrointestinal tract from the mouth to the anus, but mostfrequently it involves the terminal ileum and colon. Bowelinflammation is transmural and discontinuous, it may containgranulomas or be associated with intestinal or perianal fistulas.In contrast, in ulcerative colitis, the inflammation is continuousand limited to rectal and colonic mucosal layers, fistulas andgranulomas are not observed. Both diseases include extraintestinalinflammation of the skin, eyes, or joints.

Genetic variations in IL23R are a cause of susceptibilityto psoriasis type 7 (PSORS7) [MIM:605606]. Psoriasis is a common,chronic inflammatory disease of the skin with multifactorialetiology. It is characterized by red, scaly plaques usually foundon the scalp, elbows and knees. These lesions are caused byabnormal keratinocyte proliferation and infiltration ofinflammatory cells into the dermis and epidermis.

Genetic variations in IL2RA are associated withsusceptibility to diabetes mellitus insulin-dependent type 10(IDDM10) [MIM:601942]. A multifactorial disorder of glucosehomeostasis that is characterized by susceptibility toketoacidosis in the absence of insulin therapy. Clinical fetauresare polydipsia, polyphagia and polyuria which result fromhyperglycemia-induced osmotic diuresis and secondary thirst. Thesederangements result in long-term complications that affect theeyes, kidneys, nerves, and blood vessels.

Defects in IL2RG are the cause of severe combinedimmunodeficiency X-linked T-cell-negative/B-cell-positive/NK-cell-negative (XSCID) [MIM:300400], also known as agammaglobulinemiaSwiss type. A form of severe combined immunodeficiency (SCID), agenetically and clinically heterogeneous group of rare congenitaldisorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels.Patients present in infancy recurrent, persistent infections byopportunistic organisms. The common characteristic of all types ofSCID is absence of T-cell-mediated cellular immunity due to adefect in T-cell development.

Defects in IL2RG are the cause of X-linked combinedimmunodeficiency (XCID) [MIM:312863]. XCID is a less severe formof X-linked immunodeficiency with a less severe degree ofdeficiency in cellular and humoral immunity than that seen inXSCID.

Genetic variations in IL4 may be a cause ofsusceptibility to ischemic stroke (ISCHSTR) [MIM:601367], alsoknown as cerebrovascular accident or cerebral infarction. A strokeis an acute neurologic event leading to death of neural tissue ofthe brain and resulting in loss of motor, sensory and/or cognitivefunction. Ischemic strokes, resulting from vascular occlusion, isconsidered to be a highly complex disease consisting of a group ofheterogeneous disorders with multiple genetic and environmentalrisk factors.

Genetic variations in IL6 are associated withsusceptibility to rheumatoid arthritis systemic juvenile (RASJ)[MIM:604302]. An inflammatory articular disorder with systemic-onset beginning before the age of 16. It represents a subgroup ofjuvenile arthritis associated with severe extraarticular featuresand occasionally fatal complications. During active phases of thedisorder, patients display a typical daily spiking fever, anevanescent macular rash, lymphadenopathy, hepatosplenomegaly,serositis, myalgia and arthritis.

Note=A IL6 promoter polymorphism is associated with alifetime risk of development of Kaposi sarcoma in HIV-infectedmen.

Defects in IL7R are a cause of autosomal recessive severecombined immunodeficiency T-cell-negative/B-cell-positive/NK cell-positive (T(-)/B(+)/NK(+) SCID) [MIM:608971]. A form of severecombined immunodeficiency (SCID), a genetically and clinicallyheterogeneous group of rare congenital disorders characterized byimpairment of both humoral and cell-mediated immunity, leukopenia,and low or absent antibody levels. Patients present in infancyrecurrent, persistent infections by opportunistic organisms. Thecommon characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.

Genetic variations in IL7R are a cause of susceptibilityto multiple sclerosis type 3 (MS3) [MIM:612595]. A multifactorial,inflammatory, demyelinating disease of the central nervous system.Sclerotic lesions are characterized by perivascular infiltrationof monocytes and lymphocytes and appear as indurated areas inpathologic specimens (sclerosis in plaques). The pathologicalmechanism is regarded as an autoimmune attack of the myelin sheat,mediated by both cellular and humoral immunity. Clinicalmanifestations include visual loss, extra-ocular movementdisorders, paresthesias, loss of sensation, weakness, dysarthria,spasticity, ataxia and bladder dysfunction. Genetic andenvironmental factors influence susceptibility to the disease.Note=A polymorphism at position 244 strongly influencessusceptibility to multiple sclerosis. Overtransmission of themajor 'C' allele coding for Thr-244 is detected in offspringaffected with multiple sclerosis. In vitro analysis of transcriptsfrom minigenes containing either 'C' allele (Thr-244) or 'T'allele (Ile-244) shows that the 'C' allele results in anapproximately two-fold increase in the skipping of exon 6, leadingto increased production of a soluble form of IL7R. Thus, themultiple sclerosis associated 'C' risk allele of IL7R wouldprobably decrease membrane-bound expression of IL7R. As this riskallele is common in the general population, some additionaltriggers are probably required for the development and progressionof MS.

Defects in IMPDH1 are the cause of retinitis pigmentosatype 10 (RP10) [MIM:180105]. RP leads to degeneration of retinalphotoreceptor cells. Patients typically have night visionblindness and loss of midperipheral visual field. As theircondition progresses, they lose their far peripheral visual fieldand eventually central vision as well. RP10 inheritance isautosomal dominant.

Defects in IMMP2L may be a cause of Gilles de la Tourettesyndrome (GTS) [MIM:137580]. GTS is a neurologic disordermanifested particularly by motor and vocal tics and associatedwith behavioral abnormalities.

Defects in IMPG2 are the cause of retinitis pigmentosatype 56 (RP56) [MIM:613581]. RP56 is a retinal dystrophy belongingto the group of pigmentary retinopathies. Retinitis pigmentosa ischaracterized by retinal pigment deposits visible on fundusexamination and primary loss of rod photoreceptor cells followedby secondary loss of cone photoreceptors. Patients typically havenight vision blindness and loss of midperipheral visual field. Astheir condition progresses, they lose their far peripheral visualfield and eventually central vision as well.

Defects in IMPG2 are the cause of maculopathy IMPG2-related (MACLP-IMPG2) [MIM:613581]. MACLP-IMPG2 is a mildmaculopathy characterized by full-field electroretinogramresponses within normal limits, normal color vision, elevation ofthe photoreceptor layer in the foveal region and mild nuclearsclerosis.

Defects in INF2 are the cause of focal segmentalglomerulosclerosis type 5 (FSGS5) [MIM:613237]. A renal pathologydefined by the presence of segmental sclerosis in glomeruli andresulting in proteinuria, reduced glomerular filtration rate andedema. Renal insufficiency often progresses to end-stage renaldisease, a highly morbid state requiring either dialysis therapyor kidney transplantation.

Defects in ING1 are a cause of head and neck squamouscell carcinomas (HNSCC) [MIM:275355], also known as squamous cellcarcinoma of the head and neck.

Defects in ING3 may be a cause of head and neck squamouscell carcinomas (HNSCC) [MIM:275355], also known as squamous cellcarcinoma of the head and neck.

Defects in IFNGR1 are a cause of mendelian susceptibilityto mycobacterial disease (MSMD) [MIM:209950], also known asfamilial disseminated atypical mycobacterial infection. This rarecondition confers predisposition to illness caused by moderatelyvirulent mycobacterial species, such as Bacillus Calmette-Guerin(BCG) vaccine and environmental non-tuberculous mycobacteria, andby the more virulent Mycobacterium tuberculosis. Othermicroorganisms rarely cause severe clinical disease in individualswith susceptibility to mycobacterial infections, with theexception of Salmonella which infects less than 50% of theseindividuals. The pathogenic mechanism underlying MSMD is theimpairment of interferon-gamma mediated immunity whose severitydetermines the clinical outcome. Some patients die of overwhelmingmycobacterial disease with lepromatous-like lesions in earlychildhood, whereas others develop, later in life, disseminated butcurable infections with tuberculoid granulomas. MSMD is agenetically heterogeneous disease with autosomal recessive,autosomal dominant or X-linked inheritance.

Defects in IFNGR2 are a cause of mendelian susceptibilityto mycobacterial disease (MSMD) [MIM:209950], also known asfamilial disseminated atypical mycobacterial infection. This rarecondition confers predisposition to illness caused by moderatelyvirulent mycobacterial species, such as Bacillus Calmette-Guerin(BCG) vaccine and environmental non-tuberculous mycobacteria, andby the more virulent Mycobacterium tuberculosis. Othermicroorganisms rarely cause severe clinical disease in individualswith susceptibility to mycobacterial infections, with theexception of Salmonella which infects less than 50% of theseindividuals. The pathogenic mechanism underlying MSMD is theimpairment of interferon-gamma mediated immunity, whose severitydetermines the clinical outcome. Some patients die of overwhelmingmycobacterial disease with lepromatous-like lesions in earlychildhood, whereas others develop, later in life, disseminated butcurable infections with tuberculoid granulomas. MSMD is agenetically heterogeneous disease with autosomal recessive,autosomal dominant or X-linked inheritance.

Defects in INPP5E are the cause of Joubert syndrome type1 (JBTS1) [MIM:213300]. A disorder presenting with cerebellarataxia, oculomotor apraxia, hypotonia, neonatal breathingabnormalities and psychomotor delay. Neuroradiologically, it ischaracterized by cerebellar vermian hypoplasia/aplasia, thickenedand reoriented superior cerebellar peduncles, and an abnormallylarge interpeduncular fossa, giving the appearance of a molartooth on transaxial slices (molar tooth sign). Additional variablefeatures include retinal dystrophy and renal disease.

Defects in INPP5E are the cause of mental retardation-truncal obesity-retinal dystrophy-micropenis (MORMS) [MIM:610156].An autosomal recessive disorder characterized by moderate mentalretardation, truncal obesity, congenital non-progressive retinaldystrophy, and micropenis in males. The phenotype is similar toBardet-Biedl syndrome and Cohen syndrome Distinguishing featuresare the age of onset, the non-progressive nature of the visualimpairment, lack of dysmorphic facies, skin or gingival infection,microcephaly, mottled retina, polydactyly, and testicularanomalies.

Defects in INSL3 seems to be a cause of cryptorchidism(CRYPTO) [MIM:219050], also known as impaired testicular descent.It is one of the most frequent congenital abnormalities in humans,involving 2-5% of male births. Cryptorchidism is associated withincreased risk of infertility and testicular cancer. The frequencyof INSL3 gene mutations as a cause of cryptorchidism is low.

Defects in INSR are the cause of insulin resistance (Insresistance) [MIM:125853].

Defects in INSR are the cause of Rabson-Mendenhallsyndrome (RMS) [MIM:262190], also known as Mendenhall syndrome.RMS is a severe insulin resistance syndrome characterized byinsulin-resistant diabetes mellitus with pineal hyperplasia andsomatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominaldistension, and phallic enlargement. Inheritance is autosomalrecessive.

Defects in INSR are the cause of leprechaunism (LEPRCH)[MIM:246200], also known as Donohue syndrome. Leprechaunismrepresents the most severe form of insulin resistance syndrome,characterized by intrauterine and postnatal growth retardation anddeath in early infancy. Inheritance is autosomal recessive.

Defects in INSR may be associated with noninsulin-dependent diabetes mellitus (NIDDM) [MIM:125853], also known asdiabetes mellitus type 2.

Defects in INSR are the cause of familialhyperinsulinemic hypoglycemia type 5 (HHF5) [MIM:609968]. Familialhyperinsulinemic hypoglycemia [MIM:256450], also referred to ascongenital hyperinsulinism, nesidioblastosis, or persistenthyperinsulinemic hypoglycemia of infancy (PPHI), is the mostcommon cause of persistent hypoglycemia in infancy and is due todefective negative feedback regulation of insulin secretion by lowglucose levels.

Defects in INSR are the cause of insulin-resistantdiabetes mellitus with acanthosis nigricans type A (IRAN type A)[MIM:610549]. This syndrome is characterized by the association ofsevere insulin resistance (manifested by marked hyperinsulinemiaand a failure to respond to exogenous insulin) with the skinlesion acanthosis nigricans and ovarian hyperandrogenism inadolescent female subjects. Women frequently present withhirsutism, acne, amenorrhea or oligomenorrhea, and virilization.This syndrome is different from the type B that has beendemonstrated to be secondary to the presence of circulatingautoantibodies against the insulin receptor.

Defects in INS are the cause of familialhyperproinsulinemia (FHPRI) [MIM:176730].

Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:125852]. IDDM2 is a multifactorialdisorder of glucose homeostasis that is characterized bysusceptibility to ketoacidosis in the absence of insulin therapy.Clinical fetaures are polydipsia, polyphagia and polyuria whichresult from hyperglycemia-induced osmotic diuresis and secondarythirst. These derangements result in long-term complications thataffect the eyes, kidneys, nerves, and blood vessels.

Defects in INS are a cause of diabetes mellitus permanentneonatal (PNDM) [MIM:606176]. PNDM is a rare form of diabetesdistinct from childhood-onset autoimmune diabetes mellitus type 1.It is characterized by insulin-requiring hyperglycemia that isdiagnosed within the first months of life. Permanent neonataldiabetes requires lifelong therapy.

Defects in INS are a cause of maturity-onset diabetes ofthe young type 10 (MODY10) [MIM:613370]. MODY10 is a form ofdiabetes that is characterized by an autosomal dominant mode ofinheritance, onset in childhood or early adulthood (usually before25 years of age), a primary defect in insulin secretion andfrequent insulin-independence at the beginning of the disease.

Defects in INVS are the cause of nephronophthisis type 2(NPHP2) [MIM:602088], also known as infantile nephronophthisis.NPHP2 is an autosomal recessive disorder resulting in end-stagerenal disease. It is characterized by early onset and rapidprogression. Phenotypic manifestations include enlarged kidneys,chronic tubulo-interstitial nephritis, anemia, hyperkalemicmetabolic acidosis. Some patients also display situs inversus.Pathologically, it differs from later-onset nephronophthisis bythe absence of medullary cysts and thickened tubular basementmembranes and by the presence of cortical microcysts.

Defects in ITPKC are a cause of Kawasaki disease (KWD)[MIM:611775], also known as mucocutaneous lymph node syndrome orinfantile polyarteritis. Kawasaki disease is an acute, self-limited vasculitis of infants and children characterized byprolonged fever unresponsive to antibiotics, polymorphous skinrash, erythema of the oral mucosa, lips, and tongue, erythema ofthe palms and soles, bilateral conjunctival injection, andcervical lymphadenopathy. Coronary artery aneurysms develop in 15to 25% of those left untreated, making Kawasaki disease theleading cause of acquired heart disease among children indeveloped countries.

Defects in IQCB1 are the cause of Senior-Loken syndrometype 5 (SLSN5) [MIM:609254]. SLSN is a renal-retinal disorder,characterized by progressive wasting of the filtering unit of thekidney (nephronophthisis), with or without medullary cystic renaldisease, and progressive eye disease. Typically this disorderbecomes apparent during the first year of life.

Defects in IQSEC2 are the cause of mental retardation X-linked type 1 (MRX1) [MIM:309530]. Mental retardation ischaracterized by significantly below average general intellectualfunctioning associated with impairments in adaptative behavior andmanifested during the developmental period. In contrast tosyndromic or specific X-linked mental retardation which alsopresent with associated physical, neurological and/or psychiatricmanifestations, intellectual deficiency is the only primarysymptom of non-syndromic X-linked mental retardation.

Defects in IRAK3 are associated with susceptibility toasthma-related traits type 5 (ASRT5) [MIM:611064]. Asthma-relatedtraits include clinical symptoms of asthma, such as coughing,wheezing, dyspnea, bronchial hyperresponsiveness as assessed bymethacholine challenge test, serum IgE levels, atopy, and atopicdermatitis.

Defects in IRAK4 are the cause of recurrent isolatedinvasive pneumococcal disease type 1 (IPD1) [MIM:610799].Recurrent invasive pneumococcal disease (IPD) is defined as twoepisodes of IPD occurring at least 1 month apart, whether causedby the same or different serotypes or strains. Recurrent IPDoccurs in at least 2% of patients in most series, making IPD themost important known risk factor for subsequent IPD.

Defects in IRAK4 are the cause of IRAK4 deficiency(IRAK4D) [MIM:607676]. IRAK4 deficiency causes extracellularpyogenic bacterial and fungal infections in otherwise healthychildren.

Defects in IRF1 are a cause of gastric cancer (GASC)[MIM:613659], also called gastric cancer intestinal or stomachcancer. Gastric cancer is a malignant disease which starts in thestomach, can spread to the esophagus or the small intestine, andcan extend through the stomach wall to nearby lymph nodes andorgans. It also can metastasize to other parts of the body. Theterm gastric cancer or gastric carcinoma refers to adenocarcinomaof the stomach that accounts for most of all gastric malignanttumors. Two main histologic types are recognized, diffuse type andintestinal type carcinomas. Diffuse tumors are poorlydifferentiated infiltrating lesions, resulting in thickening ofthe stomach. In contrast, intestinal tumors are usually exophytic,often ulcerating, and associated with intestinal metaplasia of thestomach, most often observed in sporadic disease.

Defects in IRF4 are a cause of multiple myeloma (MM)[MIM:254500]. MM is a malignant tumor of plasma cells usuallyarising in the bone marrow and characterized by diffuseinvolvement of the skeletal system, hyperglobulinemia, Bence-Jonesproteinuria and anemia. Complications of multiple myeloma are bonepain, hypercalcemia, renal failure and spinal cord compression.The aberrant antibodies that are produced lead to impaired humoralimmunity and patients have a high prevalence of infection.Amyloidosis may develop in some patients. Multiple myeloma is partof a spectrum of diseases ranging from monoclonal gammopathy ofunknown significance (MGUS) to plasma cell leukemia. Note=Achromosomal aberration involving IRF4 is found in multiplemyeloma. Translocation t(6,14)(p25,q32) with the IgH locus.

Genetic variations in IRF5 are associated withsusceptibility to inflammatory bowel disease type 14 (IBD14)[MIM:612245]. IBD14 is a chronic, relapsing inflammation of thegastrointestinal tract with a complex etiology. It is subdividedinto Crohn disease and ulcerative colitis phenotypes. Crohndisease may affect any part of the gastrointestinal tract from themouth to the anus, but most frequently it involves the terminalileum and colon. Bowel inflammation is transmural anddiscontinuous, it may contain granulomas or be associated withintestinal or perianal fistulas. In contrast, in ulcerativecolitis, the inflammation is continuous and limited to rectal andcolonic mucosal layers, fistulas and granulomas are not observed.Both diseases include extraintestinal inflammation of the skin,eyes, or joints.

Genetic variations in IRF5 are associated withsusceptibility to systemic lupus erythematosus type 10 (SLEB10)[MIM:612251]. Systemic lupus erythematosus (SLE) is a chronic,inflammatory and often febrile multisystemic disorder ofconnective tissue. It affects principally the skin, joints,kidneys and serosal membranes. It is thought to represent afailure of the regulatory mechanisms of the autoimmune system.

Genetic variations in IRF5 are a cause of susceptibilityto rheumatoid arthritis (RA) [MIM:180300]. It is a systemicinflammatory disease with autoimmune features and a complexgenetic component. It primarily affects the joints and ischaracterized by inflammatory changes in the synovial membranesand articular structures, widespread fibrinoid degeneration of thecollagen fibers in mesenchymal tissues, and by atrophy andrarefaction of bony structures.

Defects in IRF6 are a cause of van der Woude syndrome(VWS) [MIM:119300], also known as lip-pit syndrome (LPS). It is anautosomal dominant developmental disorder characterized by lowerlip pits, cleft lip and/or cleft palate. Penetrance is incomplete.Van der Woude and popliteal pterygium syndrome are allelicdisorders.

Defects in IRF6 are the cause of popliteal pterygiumsyndrome (PPS) [MIM:119500]. PPS is an autosomal dominantdevelopmental disorder characterized by cleft lip and/or cleftpalate, and skin and genital anomalies. Penetrance is incompleteand expressivity is variable. It shows orofacial phenotypicsimilarities with van der Woude syndrome. Van der Woude andpopliteal pterygium syndrome are allelic disorders.

Genetic variation in IRF6 is associated with non-syndromic orofacial cleft type 6 (OFC6) [MIM:608864], also callednon-syndromic cleft lip with or without cleft palate 6. Non-syndromic orofacial cleft is a common birth defect consisting ofcleft lips with or without cleft palate. Cleft lips are associatedwith cleft palate in two-third of cases. A cleft lip can occur onone or both sides and range in severity from a simple notch in theupper lip to a complete opening in the lip extending into thefloor of the nostril and involving the upper gum.

Defects in KCNJ10 are the cause of seizures-sensorineuraldeafness-ataxia-mental retardation-electrolyte imbalance (SESAME)[MIM:612780]. A complex disorder characterized by generalizedseizures with onset in infancy, delayed psychomotor development,ataxia, sensorineural hearing loss, hypokalemia, metabolicalkalosis, and hypomagnesemia.

Defects in KCNJ11 are the cause of familialhyperinsulinemic hypoglycemia type 2 (HHF2) [MIM:601820], alsoknown as persistent hyperinsulinemic hypoglycemia of infancy(PPHI) or congenital hyperinsulinism. HHF is the most common causeof persistent hypoglycemia in infancy and is due to defectivenegative feedback regulation of insulin secretion by low glucoselevels. It causes nesidioblastosis, a diffuse abnormality of thepancreas in which there is extensive, often disorganized formationof new islets. Unless early and aggressive intervention isundertaken, brain damage from recurrent episodes of hypoglycemiamay occur.

Defects in KCNJ11 are a cause of diabetes mellituspermanent neonatal (PNDM) [MIM:606176]. PNDM is a rare form ofdiabetes distinct from childhood-onset autoimmune diabetesmellitus type 1. It is characterized by insulin-requiringhyperglycemia that is diagnosed within the first months of life.Permanent neonatal diabetes requires lifelong therapy.

Defects in KCNJ11 are the cause of transient neonataldiabetes mellitus type 3 (TNDM3) [MIM:610582]. Neonatal diabetesmellitus, defined as insulin-requiring hyperglycemia within thefirst month of life, is a rare entity. In about half of theneonates, diabetes is transient and resolves at a median age of 3months, whereas the rest have a permanent form of diabetes. In asignificant number of patients with transient neonatal diabetesmellitus, diabetes type 2 appears later in life. The onset andseverity of TNDM3 is variable with childhood-onset diabetes,gestational diabetes or adult-onset diabetes described.

Defects in KCNJ11 may contribute to non-insulin-dependentdiabetes mellitus (NIDDM), also known as diabetes mellitus type 2.

Defects in KCNJ13 are the cause of snowflakevitreoretinal degeneration (SVD) [MIM:193230]. SVD is adevelopmental and progressive hereditary eye disorder that affectsmultiple tissues within the eye. Diagnostic features of SVDinclude fibrillar degeneration of the vitreous humor, early-onsetcataract, minute crystalline deposits in the neurosensory retina,and retinal detachment.

Defects in KCNJ18 are a cause of susceptibility tothyrotoxic hypokalemic periodic paralysis (TTPP2) [MIM:613239]. Asporadic muscular disorder characterized by episodic weakness andhypokalemia during a thyrotoxic state. It is clinically similar tohereditary hypokalemic periodic paralysis, except for the factthat hyperthyroidism is an absolute requirement for diseasemanifestation. The disease presents with recurrent episodes ofacute muscular weakness of the four extremities that vary inseverity from paresis to complete paralysis. Attacks are triggeredby ingestion of a high carbohydrate load or strenuous physicalactivity followed by a period of rest. Thyrotoxic periodicparalysis can occur in association with any cause ofhyperthyroidism, but is most commonly associated with Gravesdisease.

Defects in KCNJ1 are the cause of Bartter syndrome type 2(BS2) [MIM:241200], also termed hyperprostanglandin E syndrome 2.BS refers to a group of autosomal recessive disorderscharacterized by impaired salt reabsorption in the thick ascendingloop of Henle with pronounced salt wasting, hypokalemic metabolicalkalosis, and varying degrees of hypercalciuria. BS2 is a life-threatening condition beginning in utero, with marked fetalpolyuria that leads to polyhydramnios and premature delivery.Another hallmark of BS2 is a marked hypercalciuria and, as asecondary consequence, the development of nephrocalcinosis andosteopenia.

Defects in KCNJ2 are the cause of long QT syndrome type 7(LQT7) [MIM:170390], also called Andersen syndrome or Andersencardiodysrhythmic periodic paralysis. Long QT syndromes are heartdisorders characterized by a prolonged QT interval on the ECG andpolymorphic ventricular arrhythmias. They cause syncope and suddendeath in response to excercise or emotional stress. LQT7 manifestsitself as a clinical triad consisting of potassium-sensitiveperiodic paralysis, ventricular ectopy and dysmorphic features.

Defects in KCNJ2 are the cause of short QT syndrome type3 (SQT3) [MIM:609622]. Short QT syndromes are heart disorderscharacterized by idiopathic persistently and uniformly short QTinterval on ECG in the absence of structural heart disease inaffected individuals. They cause syncope and sudden death. SQT3has a unique ECG phenotype characterized by asymmetrical T waves.

Defects in KCNJ5 are the cause of long QT syndrome type13 (LQT13) [MIM:613485]. It is a heart disorder characterized by aprolonged QT interval on the ECG and polymorphic ventriculararrhythmias. They cause syncope and sudden death in response toexcercise or emotional stress, and can present with a sentinelevent of sudden cardiac death in infancy.

Note=Defects in KCNJ8 may be associated withsusceptibility to J-wave syndromes, a group of heart disorderscharacterized by early repolarization events as indicated byabnormal J-wave manifestation on electrocardiogram (ECG). The Jpoint denotes the junction of the QRS complex and the ST segmenton the ECG, marking the end of depolarization and the beginning ofrepolarization. An abnormal J wave is a deflection with a dome orhump morphology immediately following the QRS complex of thesurface ECG. Examples of J-wave disorders are arrhythmiasassociated with an early repolarization pattern in the inferior ormid to lateral precordial leads, Brugada syndrome, some cases ofidiopathic ventricular fibrillation (VF) with an earlyrepolarization pattern in the inferior, inferolateral or globalleads, as well as arrhythmias associated with hypothermia.

Defects in IL1RAPL1 are the cause of mental retardationX-linked type 21 (MRX21) [MIM:300143]. Mental retardation is amental disorder characterized by significantly sub-average generalintellectual functioning associated with impairments in adaptativebehavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest otherclinical signs.

Polymorphisms in IRS1 may be involved in the etiology ofnon-insulin-dependent diabetes mellitus (NIDDM) [MIM:125853].

Defects in ISCU are the cause of myopathy with exerciseintolerance Swedish type (MEIS) [MIM:255125], also known asmyopathy with deficiency of succinate dehydrogenase and aconitaseor myoglobinuria due to abnormal glycolysis or hereditary myopathywith lactic acidosis (HML). This autosomal recessive metabolicdisease is characterized by lifelong severe exercise intolerance,in which minor exertion causes fatigue of active muscles,shortness of breath, and cardiac palpitations in association withlactic acidosis. The biochemical phenotype is characterized by adeficiency in mitochondrial iron-sulfur proteins and impairedmuscle oxidative metabolism.

Defects in SPINK1 are a cause of hereditary pancreatitis(HPC) [MIM:167800], also known as chronic pancreatitis (CP). HPCis an autosomal dominant disease characterized by the presence ofcalculi in pancreatic ducts. It causes severe abdominal painattacks.

Defects in SPINK1 are the cause of susceptibility totropical calcific pancreatitis (TCP) [MIM:608189]. TCP is anidiopathic, juvenile, nonalcoholic form of chronic pancreatitiswidely prevalent in several tropical countries. It can beassociated with fibrocalculous pancreatic diabetes (FCPD)depending on both environmental and genetic factors. TCP differsfrom alcoholic pancreatitis by a much younger age of onset,pancreatic calcification, a high incidence of insulin dependentbut ketosis resistant diabetes mellitus, and an exceptionally highincidence of pancreatic cancer.

Defects in SPINK5 are the cause of Netherton syndrome(NETH) [MIM:256500]. NETH is an autosomal recessive congenitalichthyosis associated with hair shaft abnormalities and anomaliesof the immune system. Typical features are ichthyosis lineariscircumflexa, ichthyosiform erythroderma, trichorrhexis invaginata(bamboo hair), atopic dermatitis, and hayfever. High postnatalmortality is due to failure to thrive, infections andhypernatremic dehydration.

Defects in ITGA2B are a cause of Glanzmann thrombasthenia(GT) [MIM:273800], also known as thrombasthenia of Glanzmann andNaegeli. GT is the most common inherited disease of platelets. Itis an autosomal recessive disorder characterized by mucocutaneousbleeding of mild-to-moderate severity and the inability of thisintegrin to recognize macromolecular or synthetic peptide ligands.GT has been classified clinically into types I and II. In type I,platelets show absence of the glycoprotein IIb/beta-3 complexes attheir surface and lack fibrinogen and clot retraction capability.In type II, the platelets express the glycoprotein IIb/beta-3complex at reduced levels (5-20% controls), have detectableamounts of fibrinogen, and have low or moderate clot retractioncapability. The platelets of GT 'variants' have normal or nearnormal (60-100%) expression of dysfunctional receptors.

Defects in ITGA6 are a cause of epidermolysis bullosaletalis with pyloric atresia (EB-PA) [MIM:226730], also known asjunctional epidermolysis bullosa with pyloric atresia (PA-JEB) oraplasia cutis congenita with gastrointestinal atresia. EB-PA is anautosomal recessive, frequently lethal, epidermolysis bullosa withvariable involvement of skin, nails, mucosa, and with variableeffects on the digestive system. It is characterized bymucocutaneous fragility, aplasia cutis congenita, andgastrointestinal atresia, which most commonly affects the pylorus.Pyloric atresia is a primary manifestation rather than a scarringprocess secondary to epidermolysis bullosa.

Defects in ITGA7 are the cause of muscular dystrophycongenital ITGA7-related (CMD-ITGA7) [MIM:613204]. It is a form ofcongenital muscular dystrophy. Patients present at birth, orwithin the first few months of life, with hypotonia, muscleweakness and often with joint contractures.

Genetic variations in ITGAM has been associated withsusceptibility to systemic lupus erythematosus type 6 (SLEB6)[MIM:609939]. Systemic lupus erythematosus (SLE) is a chronic,inflammatory and often febrile multisystemic disorder ofconnective tissue. It affects principally the skin, joints,kidneys and serosal membranes. It is thought to represent afailure of the regulatory mechanisms of the autoimmune system.

Defects in ITGB2 are the cause of leukocyte adhesiondeficiency type 1 (LAD1) [MIM:116920]. LAD1 patients haverecurrent bacterial infections and their leukocytes are deficientin a wide range of adhesion-dependent functions.

Defects in ITGB3 are a cause of Glanzmann thrombasthenia(GT) [MIM:273800], also known as thrombasthenia of Glanzmann andNaegeli. GT is the most common inherited disease of platelets. Itis an autosomal recessive disorder characterized by mucocutaneousbleeding of mild-to-moderate severity and the inability of thisintegrin to recognize macromolecular or synthetic peptide ligands.GT has been classified clinically into types I and II. In type I,platelets show absence of the glycoprotein IIb/beta-3 complexes attheir surface and lack fibrinogen and clot retraction capability.In type II, the platelets express the glycoprotein IIb/beta-3complex at reduced levels (5-20% controls), have detectableamounts of fibrinogen, and have low or moderate clot retractioncapability. The platelets of GT 'variants' have normal or nearnormal (60-100%) expression of dysfunctional receptors.

Defects in ITGB4 are a cause of epidermolysis bullosaletalis with pyloric atresia (EB-PA) [MIM:226730], also known asjunctional epidermolysis bullosa with pyloric atresia (PA-JEB) oraplasia cutis congenita with gastrointestinal atresia. EB-PA is anautosomal recessive, frequently lethal, epidermolysis bullosa withvariable involvement of skin, nails, mucosa, and with variableeffects on the digestive system. It is characterized bymucocutaneous fragility, aplasia cutis congenita, andgastrointestinal atresia, which most commonly affects the pylorus.Pyloric atresia is a primary manifestation rather than a scarringprocess secondary to epidermolysis bullosa.

Defects in ITGB4 are a cause of generalized atrophicbenign epidermolysis bullosa (GABEB) [MIM:226650]. GABEB is a non-lethal, adult form of junctional epidermolysis bullosacharacterized by life-long blistering of the skin, associated withhair and tooth abnormalities.

Defects in ITCH are the cause of syndromic multisystemautoimmune disease (SMAD) [MIM:613385]. SMAD is characterized byorganomegaly, failure to thrive, developmental delay, dysmorphicfeatures and autoimmune inflammatory cell infiltration of thelungs, liver and gut.

Defects in TCF4 are a cause of Pitt-Hopkins syndrome(PTHS) [MIM:610954]. PTHS is a rare syndromic encephalopathycharacterized by severe psychomotor delay, epilepsy, daily boutsof diurnal hyperventilation starting in infancy, mild postnatalgrowth retardation, postnatal microcephaly, and distinctive facialfeatures. Since most hitherto reported cases have been sporadic,with males and females equally affected, PTHS is regarded as anautosomal dominant condition.

Defects in ITK are the cause of lymphoproliferativesyndrome EBV-associated autosomal type 1 (LPSA1) [MIM:613011].LPSA1 is a rare immunodeficiency characterized by extremesusceptibility to infection with Epstein-Barr virus (EBV).Inadequate immune response to EBV can have a fatal outcome.Clinical features include splenomegaly, lymphadenopathy, anemia,thrombocytopenia, pancytopenia, recurrent infections. There is anincreased risk for lymphoma.

Defects in ITM2B are a cause of cerebral amyloidangiopathy ITM2B-related type 1 (CAA-ITM2B1) [MIM:176500]. Adisorder characterized by amyloid deposition in the walls ofcerebral blood vessels and neurodegeneration in the centralnervous system. Cerebral amyloid angiopathy, non-neuritic andperivascular plaques and neurofibrillary tangles are thepredominant pathological lesions. Clinical features includeprogressive mental deterioration, spasticity and muscularrigidity.

Defects in ITM2B are a cause of cerebral amyloidangiopathy ITM2B-related type 2 (CAA-ITM2B2) [MIM:117300], alsoknown as heredopathia ophthalmo-oto-encephalica. A disordercharacterized by amyloid deposition in the walls of the bloodvessels of the cerebrum, choroid plexus, cerebellum, spinal cordand retina. Plaques and neurofibrillary tangles are observed inthe hippocampus. Clinical features include progressive ataxia,dementia, cataracts and deafness.

Defects in ITPA are the cause of inosine triphosphatepyrophosphohydrolase deficiency (ITPA deficiency) [MIM:147520]. Itis a common inherited trait characterized by the abnormalaccumulation of inosine triphosphate (ITP) in erythrocytes andalso leukocytes and fibroblasts. The pathological consequences ofITPA deficiency, if any, are unknown. However, it might havepharmacogenomic implications and be related to increased drugtoxicity of purine analog drugs. Three different human populationshave been reported with respect to their ITPase activity: high,mean (25% of high) and low activity. The variant Thr-32 isassociated with complete loss of enzyme activity, may be byaltering the local secondary structure of the protein.Heterozygotes for this polymorphism have 22.5% of the controlactivity: this is consistent with a dimeric structure of theenzyme.

Defects in ITPR1 are the cause of spinocerebellar ataxiatype 15 (SCA15) (SCA15) [MIM:606658]. Spinocerebellar ataxia is aclinically and genetically heterogeneous group of cerebellardisorders. Patients show progressive incoordination of gait andoften poor coordination of hands, speech and eye movements, due todegeneration of the cerebellum with variable involvement of thebrainstem and spinal cord. SCA15 is an autosomal dominantcerebellar ataxia (ADCA). It is very slow progressing form with awide range of onset, ranging from childhood to adult. Mostpatients remain ambulatory.

Defects in IVD are the cause of isovaleric acidemia (IVA)[MIM:243500]. IVA is characterized by retarded psychomotordevelopment, a peculiar odor resembling sweaty feet, an aversionto dietary protein, and pernicious vomiting, leading to acidosisand coma. The acute neonatal form leads to massive metabolicacidosis from the first days of life and rapid death.

Defects in IYD are the cause of congenital hypothyroidismdue to dyshormonogenesis type 4 (CHDH4) [MIM:274800], also knownas genetic defect in thyroid hormonogenesis type 4 or iodotyrosinedehalogenase deficiency or deiodinase deficiency. Patients withthis defect present a phenotype of severe hypothyroidism, goiter,excessive levels of iodotyrosine in serum and urine, and variablemental deficits derived from unrecognized hypothyroidism.

Defects in JAG1 are the cause of Alagille syndrome type 1(ALGS1) [MIM:118450]. Alagille syndrome is an autosomal dominantmultisystem disorder defined clinically by hepatic bile ductpaucity and cholestasis in association with cardiac, skeletal, andophthalmologic manifestations. There are characteristic facialfeatures and less frequent clinical involvement of the renal andvascular systems.

Defects in JAG1 are a cause of tetralogy of Fallot (TOF)[MIM:187500]. TOF is a congenital heart anomaly which consists ofpulmonary stenosis, ventricular septal defect, dextroposition ofthe aorta (aorta is on the right side instead of the left) andhypertrophy of the right ventricle. This condition results in ablue baby at birth due to inadequate oxygenation. Surgicalcorrection is emergent.

Note=Chromosomal aberrations involving JAK2 are found inboth chronic and acute forms of eosinophilic, lymphoblastic andmyeloid leukemia. Translocation t(8,9)(p22,p24) with PCM1 linksthe protein kinase domain of JAK2 to the major portion of PCM1.Translocation t(9,12)(p24,p13) with ETV6.

Defects in JAK2 are a cause of susceptibility to Budd-Chiari syndrome (BCS) [MIM:600880]. It is a syndrome caused byobstruction of hepatic venous outflow involving either the hepaticveins or the terminal segment of the inferior vena cava.Obstructions are generally caused by thrombosis and lead tohepatic congestion and ischemic necrosis. Clinical manifestationsobserved in the majority of patients include hepatomegaly, rightupper quadrant pain and abdominal ascites. Budd-Chiari syndrome isassociated with a combination of disease states including primarymyeloproliferative syndromes and thrombophilia due to factor VLeiden, protein C deficiency and antithrombin III deficiency.Budd-Chiari syndrome is a rare but typical complication inpatients with polycythemia vera.

Defects in JAK2 are a cause of polycythemia vera (PV)[MIM:263300]. A myeloproliferative disorder characterized byabnormal proliferation of all hematopoietic bone marrow elements,erythroid hyperplasia, an absolute increase in total blood volume,but also by myeloid leukocytosis, thrombocytosis and splenomegaly.

Defects in JAK2 gene may be a cause of essentialthrombocythemia (ET) [MIM:187950]. ET is characterized by elevatedplatelet levels due to sustained proliferation of megakaryocytes,and frequently lead to thrombotic and haemorrhagic complications.

Defects in JAK2 are a cause of myelofibrosis (MYELOF)[MIM:254450]. Myelofibrosis is a disorder characterized byreplacement of the bone marrow by fibrous tissue, occurring inassociation with a myeloproliferative disorder. Clinicalmanifestations may include anemia, pallor, splenomegaly,hypermetabolic state, petechiae, ecchymosis, bleeding,lymphadenopathy, hepatomegaly, portal hypertension.

Defects in JAK2 are a cause of acute myelogenous leukemia(AML) [MIM:601626]. AML is a malignant disease in whichhematopoietic precursors are arrested in an early stage ofdevelopment.

Defects in JAK3 are a cause of severe combinedimmunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-negative (T(-)B(+)NK(-) SCID) [MIM:600802]. Aform of severe combined immunodeficiency (SCID), a genetically andclinically heterogeneous group of rare congenital disorderscharacterized by impairment of both humoral and cell-mediatedimmunity, leukopenia, and low or absent antibody levels. Patientspresent in infancy recurrent, persistent infections byopportunistic organisms. The common characteristic of all types ofSCID is absence of T-cell-mediated cellular immunity due to adefect in T-cell development.

Defects in JAM3 are the cause of hemorrhagic destructionof the brain with subependymal calcification and cataracts(HDBSCC) [MIM:613730]. A syndrome characterized by congenitalcataracts and severe brain abnormalities apparently resulting fromhemorrhagic destruction of the brain tissue, including thecerebral white matter and basal ganglia. Patients manifestprofound developmental delay, and other neurologic featuresincluded seizures, spasticity, and hyperreflexia. Brain imagingshows multifocal intraparenchymal hemorrhage with associatedliquefaction and massive cystic degeneration, and calcification inthe subependymal region and in brain tissue.

Note=A chromosomal aberration involving JAZF1 may be acause of endometrial stromal tumors. Translocationt(7,17)(p15,q21) with SUZ12. The translocation generates theJAZF1-SUZ12 oncogene consisting of the N-terminus part of JAZF1and the C-terminus part of SUZ12. It is frequently found in allcases of endometrial stromal tumors, except in endometrial stromalsarcomas, where it is rarer.

Defects in MAPK8IP1 are a cause of non-insulin-dependentdiabetes mellitus (NIDDM) [MIM:125853]. NIDDM is characterized byan autosomal dominant mode of inheritance, onset during adulthoodand insulin resistance.

Defects in JPH3 are the cause of Huntington disease-liketype 2 (HDL2) [MIM:606438]. Huntington disease (HD) is aneurodegenerative disorder resulting primarily from the loss ofmedium spiny projection neurons in the striatum, especially in thecaudate nucleus, and, to a lesser extent, atrophy of mesencephalicand cortical structures. The typical clinical picture of HDcombines familial adult onset chorea and subcortical dementia thatusually begin during the fourth decade of life.

Defects in KIAA0319 may be a cause of susceptibility todyslexia type 2 (DYX2) [MIM:600202], also known as specificreading disability type 2. Dyslexia is a relatively common,complex cognitive disorder that affects 5% to 10% of school-agedchildren. The disorder is characterized by an impairment ofreading performance despite adequate motivational, educational andintellectual opportunities and in the absence of sensory orneurological disability. Note=A lower expression is associatedwith the risk haplotype.

Defects in KIAA0415 are the cause of spastic paraplegiaautosomal recessive type 48 (SPG48) [MIM:613647]. A form ofspastic paraplegia, a neurodegenerative disorder characterized bya slow, gradual, progressive weakness and spasticity of the lowerlimbs. Rate of progression and the severity of symptoms are quitevariable. Initial symptoms may include difficulty with balance,weakness and stiffness in the legs, muscle spasms, and draggingthe toes when walking. In some forms of the disorder, bladdersymptoms (such as incontinence) may appear, or the weakness andstiffness may spread to other parts of the body.

Note=A chromosomal aberration involving KIAA1549 is foundin pilocytic astrocytoma. A tandem duplication of 2 Mb at 7q34leads to the expression of a KIAA1549-BRAF fusion protein with aconstitutive kinase activity and inducing cell transformation.

Defects in KRT10 are a cause of bullous congenitalichthyosiform erythroderma (BCIE) [MIM:113800], also known asepidermolytic hyperkeratosis (EHK) or bullous erythrodermaichthyosiformis congenita of Brocq. BCIE is an autosomal dominantskin disorder characterized by widespread blistering and anichthyotic erythroderma at birth that persist into adulthood.Histologically there is a diffuse epidermolytic degeneration inthe lower spinous layer of the epidermis. Within a few weeks frombirth, erythroderma and blister formation diminish andhyperkeratoses develop.

Defects in KRT10 are a cause of ichthyosis annularepidermolytic (AEI) [MIM:607602], also known as cyclic ichthyosiswith epidermolytic hyperkeratosis. AEI is a skin disorderresembling bullous congenital ichthyosiform erythroderma. Affectedindividuals present with bullous ichthyosis in early childhood andhyperkeratotic lichenified plaques in the flexural areas andextensor surfaces at later ages. The feature that distinguishesAEI from BCIE is dramatic episodes of flares of annular polycyclicplaques with scale, which coalesce to involve most of the bodysurface and can persist for several weeks or even months.

Defects in KRT10 are the cause of reticular congenitalichthyosiform erythroderma (CRIE) [MIM:609165], also calledichthyosis with confetti (IWC) or reticular erythrokeratoderma.CRIE is a rare skin condition characterized by slowly enlargingislands of normal skin surrounded by erythematous ichthyoticpatches in a reticulated pattern. The condition starts in infancyas a lamellar ichthyosis, with small islands of normal skinresembling confetti appearing in late childhood and at puberty.Histopathologic findings include band-like parakeratosis,psoriasiform acanthosis, and vacuolization of keratinocytes withbinucleated cells in the upper epidermis, sometimes associatedwith amyloid deposition in the dermis. Ultrastructuralabnormalities include perinuclear shells formed from a network offine filaments in the upper epidermis.

Defects in KRT12 are a cause of Meesmann cornealdystrophy (MECD) [MIM:122100], also abbreviated MCD and known asjuvenile epithelial corneal dystrophy of Meesmann. MECD is anautosomal dominant disease that causes fragility of the anteriorcorneal epithelium. Patients are usually asymptomatic untiladulthood when rupture of the corneal microcysts may causeerosions, producing clinical symptoms such as photophobia, contactlens intolerance and intermittent diminution of visual acuity.Rarely, subepithelial scarring causes irregular cornealastigmatism and permanent visual impairment. Histologicalexamination shows a disorganized and thickened epithelium withwidespread cytoplasmic vacuolation and numerous small, round,debris-laden intraepithelial cysts.

Defects in KRT13 are a cause of white sponge nevus ofcannon (WSN) [MIM:193900]. WSN is a rare autosomal dominantdisorder which predominantly affects non-cornified stratifiedsquamous epithelia. Clinically, it is characterized by thepresence of soft, white, and spongy plaques in the oral mucosa.The characteristic histopathologic features are epithelialthickening, parakeratosis, and vacuolization of the suprabasallayer of oral epithelial keratinocytes. Less frequently the mucousmembranes of the nose, esophagus, genitalia and rectum areinvolved.

Defects in KRT14 are a cause of epidermolysis bullosasimplex Dowling-Meara type (DM-EBS) [MIM:131760]. DM-EBS is asevere form of intraepidermal epidermolysis bullosa characterizedby generalized herpetiform blistering, milia formation, dystrophicnails, and mucous membrane involvement.

Defects in KRT14 are a cause of epidermolysis bullosasimplex Weber-Cockayne type (WC-EBS) [MIM:131800]. WC-EBS is aform of intraepidermal epidermolysis bullosa characterized byblistering limited to palmar and plantar areas of the skin.

Defects in KRT14 are a cause of epidermolysis bullosasimplex Koebner type (K-EBS) [MIM:131900]. K-EBS is a form ofintraepidermal epidermolysis bullosa characterized by generalizedskin blistering. The phenotype is not fundamentally distinct fromthe Dowling-Meara type, although it is less severe.

Defects in KRT14 are the cause of epidermolysis bullosasimplex autosomal recessive (AREBS) [MIM:601001]. AREBS is anintraepidermal epidermolysis bullosa characterized by localizedblistering on the dorsal, lateral and plantar surfaces of thefeet.

Defects in KRT14 are the cause of Naegeli-Franceschetti-Jadassohn syndrome (NFJS) [MIM:161000], also known as Naegelisyndrome. NFJS is a rare autosomal dominant form of ectodermaldysplasia. The cardinal features are absence of dermatoglyphics(fingerprints), reticular cutaneous hyperpigmentation (starting atabout the age of 2 years without a preceding inflammatory stage),palmoplantar keratoderma, hypohidrosis with diminished sweat glandfunction and discomfort provoked by heat, nail dystrophy, andtooth enamel defects.

Defects in KRT14 are the cause of dermatopathiapigmentosa reticularis (DPR) [MIM:125595]. DPR is a rareectodermal dysplasia characterized by lifelong persistentreticulate hyperpigmentation, noncicatricial alopecia, and naildystrophy.

Defects in KRT16 are a cause of pachyonychia congenitatype 1 (PC1) [MIM:167200], also known as Jadassohn-Lewandowskysyndrome. PC1 is an autosomal dominant ectodermal dysplasiacharacterized by hypertrophic nail dystrophy resulting inonchyogryposis (thickening and increase in curvature of the nail),palmoplantar keratoderma, follicular hyperkeratosis, and oralleukokeratosis. Hyperhidrosis of the hands and feet is usuallypresent.

Defects in KRT16 are the cause of palmoplantarkeratoderma non-epidermolytic focal (FNEPPK) [MIM:613000]. Adermatological disorder characterized by non-epidermolyticpalmoplantar keratoderma limited to the pressure points on theballs of the feet, with later mild involvement on the palms. Oral,genital and follicular keratotic lesions are often present.

Defects in KRT16 are a cause of unilateral palmoplantarverrucous nevus (UPVN) [MIM:144200]. UPVN is characterized by alocalized thickening of the skin in parts of the right palm andthe right sole.

Note=KRT16 and KRT17 are coexpressed only in pathologicalsituations such as metaplasias and carcinomas of the uterinecervix and in psoriasis vulgaris.

Defects in KRT17 are a cause of pachyonychia congenitatype 2 (PC2) [MIM:167210], also known as pachyonychia congenitaJackson-Lawler type. PC2 is an autosomal dominant ectodermaldysplasia characterized by hypertrophic nail dystrophy resultingin onchyogryposis (thickening and increase in curvature of thenail), palmoplantar keratoderma and hyperhidrosis, follicularhyperkeratosis, multiple epidermal cysts, absent/sparse eyebrowand body hair, and by the presence of natal teeth.

Defects in KRT17 are a cause of steatocystoma multiplex(SM) [MIM:184500]. SM is a disease characterized by round or ovalcystic tumors widely distributed on the back, anterior trunk,arms, scrotum, and thighs.

Note=KRT16 and KRT17 are coexpressed only in pathologicalsituations such as metaplasias and carcinomas of the uterinecervix and in psoriasis vulgaris.

Defects in KRT18 are a cause of cirrhosis (CIRRH)[MIM:215600].

Defects in KRT9 are a cause of palmoplantar keratodermaepidermolytic (EPPK) [MIM:144200], also abbreviated as EHPPK. EPPKis a dermatological disorder characterized by diffuse thickeningof the epidermis on the entire surface of palms and soles sharplybordered with erythematous margins. Some patients may present withknuckle pads, thick pads of skin appearing over the proximalphalangeal joints.

Note=A chromosomal aberration involving KIAA2022 is foundin 2 patients with severe mental retardation (MR). Pericentricinversion inv(X)(p22.3,q13.2). The Xq13 breakpoint lies within apredicted intron of KIAA2022 gene. KIAA2022 protein is no longerexpressed in these patients lymphocytes.

Defects in KRT2 are a cause of ichthyosis bullosa ofSiemens (IBS) [MIM:146800]. IBS is a rare autosomal dominant skindisorder displaying a type of epidermolytic hyperkeratosischaracterized by generalized erythema and extensive blisteringfrom birth. Large, dark gray hyperkeratoses are observed in laterweeks. The skin of IBS patients is unusually fragile and has atendency to shed the outer layers of the epidermis, producinglocalized denuded areas (molting effect). IBS usually improveswith age so that in most middle-aged patients the hyperkeratosisand keratotic lichenification is limited to the flexural folds ofthe major joints.

Defects in KRT1 are a cause of bullous congenitalichthyosiform erythroderma (BCIE) [MIM:113800], also known asepidermolytic hyperkeratosis (EHK) or bullous erythrodermaichthyosiformis congenita of Brocq. BCIE is an autosomal dominantskin disorder characterized by widespread blistering and anichthyotic erythroderma at birth that persist into adulthood.Histologically there is a diffuse epidermolytic degeneration inthe lower spinous layer of the epidermis. Within a few weeks frombirth, erythroderma and blister formation diminish andhyperkeratoses develop.

Defects in KRT1 are the cause of ichthyosis hystrixCurth-Macklin type (IHCM) [MIM:146590]. IHCM is a genodermatosiswith severe verrucous hyperkeratosis. Affected individualsmanifest congenital verrucous black scale on the scalp, neck, andlimbs with truncal erythema, palmoplantar keratoderma andkeratoses on the lips, ears, nipples and buttocks.

Defects in KRT1 are a cause of palmoplantar keratodermanon-epidermolytic (NEPPK) [MIM:600962]. NEPKK is a dermatologicaldisorder characterized by focal palmoplantar keratoderma withoral, genital, and follicular lesions.

Defects in KRT1 are a cause of ichthyosis annularepidermolytic (AEI) [MIM:607602], also known as cyclic ichthyosiswith epidermolytic hyperkeratosis. AEI is a skin disorderresembling bullous congenital ichthyosiform erythroderma. Affectedindividuals present with bullous ichthyosis in early childhood andhyperkeratotic lichenified plaques in the flexural areas andextensor surfaces at later ages. The feature that distinguishesAEI from BCIE is dramatic episodes of flares of annular polycyclicplaques with scale, which coalesce to involve most of the bodysurface and can persist for several weeks or even months.

Defects in KRT1 are the cause of palmoplantar keratodermastriate type 3 (SPPK3) [MIM:607654], also known as keratosispalmoplantaris striata III. SPPK3 is a dermatological disorderaffecting palm and sole skin where stratum corneum and epidermallayers are thickened. There is no involvement of non-palmoplantarskin, and both hair and nails are normal.

Defects in KRT3 are a cause of Meesmann corneal dystrophy(MECD) [MIM:122100], also abbreviated as MCD and known as juvenileepithelial corneal dystrophy of Meesmann. MECD is an autosomaldominant disease that causes fragility of the anterior cornealepithelium. Patients are usually asymptomatic until adulthood whenrupture of the corneal microcysts may cause erosions, producingclinical symptoms such as photophobia, contact lens intoleranceand intermittent diminution of visual acuity. Rarely,subepithelial scarring causes irregular corneal astigmatism andpermanent visual impairment. Histological examination shows adisorganized and thickened epithelium with widespread cytoplasmicvacuolation and numerous small, round, debris-ladenintraepithelial cysts.

Defects in KRT4 are a cause of white sponge nevus ofcannon (WSN) [MIM:193900]. WSN is a rare autosomal dominantdisorder which predominantly affects non-cornified stratifiedsquamous epithelia. Clinically, it is characterized by thepresence of soft, white, and spongy plaques in the oral mucosa.The characteristic histopathologic features are epithelialthickening, parakeratosis, and vacuolization of the suprabasallayer of oral epithelial keratinocytes. Less frequently the mucousmembranes of the nose, esophagus, genitalia and rectum areinvolved.

Defects in KRT5 are a cause of epidermolysis bullosasimplex Dowling-Meara type (DM-EBS) [MIM:131760]. DM-EBS is asevere form of intraepidermal epidermolysis bullosa characterizedby generalized herpetiform blistering, milia formation, dystrophicnails, and mucous membrane involvement.

Defects in KRT5 are the cause of epidermolysis bullosasimplex with migratory circinate erythema (EBSMCE) [MIM:609352].EBSMCE is a form of intraepidermal epidermolysis bullosacharacterized by unusual migratory circinate erythema. Skinlesions appear from birth primarily on the hands, feet, and legsbut spare nails, ocular epithelia and mucosae. Lesions heal withbrown pigmentation but no scarring. Electron microscopy findingsare distinct from those seen in the DM-EBS, with no evidence oftonofilament clumping.

Defects in KRT5 are a cause of epidermolysis bullosasimplex Weber-Cockayne type (WC-EBS) [MIM:131800]. WC-EBS is aform of intraepidermal epidermolysis bullosa characterized byblistering limited to palmar and plantar areas of the skin.

Defects in KRT5 are a cause of epidermolysis bullosasimplex Koebner type (K-EBS) [MIM:131900]. K-EBS is a form ofintraepidermal epidermolysis bullosa characterized by generalizedskin blistering. The phenotype is not fundamentally distinct fromthe Dowling-Meara type, althought it is less severe.

Defects in KRT5 are the cause of epidermolysis bullosasimplex with mottled pigmentation (MP-EBS) [MIM:131960]. MP-EBS isa form of intraepidermal epidermolysis bullosa characterized byblistering at acral sites and 'mottled' pigmentation of the trunkand proximal extremities with hyper- and hypopigmentation macules.

Defects in KRT5 are the cause of Dowling-Degos disease(DDD) [MIM:179850], also known as Dowling-Degos-Kitamura diseaseor reticulate acropigmentation of Kitamura. DDD is an autosomaldominant genodermatosis. Affected individuals develop apostpubertal reticulate hyperpigmentation that is progressive anddisfiguring, and small hyperkeratotic dark brown papules thataffect mainly the flexures and great skin folds. Patients usuallyshow no abnormalities of the hair or nails.

Defects in KRT6A are a cause of pachyonychia congenitatype 1 (PC1) [MIM:167200], also known as Jadassohn-Lewandowskysyndrome. PC1 is an autosomal dominant ectodermal dysplasiacharacterized by hypertrophic nail dystrophy resulting inonchyogryposis (thickening and increase in curvature of the nail),palmoplantar keratoderma, follicular hyperkeratosis, and oralleukokeratosis. Hyperhidrosis of the hands and feet is usuallypresent.

Defects in KRT6B are a cause of pachyonychia congenitatype 2 (PC2) [MIM:167210], also known as pachyonychia congenitaJackson-Lawler type. PC2 is an autosomal dominant ectodermaldysplasia characterized by hypertrophic nail dystrophy resultingin onchyogryposis (thickening and increase in curvature of thenail), palmoplantar keratoderma and hyperhidrosis, follicularhyperkeratosis, multiple epidermal cysts, absent/sparse eyebrowand body hair, and by the presence of natal teeth.

Defects in KRT74 are a cause of woolly hair autosomaldominant (ADWH) [MIM:194300]. A hair shaft disorder characterizedby fine and tightly curled hair. Compared to normal curly hairthat is observed in some populations, woolly hair grows slowly andstops growing after a few inches. Under light microscopy, woollyhair shows some structural anomalies, including trichorrexisnodosa and tapered ends.

Defects in KRT75 may be a cause of loose anagen hairsyndrome (LAHS) [MIM:600628]. In LAHS, anagen hairs are easilypulled from the scalp. The hair is relatively sparse and does notgrow long. Hair of fair color and hair shafts of reduced caliber,and an early age of onset are features. Usually the hairs are notfragile and there are no areas of breakage.

Defects in KRT8 are a cause of cirrhosis (CIRRH)[MIM:215600].

Defects in PFKM are the cause of glycogen storage diseasetype 7 (GSD7) [MIM:232800], also known as Tarui disease. GSD7 isan autosomal recessive disorder characterized by exerciseintolerance with associated nausea and vomiting. Short bursts ofintense activity are particularly difficult. Severe muscle crampsand myoglobinuria develop after vigorous exercise. Most patientsobtain a "second wind" when the onset of exercise is followed by abrief rest period. In time patients adjust their activity leveland are well compensated.

Defects in AK1 are the cause of hemolytic anemia due toadenylate kinase deficiency [MIM:612631].

Defects in AK2 are the cause of reticular dysgenesis(RDYS) [MIM:267500], also known as aleukocytosis. RDYS is the mostsevere form of inborn severe combined immunodeficiencies (SCID)and is characterized by absence of granulocytes and almostcomplete deficiency of lymphocytes in peripheral blood, hypoplasiaof the thymus and secondary lymphoid organs, and lack of innateand adaptive humoral and cellular immune functions, leading tofatal septicemia within days after birth. In bone marrow ofindividuals with reticular dysgenesis, myeloid differentiation isblocked at the promyelocytic stage, whereas erythro- andmegakaryocytic maturation is generally normal.In addition,affected newborns have bilateral sensorineural deafness. Defectsmay be due to its absence in leukocytes and inner ear, in whichits absence can not be compensated by AK1.

Defects in KAL1 are the cause of Kallmann syndrome type 1(KAL1) [MIM:308700], also known as hypogonadotropic hypogonadismand anosmia. Anosmia or hyposmia is related to the absence orhypoplasia of the olfactory bulbs and tracts. Hypogonadism is dueto deficiency in gonadotropin-releasing hormone and probablyresults from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In some patients otherdevelopmental anomalies can be present, which include renalagenesis, cleft lip and/or palate, selective tooth agenesis, andbimanual synkinesis. In some cases anosmia may be absent orinconspicuous.

Genetic variation in KALRN is associated withsusceptibility to coronary heart disease type 5 (CHDS5)[MIM:608901]. CHD is the leading cause of death and disabilityworldwide. CHD is multifactorial disease with a strong geneticcomponent. Classic epidemiologic studies have revealed many riskfactors for CHD, including age, sex, hypertension, dyslipidemia,diabetes mellitus, smoking, and physical inactivity.

Defects in KANK1 are the cause of cerebral palsy spasticquadriplegic type 2 (CPSQ2) [MIM:612900]. A non-progressivedisorder of movement and/or posture resulting from defects in thedeveloping central nervous system. Affected individuals manifestcongenital hypotonia evolving over the first year to spasticquadriplegia with accompanying transient nystagmus and varyingdegrees of mental retardation. Neuroimaging shows brain atrophyand ventriculomegaly.

Defects in PRKAR1A are the cause of Carney complex type 1(CNC1) [MIM:160980]. CNC is a multiple neoplasia syndromecharacterized by spotty skin pigmentation, cardiac and othermyxomas, endocrine tumors, and psammomatous melanotic schwannomas.

Defects in PRKAR1A are the cause of intracardiac myxoma(INTMYX) [MIM:255960]. Inheritance is autosomal recessive.

Defects in PRKAR1A are the cause of primary pigmentednodular adrenocortical disease type 1 (PPNAD1) [MIM:610489].Primary pigmented nodular adrenocortical disease is a rarebilateral adrenal defect causing ACTH-independent Cushingsyndrome. Macroscopic appearance of the adrenals is characteristicwith small pigmented micronodules observed in the cortex. PPNAD1is most often diagnosed in patients with Carney complex, but itcan also be observed in patients without other manifestations orfamilial history.

Defects in KIAA1279 are the cause of Goldberg-Shprintzenmegacolon syndrome (GOSHS) [MIM:609460]. GOSHS is characterized bymicrocephaly, mental retardation and facial dysmorphism, as wellas phenotypes related to Hirschsprung disease syndrome.

Defects in KBTBD13 are the cause of nemaline myopathytype 6 (NEM6) [MIM:609273]. A form of nemaline myopathycharacterized by childhood onset of slowly progressive proximalmuscle weakness, exercise intolerance, and slow movements withstiff muscles. Patients are unable to run or correct themselvesfrom falling over.

Defects in CSNK1D are a cause of familial advanced sleep-phase syndrome (FASPS) [MIM:604348]. FASPS is characterized byvery early sleep onset and offset. Individuals are 'morning larks'with a 4 hours advance of the sleep, temperature and melatoninrhythms.

Defects in KCNE1L are involved in Alport syndrome withmental retardation midface hypoplasia and elliptocytosis (ATS-MR)[MIM:300194]. A X-linked contiguous gene deletion syndromecharacterized by glomerulonephritis, deafness, mental retardation,midface hypoplasia and elliptocytosis.

Defects in KCNMA1 are the cause of generalized epilepsyand paroxysmal dyskinesia (GEPD) [MIM:609446]. Epilepsy is one ofthe most common and debilitating neurological disorders.Paroxysmal dyskinesias are neurological disorders characterized bysudden, unpredictable, disabling attacks of involuntary movementoften requiring life-long treatment. The coexistence of epilepsyand paroxysmal dyskinesia in the same individual or family is anincreasingly recognized phenomenon. Patients manifest absenceseizures, generalized tonic-clonic seizures, paroxysmalnonkinesigenic dyskinesia, involuntary dystonic or choreiformmovements. Onset is usually in childhood and patients may haveseizures only, dyskinesia only, or both.

Defects in KCNA1 are the cause of episodic ataxia type 1(EA1) [MIM:160120], also known as paroxysmal or episodic ataxiawith myokymia (EAM) or paroxysmal ataxia with neuromyotonia. EA1is an autosomal dominant disorder characterized by brief episodesof ataxia and dysarthria. Neurological examination during andbetween the attacks demonstrates spontaneous, repetitivedischarges in the distal musculature (myokymia) that arise fromperipheral nerve. Nystagmus is absent.

Defects in KCNA1 are the cause of myokymia isolated type1 (MK1) [MIM:160120]. Myokymia is a condition characterized byspontaneous involuntary contraction of muscle fiber groups thatcan be observed as vermiform movement of the overlying skin.Electromyography typically shows continuous motor unit activitywith spontaneous oligo- and multiplet-discharges of highintraburst frequency (myokymic discharges). Isolated spontaneousmuscle twitches occur in many persons and have no gravesignificance.

Defects in KCNA5 are the cause of atrial fibrillationfamilial type 7 (ATFB7) [MIM:612240]. Atrial fibrillation is acommon disorder of cardiac rhythm that is hereditary in a smallsubgroup of patients. It is characterized by disorganized atrialelectrical activity, progressive deterioration of atrialelectromechanical function and ineffective pumping of blood intothe ventricles. It can be associated with palpitations, syncope,thromboembolic stroke, and congestive heart failure.

Defects in KCNC3 are the cause of spinocerebellar ataxiatype 13 (SCA13) [MIM:605259]. Spinocerebellar ataxia is aclinically and genetically heterogeneous group of cerebellardisorders. Patients show progressive incoordination of gait andoften poor coordination of hands, speech and eye movements, due todegeneration of the cerebellum with variable involvement of thebrainstem and spinal cord. SCA13 is an autosomal dominantcerebellar ataxia (ADCA) characterized by slow progression andvariable age at onset, ranging from childhood to late adulthood.Mental retardation can be present in some patients.

Defects in KCNE1 are the cause of Jervell and Lange-Nielsen syndrome type 2 (JLNS2) [MIM:612347]. JLNS2 is anautosomal recessive disorder characterized by congenital deafness,prolongation of the QT interval, syncopal attacks due toventricular arrhythmias, and a high risk of sudden death.

Defects in KCNE1 are the cause of long QT syndrome type 5(LQT5) [MIM:613695]. Long QT syndromes are heart disorderscharacterized by a prolonged QT interval on the ECG andpolymorphic ventricular arrhythmias. They cause syncope and suddendeath in response to exercise or emotional stress. KCNE1 mutantsform channels that open slowly and close rapidly, therebydiminishing potassium currents.

Defects in KCNE2 are the cause of long QT syndrome type 6(LQT6) [MIM:613693]. Long QT syndromes are heart disorderscharacterized by a prolonged QT interval on the ECG andpolymorphic ventricular arrhythmias. They cause syncope and suddendeath in response to exercise or emotional stress. KCNE2 mutantsform channels that open slowly and close rapidly, therebydiminishing potassium currents.

Defects in KCNE2 are the cause of atrial fibrillationfamilial type 4 (ATFB4) [MIM:611493]. Atrial fibrillation is acommon disorder of cardiac rhythm that is hereditary in a smallsubgroup of patients. It is characterized by disorganized atrialelectrical activity and ineffective atrial contraction promotingblood stasis in the atria and reduces ventricular filling. It canresult in palpitations, syncope, thromboembolic stroke, andcongestive heart failure.

Defects in KCNE3 are the cause of Brugada syndrome type 6(BRS6) [MIM:613119]. A tachyarrhythmia characterized by rightbundle branch block and ST segment elevation on anelectrocardiogram (ECG). It can cause the ventricles to beat sofast that the blood is prevented from circulating efficiently inthe body. When this situation occurs (called ventricularfibrillation), the individual will faint and may die in a fewminutes if the heart is not reset.

Defects in KCNH2 are the cause of long QT syndrome type 2(LQT2) [MIM:613688]. Long QT syndromes are heart disorderscharacterized by a prolonged QT interval on the ECG andpolymorphic ventricular arrhythmias. They cause syncope and suddendeath in response to exercise or emotional stress. Deafness isoften associated with LQT2.

Defects in KCNH2 are the cause of short QT syndrome type1 (SQT1) [MIM:609620]. Short QT syndromes are heart disorderscharacterized by idiopathic persistently and uniformly short QTinterval on ECG in the absence of structural heart disease inaffected individuals. They cause syncope and sudden death.

Defects in KCNK9 are the cause of Birk-Barel syndrome(BIBAS) [MIM:612292]. A syndrome characterized by mentalretardation, hypotonia, hyperactivity, and facial dysmorphism.

Defects in KCNK18 are a cause of migraine with or withoutaura type 13 (MGR13) [MIM:613656]. A form of migraine trasmittedin an autosomal dominant pattern. Migraine is a disabling symptomcomplex of periodic headaches, usually temporal and unilateral.Headaches are often accompanied by irritability, nausea, vomitingand photobia, preceded by constriction of the cranial arteries.The two major subtypes are common migraine (migraine without aura)and classic migraine (migraine with aura). Classic migraine ischaracterized by recurrent attacks of reversible neurologicalsymptoms (aura) that precede or accompany the headache. Aura mayinclude a combination of sensory disturbances, such as blurredvision, hallucinations, vertigo, numbness and difficulty inconcentrating and speaking. Note=Susceptibility to migraine hasbeen shown to be conferred by a frameshift mutation thatsegregates with the disorder in a large multigenerational family.Migraine was associated with sensitivity to lights, sounds, andsmells, as well as nausea and occasional vomiting. Triggersincluded fatigue, alcohol and bright lights. Mutations in KCNK18are a rare cause of migraine.

Defects in KCNQ1 are the cause of long QT syndrome type 1(LQT1) [MIM:192500], also known as Romano-Ward syndrome (RWS).Long QT syndromes are heart disorders characterized by a prolongedQT interval on the ECG and polymorphic ventricular arrhythmias.They cause syncope and sudden death in response to exercise oremotional stress. LQT1 inheritance is an autosomal dominant.

Defects in KCNQ1 are the cause of Jervell and Lange-Nielsen syndrome type 1 (JLNS1) [MIM:220400]. JLNS1 is anautosomal recessive disorder characterized by congenital deafness,prolongation of the QT interval, syncopal attacks due toventricular arrhythmias, and a high risk of sudden death.

Defects in KCNQ1 are the cause of atrial fibrillationfamilial type 3 (ATFB3) [MIM:607554]. Atrial fibrillation is acommon disorder of cardiac rhythm that is hereditary in a smallsubgroup of patients. It is characterized by disorganized atrialelectrical activity and ineffective atrial contraction promotingblood stasis in the atria and reduces ventricular filling. It canresult in palpitations, syncope, thromboembolic stroke, andcongestive heart failure.

Defects in KCNQ1 are the cause of short QT syndrome type2 (SQT2) [MIM:609621]. Short QT syndromes are heart disorderscharacterized by idiopathic persistently and uniformly short QTinterval on ECG in the absence of structural heart disease inaffected individuals. They cause syncope and sudden death.

Defects in KCNQ2 are the cause of benign neonatalepilepsy type 1 (EBN1) [MIM:121200]. A disorder characterized byclusters of seizures occurring in the first days of life. Mostpatients have spontaneous remission by 12 months of age and shownormal psychomotor development. Some rare cases manifest anatypical severe phenotype associated with epileptic encephalopathyand psychomotor retardation. The disorder is distinguished frombenign familial infantile seizures by an earlier age at onset. Insome patients, neonatal convulsions are followed later in life bymyokymia, a benign condition characterized by spontaneousinvoluntary contractions of skeletal muscles fiber groups that canbe observed as vermiform movement of the overlying skin.Electromyography typically shows continuous motor unit activitywith spontaneous oligo- and multiplet-discharges of highintraburst frequency (myokymic discharges). Some patients may haveisolated myokymia.

Defects in KCNQ2 are the cause of epilepticencephalopathy early infantile type 7 (EIEE7) [MIM:613720]. EIEE7is an autosomal dominant seizure disorder characterized byinfantile onset of refractory seizures with resultant delayedneurologic development and persistent neurologic abnormalities.

Defects in KCNQ3 are the cause of benign neonatalepilepsy type 2 (EBN2) [MIM:121201]. Benign neonatal epilepsy ischaracterized by clusters of seizures occurring in the first daysof life. Most patients have spontaneous remission by 12 months ofage and show normal psychomotor development. The disorder isdistinguished from benign familial infantile seizures by anearlier age at onset.

Defects in KCNQ4 are the cause of deafness autosomaldominant type 2A (DFNA2A) [MIM:600101]. DFNA2A is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in KCNV2 are the cause of cone dystrophy retinaltype 3B (RCD3B) [MIM:610356], also called cone dystrophy withnight blindness and supernormal rod responses KCNV2-related. RCD3Bis a rare form of cone dystrophy associated with supernormal rodresponses. The disorder is characterized by reduced visual acuity,photoaversion, night blindness, and abnormal color vision. At anearly age, the retina shows subtle depigmentation at the maculaand, later, more obvious areas of atrophy.

Defects in KCTD7 are the cause of progressive myoclonicepilepsy type 3 (EPM3) [MIM:611726]. EPM3 is an autosomalrecessive, severe, progressive myoclonic epilepsy with early-onset. Multifocal myoclonic seizures begin between 16 and 24months of age after normal initial development. Neurodegenerationand regression occur with seizure onset. Other features includemental retardation, dysarthria, truncal ataxia, and loss of finefinger movements. EEG shows slow dysrhythmia, multifocal andoccasionally generalized epileptiform discharges.

Defects in KDM5C are the cause of mental retardationsyndromic X-linked JARID1C-related (MRXSJ) [MIM:300534]. MRXSJ ischaracterized by significantly sub-average general intellectualfunctioning associated with impairments in adaptative behavior andmanifested during the developmental period. MRXSJ patientsmanifest mental retardation associated with variable features suchas slowly progressive spastic paraplegia, seizures, facialdysmorphism.

Note=A chromosomal aberration involving KDSR is a causeof follicular lymphoma, also known as type II chronic lymphaticleukemia. Translocation t(2,18)(p11,q21) with a Ig J kappa chainregion.

Defects in KERA are the cause of the autosomal recessivecornea plana 2 (CNA2) [MIM:217300]. In CNA2, the forward convexcurvature is flattened, leading to a decrease in refraction,reduced visual activity, extreme hyperopia (usually plus 10 d ormore), hazy corneal limbus, opacities in the corneal parenchyma,and marked arcus senilis (often detected at an early age). CNA2 isa rare disorder with a worldwide distribution, but a highprevalence in the Finnish population.

Defects in KHK are the cause of fructosuria (FRUCT)[MIM:229800]. Fructosuria is a benign defect of intermediarymetabolism.

Defects in KIF21A are a cause of congenital fibrosis ofextraocular muscles type 1 (CFEOM1) [MIM:135700]. CFEOMencompasses several different inherited strabismus syndromescharacterized by congenital restrictive ophthalmoplegia affectingextraocular muscles innervated by the oculomotor and/or trochlearnerves. CFEOM is characterized clinically by anchoring of the eyesin downward gaze, ptosis, and backward tilt of the head. CFEOM1individuals show an absence of the superior division of theoculomotor nerve (cranial nerve III) and corresponding oculomotorsubnuclei.

Defects in KIF1B are the cause of Charcot-Marie-Toothdisease type 2A1 (CMT2A1) [MIM:118210]. CMT2A1 is a form ofCharcot-Marie-Tooth disease, the most common inherited disorder ofthe peripheral nervous system. Charcot-Marie-Tooth disease isclassified in two main groups on the basis of electrophysiologicproperties and histopathology: primary peripheral demyelinatingneuropathy or CMT1, and primary peripheral axonal neuropathy orCMT2. Neuropathies of the CMT2 group are characterized by signs ofaxonal regeneration in the absence of obvious myelin alterations,normal or slightly reduced nerve conduction velocities, andprogressive distal muscle weakness and atrophy.

Defects in KIF1B are the cause of susceptibility toneuroblastoma type 1 (NBLST1) [MIM:256700]. A common neoplasm ofearly childhood arising from embryonic cells that form theprimitive neural crest and give rise to the adrenal medulla andthe sympathetic nervous system.

Defects in KIF1B are a cause of susceptibility topheochromocytoma (PCC) [MIM:171300]. A catecholamine-producingtumor of chromaffin tissue of the adrenal medulla or sympatheticparaganglia. The cardinal symptom, reflecting the increasedsecretion of epinephrine and norepinephrine, is hypertension,which may be persistent or intermittent.

Defects in KIF5A are the cause of spastic paraplegiaautosomal dominant type 10 (SPG10) [MIM:604187]. An inheriteddegenerative spinal cord disorder characterized by a slow,gradual, progressive weakness and spasticity (stiffness) of thelegs. Rate of progression and the severity of symptoms is quitevariable. Initial symptoms may include difficulty with balance,weakness and stiffness in the legs, muscle spasms, and draggingthe toes when walking. In some forms of the disorder, bladdersymptoms (such as incontinence) may appear, or the weakness andstiffness may spread to other parts of the body.

Defects in MVK are the cause of mevalonic aciduria (MEVA)[MIM:610377]. It is an accumulation of mevalonic acid which causesa variety of symptoms such as psychomotor retardation, dysmorphicfeatures, cataracts, hepatosplenomegaly, lymphadenopathy, anemia,hypotonia, myopathy, and ataxia.

Defects in MVK are the cause of hyperimmunoglobulinemia Dand periodic fever syndrome (HIDS) [MIM:260920]. HIDS is anautosomal recessive disease characterized by recurrent episodes ofunexplained high fever associated with skin rash, diarrhea,adenopathy (swollen, tender lymph nodes), athralgias and/orarthritis. Concentration of IgD, and often IgA, are above normal.

Note=A chromosomal aberration involving KIRREL3 and CDH15is found in a patient with severe mental retardation anddysmorphic facial features. Translocation t(11,16)(q24.2,q24).

Defects in KIRREL3 are the cause of mental retardationautosomal dominant type 4 (MRD4) [MIM:612581]. Mental retardationis characterized by significantly sub-average general intellectualfunctioning associated with impairments in adaptative behavior andmanifested during the developmental period.

Defects in KISS1R are a cause of idiopathichypogonadotropic hypogonadism (IHH) [MIM:146110]. IHH is definedas a deficiency of the pituitary secretion of follicle-stimulatinghormone and luteinizing hormone, which results in the impairmentof pubertal maturation and of reproductive function.

Defects in KISS1R are a cause of central precociouspuberty (CEPREPU) [MIM:176400]. Precocious puberty is defined asthe development of secondary sexual characteristics before the ageof 8 years in girls and 9 years in boys. Central precociouspuberty refers to a gonadotropin-dependent type which results frompremature activation of the hypothalamic-pituitary-gonadal axis.

Defects in TK2 are a cause of mitochondrial DNA depletionsyndrome type 2 (MTDPS2) [MIM:609560]. A disorder characterizedprimarily by childhood onset of muscle weakness associated withdepletion of mtDNA in skeletal muscle. There is wide clinicalvariability, some patients have onset in infancy and show arapidly progressive course with early death due to respiratoryfailure, whereas others have later onset of a slowly progressivemyopathy.

Defects in KIT are a cause of piebald trait (PBT)[MIM:172800]. PBT is an autosomal dominant genetic developmentalabnormality of pigmentation characterized by congenital patches ofwhite skin and hair that lack melanocytes.

Defects in KIT are a cause of gastrointestinal stromaltumor (GIST) [MIM:606764].

Defects in KIT have been associated with testiculartumors (TEST) [MIM:273300]. A common solid malignancy in males.Germ cell tumors of the testis constitute 95% of all testicularneoplasms.

Defects in KLHDC8B are a cause of Hodgkin lymphoma (HL)[MIM:236000]. A malignant disease characterized by progressiveenlargement of the lymph nodes, spleen and general lymphoidtissue, and the presence of large, usually multinucleate, cells(Reed-Sternberg cells). Reed-Sternberg cells compose only 1-2% ofthe total tumor cell mass. The remainder is composed of a varietyof reactive, mixed inflammatory cells consisting of lymphocytes,plasma cells, neutrophils, eosinophils and histiocytes. Note=Achromosomal aberration disrupting KLHDC8B has been found in afamily with the nodular sclerosis type of classic Hodgkinlymphoma. Translocation t(2,3)(q11.2,p21.31).

Defects in KLF11 are the cause of maturity-onset diabetesof the young type 7 (MODY7) [MIM:610508]. MODY is a form ofdiabetes that is characterized by an autosomal dominant mode ofinheritance, onset in childhood or early adulthood (usually before25 years of age), a primary defect in insulin secretion andfrequent insulin-independence at the beginning of the disease.

Defects in KLF1 are the cause of congenitaldyserythropoietic anemia type 4 (CDA4) [MIM:613673]. It is a blooddisorder characterized by ineffective erythropoiesis and hemolysisresulting in anemia. Circulating erythroblasts and erythroblastsin the bone marrow show various morphologic abnormalities.Affected individuals with CDA4 also have increased levels of fetalhemoglobin.

Defects in KLF6 are a cause of gastric cancer (GASC)[MIM:613659], also called gastric cancer intestinal or stomachcancer. Gastric cancer is a malignant disease which starts in thestomach, can spread to the esophagus or the small intestine, andcan extend through the stomach wall to nearby lymph nodes andorgans. It also can metastasize to other parts of the body. Theterm gastric cancer or gastric carcinoma refers to adenocarcinomaof the stomach that accounts for most of all gastric malignanttumors. Two main histologic types are recognized, diffuse type andintestinal type carcinomas. Diffuse tumors are poorlydifferentiated infiltrating lesions, resulting in thickening ofthe stomach. In contrast, intestinal tumors are usually exophytic,often ulcerating, and associated with intestinal metaplasia of thestomach, most often observed in sporadic disease.

Defects in KLF6 are a cause of prostate cancer (PC)[MIM:176807]. Prostate cancer is a malignancy originating intissues of the prostate. Most prostate cancers are adenocarcinomasthat develop in the acini of the prostatic ducts. Other rarehistopathologic types of prostate cancer that occur inapproximately 5% of patients include small cell carcinoma,mucinous carcinoma, prostatic ductal carcinoma, transitional cellcarcinoma, squamous cell carcinoma, basal cell carcinoma, adenoidcystic carcinoma (basaloid), signet-ring cell carcinoma andneuroendocrine carcinoma.

Defects in KLHL7 are the cause of retinitis pigmentosatype 42 (RP42) [MIM:612943]. A retinal dystrophy belonging to thegroup of pigmentary retinopathies. RP is characterized by retinalpigment deposits visible on fundus examination and primary loss ofrod photoreceptor cells followed by secondary loss of conephotoreceptors. Patients typically have night vision blindness andloss of midperipheral visual field. As their condition progresses,they lose their far peripheral visual field and eventually centralvision as well.

Defects in KLK4 are the cause of amelogenesis imperfectahypomaturation type 2A1 (AI2A1) [MIM:204700]. AI2A1 is anautosomal recessive defect of enamel formation. The disorderinvolves both primary and secondary dentitions. The teeth have ashiny agar jelly appearance and the enamel is softer than normal.Brown pigment is present in middle layers of enamel.

Defects in KLKB1 are the cause of prekallikreindeficiency (PKK deficiency) [MIM:612423], also known as Fletcherfactor deficiency. This disorder is a blood coagulation defect.

Defects in KL are a cause of hyperphosphatemic familialtumoral calcinosis (HFTC) [MIM:211900]. A severe metabolicdisorder that manifests with hyperphosphatemia and massive calciumdeposits in the skin and subcutaneous tissues. Some patientsmanifest recurrent, transient, painful swellings of the long bonesassociated with the radiographic findings of periosteal reactionand cortical hyperostosis and absence of skin involvement.

Defects in KNG1 are the cause of high molecular weightkininogen deficiency (HMWK deficiency) [MIM:228960]. HMWKdeficiency is an autosomal recessive coagulation defect. Patientswith HWMK deficiency do not have a hemorrhagic tendency, but theyexhibit abnormal surface-mediated activation of fibrinolysis.

Defects in PHKA1 are the cause of glycogen storagedisease type 9D (GSD9D) [MIM:300559], also known as X-linkedmuscle glycogenosis. GSD9D is a metabolic disorder characterizedby slowly progressive, predominantly distal muscle weakness andatrophy. Clinical features include exercise intolerance with earlyfatigability, pain, cramps and occasionally myoglobinuria.

Defects in PHKA2 are the cause of glycogen storagedisease type 9A (GSD9A) [MIM:306000], also known as X-linked liverglycogenosis (XLG). GSD9A is a metabolic disorder resulting in amild glycogenosis with clinical symptoms that includehepatomegaly, growth retardation, muscle weakness, elevation ofglutamate-pyruvate transaminase and glutamate-oxaloacetatetransaminase, hypercholesterolemia, hypertriglyceridemia, andfasting hyperketosis. Two subtypes are known: type 1 or classictype with no phosphorylase kinase activity in liver orerythrocytes, and type 2 or variant type with no phosphorylasekinase activity in liver, but normal activity in erythrocytes.Unlike other glycogenosis diseases, glycogen storage disease type9A is generally a benign condition. Patients improve with age andare often asymptomatic as adults. Accurate diagnosis is thereforealso of prognostic interest.

Defects in PHKB are the cause of glycogen storage diseasetype 9B (GSD9B) [MIM:261750], also known as phosphorylase kinasedeficiency of liver and muscle (PKD). GSD9B is a metabolicdisorder characterized by hepathomegaly, only slightly elevatedtransaminases and plasma lipids, clinical improvement withincreasing age, and remarkably no clinical muscle involvement.Biochemical observations suggest that this mild phenotype iscaused by an incomplete holoenzyme that lacks the beta subunit,but that may possess residual activity.

Defects in PRKCG are the cause of spinocerebellar ataxiatype 14 (SCA14) [MIM:605361]. Spinocerebellar ataxia is aclinically and genetically heterogeneous group of cerebellardisorders. Patients show progressive incoordination of gait andoften poor coordination of hands, speech and eye movements, due todegeneration of the cerebellum with variable involvement of thebrainstem and spinal cord. SCA14 is an autosomal dominantcerebellar ataxia (ADCA).

Defects in PRKCH may be a cause of susceptibility toischemic stroke (ISCHSTR) [MIM:601367], also known ascerebrovascular accident or cerebral infarction. A stroke is anacute neurologic event leading to death of neural tissue of thebrain and resulting in loss of motor, sensory and/or cognitivefunction. Ischemic strokes, resulting from vascular occlusion, isconsidered to be a highly complex disease consisting of a group ofheterogeneous disorders with multiple genetic and environmentalrisk factors.

Defects in PKLR are the cause of pyruvate kinasehyperactivity (PKHYP) [MIM:102900], also known as high red cellATP syndrome. This autosomal dominant phenotype is characterizedby increase of red blood cell ATP.

Defects in PKLR are the cause of pyruvate kinasedeficiency of red cells (PKRD) [MIM:266200]. A frequent cause ofhereditary non-spherocytic hemolytic anemia. Clinically, pyruvatekinase-deficient patients suffer from a highly variable degree ofchronic hemolysis, ranging from severe neonatal jaundice and fatalanemia at birth, severe transfusion-dependent chronic hemolysis,moderate hemolysis with exacerbation during infection, to a fullycompensated hemolysis without apparent anemia.

Defects in KRIT1 are the cause of cerebral cavernousmalformations type 1 (CCM1) [MIM:116860]. Cerebral cavernousmalformations (CCMs) are congenital vascular anomalies of thecentral nervous system that can result in hemorrhagic stroke,seizures, recurrent headaches, and focal neurologic deficits. CCMshave an incidence of 0.1%-0.5% in the general population andusually present clinically during the 3rd to 5th decade of life.The lesions are characterized by grossly enlarged blood vesselsconsisting of a single layer of endothelium and without anyintervening neural tissue, ranging in diameter from a fewmillimeters to several centimeters.

Defects in KRT81 are a cause of monilethrix (MLTRX)[MIM:158000]. Monilethrix is an autosomal dominant hair disordercharacterized clinically by alopecia and follicular papules.Affected hairs have uniform elliptical nodes of normal thicknessand intermittent constrictions, internodes at which the haireasily breaks. Usually only the scalp is involved, but in severeforms, the secondary sexual hair, eyebrows, eyelashes, and nailsmay also be affected.

Defects in KRT83 are a cause of monilethrix (MLTRX)[MIM:158000]. Monilethrix is an autosomal dominant hair disordercharacterized clinically by alopecia and follicular papules.Affected hairs have uniform elliptical nodes of normal thicknessand intermittent constrictions, internodes at which the haireasily breaks. Usually only the scalp is involved, but in severeforms, the secondary sexual hair, eyebrows, eyelashes, and nailsmay also be affected.

Defects in KRT85 are the cause of ectodermal dysplasiapure hair-nail type (EDPHN) [MIM:602032]. Ectodermal dysplasiadefines a heterogeneous group of disorders due to abnormaldevelopment of two or more ectodermal structures. EDPHN ischaracterized by complete alopecia, hypotricosis and naildystrophy in all digits. There is no evidence of any otherabnormality. Inheritance can be autosomal dominant or recessive.

Defects in KRT86 are a cause of monilethrix (MLTRX)[MIM:158000]. Monilethrix is an autosomal dominant hair disordercharacterized clinically by alopecia and follicular papules.Affected hairs have uniform elliptical nodes of normal thicknessand intermittent constrictions, internodes at which the haireasily breaks. Usually only the scalp is involved, but in severeforms, the secondary sexual hair, eyebrows, eyelashes, and nailsmay also be affected.

Defects in RPS6KA3 are the cause of Coffin-Lowry syndrome(CLS) [MIM:303600], an X-linked dominant disorder characterized bysevere mental retardation with facial and digital dysmorphisms,and progressive skeletal deformations.

Defects in KTU are the cause of primary ciliarydyskinesia type 10 (CILD10) [MIM:612518]. CILD is an autosomalrecessive disorder characterized by axonemal abnormalities ofmotile cilia. Respiratory infections leading to chronicinflammation and bronchiectasis are recurrent, due to defects inthe respiratory cilia, reduced fertility is often observed in malepatients due to abnormalities of sperm tails. Half of the patientsexhibit situs inversus, due to dysfunction of monocilia at theembryonic node and randomization of left-right body asymmetry.Primary ciliary dyskinesia associated with situs inversus isreferred to as Kartagener syndrome.

Note=Xanthurenic aciduria manifesting as massive urinaryexcretion of large amounts of kynurenine, 3-hydroxykynurenine andxanthurenic acid has been observed in an individual carrying ahomozygous missense change in KYNU (PubMed:17334708). The urinarypattern in the patient suggests kynureninase deficiency and ablock in the conversion of kynurenine and 3-hydroxykynurenine toanthranilate and 3-hydroxyanthranilate, respectively.

Defects in L1CAM are the cause of hydrocephalus due tostenosis of the aqueduct of Sylvius (HSAS) [MIM:307000].Hydrocephalus is a condition in which abnormal accumulation ofcerebrospinal fluid in the brain causes increased intracranialpressure inside the skull. This is usually due to blockage ofcerebrospinal fluid outflow in the brain ventricles or in thesubarachnoid space at the base of the brain. In children istypically characterized by enlargement of the head, prominence ofthe forehead, brain atrophy, mental deterioration, andconvulsions. In adults the syndrome includes incontinence,imbalance, and dementia. HSAS is characterized by mentalretardation and enlarged brain ventricles.

Defects in L1CAM are the cause of mental retardation-aphasia-shuffling gait-adducted thumbs syndrome (MASA)[MIM:303350], also known as corpus callosum hypoplasia,psychomotor retardation, adducted thumbs, spastic paraparesis, andhydrocephalus or CRASH syndrome. MASA is an X-linked recessivesyndrome with a highly variable clinical spectrum. Main clinicalfeatures include spasticity and hyperreflexia of lower limbs,shuffling gait, mental retardation, aphasia and adducted thumbs.The features of spasticity have been referred to as complicatedspastic paraplegia type 1 (SPG1). Some patients manifest corpuscallosum hypoplasia and hydrocephalus. Inter- and intrafamilialvariability is very wide, such that patients with hydrocephalus,MASA, SPG1, and agenesis of corpus callosum can be present withinthe same family.

Defects in L1CAM are the cause of spastic paraplegia X-linked type 1 (SPG1) [MIM:303350]. Spastic paraplegia is adegenerative spinal cord disorder characterized by a slow,gradual, progressive weakness and spasticity of the lower limbs.

Note=Defects in L1CAM may contribute to Hirschsprungdisease by modifying the effects of Hirschsprung disease-associated genes to cause intestinal aganglionosis.

Defects in L1CAM are a cause of partial agenesis of thecorpus callosum (ACCPX) [MIM:304100]. A syndrome characterized bypartial corpus callosum agenesis, hypoplasia of inferior vermisand cerebellum, mental retardation, seizures and spasticity. Otherfeatures include microcephaly, unusual facies, and Hirschsprungdisease in some patients.

Defects in L2HGDH are the cause of L-2-hydroxyglutaricaciduria (L2HGA) [MIM:236792]. L2HGA is a rare autosomal recessivedisorder clinically characterized by mild psychomotor delay in thefirst years of life, followed by progressive cerebellar ataxia,dysarthria and moderate to severe mental retardation. Diagnosis isbased on the presence of an excess of L-2-hydroxyglutaric acid inurine, blood and cerebrospinal fluid.

Defects in LAMA3 are a cause of epidermolysis bullosajunctional Herlitz type (H-JEB) [MIM:226700], also known asjunctional epidermolysis bullosa Herlitz-Pearson type. JEB definesa group of blistering skin diseases characterized by tissueseparation which occurs within the dermo-epidermal basementmembrane. H-JEB is a severe, infantile and lethal form. Deathoccurs usually within the first six months of life. Occasionally,children survive to teens. H-JEB is marked by bullous lesions atbirth and extensive denudation of skin and mucous membranes thatmay be hemorrhagic.

Defects in LAMA3 are the cause of laryngoonychocutaneoussyndrome (LOCS) [MIM:245660]. LOCS is an autosomal recessiveepithelial disorder confined to the Punjabi Muslim population. Thecondition is characterized by cutaneous erosions, nail dystrophyand exuberant vascular granulation tissue in certain epithelia,especially conjunctiva and larynx.

Defects in LAMB2 are the cause of Pierson syndrome(PIERSS) [MIM:609049], also known as microcoria-congenitalnephrotic syndrome. Pierson syndrome is characterized by nephroticsyndrome with neonatal onset, diffuse mesangial sclerosis and eyeabnormalities with microcoria as the leading clinical feature.Death usually occurs within the first weeks of life. Diseaseseverity depends on the mutation type: nontruncating LAMB2mutations may display variable phenotypes ranging from a mildervariant of Pierson syndrome to isolated congenital nephroticsyndrome.

Defects in LAMB2 are a cause of congenital nephroticsyndrome (CONPHS) [MIM:609049]. Congenital nephrotic syndromeconstitutes a heterogeneous group of conditions having in commonthe disruption of normal glomerular permselectivity. Congenitalnephrotic syndrome due to LAMB2 mutations may be associated withocular abnormalities.

Defects in LAMB3 are a cause of epidermolysis bullosajunctional Herlitz type (H-JEB) [MIM:226700], also known asjunctional epidermolysis bullosa Herlitz-Pearson type. JEB definesa group of blistering skin diseases characterized by tissueseparation which occurs within the dermo-epidermal basementmembrane. H-JEB is a severe, infantile and lethal form. Deathoccurs usually within the first six months of life. Occasionally,children survive to teens. H-JEB is marked by bullous lesions atbirth and extensive denudation of skin and mucous membranes thatmay be hemorrhagic.

Defects in LAMB3 are a cause of generalized atrophicbenign epidermolysis bullosa (GABEB) [MIM:226650]. GABEB is a non-lethal, adult form of junctional epidermolysis bullosacharacterized by life-long blistering of the skin, associated withhair and tooth abnormalities.

Defects in LAMC2 are a cause of epidermolysis bullosajunctional Herlitz type (H-JEB) [MIM:226700], also known asjunctional epidermolysis bullosa Herlitz-Pearson type. JEB definesa group of blistering skin diseases characterized by tissueseparation which occurs within the dermo-epidermal basementmembrane. H-JEB is a severe, infantile and lethal form. Deathoccurs usually within the first six months of life. Occasionally,children survive to teens. H-JEB is marked by bullous lesions atbirth and extensive denudation of skin and mucous membranes thatmay be hemorrhagic.

Defects in LAMP2 are the cause of Danon disease (DAND)[MIM:300257], also known as glycogen storage disease type 2B(GSD2B). DAND is a lysosomal glycogen storage diseasecharacterized by the clinical triad of cardiomyopathy, vacuolarmyopathy and mental retardation. It is often associated with anaccumulation of glycogen in muscle and lysosomes.

Defects in TMPO are the cause of cardiomyopathy dilatedtype 1T (CMD1T) [MIM:613740]. A disorder characterized byventricular dilation and impaired systolic function, resulting incongestive heart failure and arrhythmia. Patients are at risk ofpremature death.

Defects in LARGE are the cause of muscular dystrophy-dystroglycanopathy congenital with mental retardation type B6(MDDGB6) [MIM:608840]. A congenital muscular dystrophy associatedwith profound mental retardation, white matter changes andstructural brain abnormalities. Skeletal muscle biopsies showreduced immunolabeling of alpha-dystroglycan.

Defects in LARGE are the cause of muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies type A6(MDDGA6) [MIM:613154], also called muscle-eye-brain disease LARGE-related or Walker-Warburg syndrome LARGE-related. MDDGA6 is anautosomal recessive disorder characterized by congenital musculardystrophy associated with cobblestone lissencephaly and otherbrain anomalies, eye malformations, profound mental retardation,and death usually in the first years of life. Included diseasesare the more severe Walker-Warburg syndrome and the slightly lesssevere muscle-eye-brain disease.

Defects in EVC2 are a cause of Ellis-van Creveld syndrome(EVC) [MIM:225500], also known as chondroectodermal dysplasia. EVCis an autosomal recessive disorder characterized by the clinicaltetrad of chondrodystrophy, polydactyly, ectodermal dysplasia andcardiac anomalies. Patients manifest short-limb dwarfism, shortribs, postaxial polydactyly and dysplastic nails and teeth.Congenital heart defects, most commonly an atrioventricular septaldefect, are observed in 60% of affected individuals.

Defects in EVC2 are a cause of acrofacial dysostosisWeyers type (WAD) [MIM:193530], also known as Curry-Hall syndrome.Acrofacial dysostoses are a heterogeneous group of disorderscombining limb defects with facial abnormalities. WAD is anautosomal dominant disorder characterized by dysplastic nails,postaxial polydactyly, acrofacial dysostosis, short limbs andshort stature. The phenotype is milder than Ellis-van Creveldsyndrome.

Defects in LBR are a cause of Pelger-Huet anomaly (PHA)[MIM:169400]. PHA is an autosomal dominant inherited abnormalityof neutrophils, characterized by reduced nuclear segmentation andan apparently looser chromatin structure. Heterozygotes showhypolobulated neutrophil nuclei with coarse chromatin. Presumedhomozygous individuals have ovoid neutrophil nuclei, as well asvarying degrees of developmental delay, epilepsy, and skeletalabnormalities.

Defects in LBR are the cause of hydrops-ectopiccalcification-moth-eaten skeletal dysplasia (HEM) [MIM:215140],also known as Greenberg skeletal dysplasia. HEM is a rareautosomal recessive chondrodystrophy characterized by early inutero lethality and, therefore, considered to be nonviable.Affected fetuses typically present with fetal hydrops, short-limbed dwarfism, and a marked disorganization of chondro-osseouscalcification and may present with polydactyly and additionalnonskeletal malformations.

Defects in LBR may be a cause of Reynolds syndrome(REYNS) [MIM:613471]. It is a syndrome specifically associatinglimited cutaneous systemic sclerosis and primary biliraycirrhosis. It is characterized by liver disease, telangiectasia,abrupt onset of digital paleness or cyanosis in response to coldexposure or stress (Raynaud phenomenon), and variable features ofscleroderma. The liver disease is characterized by pruritis,jaundice, hepatomegaly, increased serum alkaline phosphatase andpositive serum mitochondrial autoantibodies, all consistent withprimary biliary cirrhosis.

Defects in LCA5 are the cause of Leber congenitalamaurosis type 5 (LCA5) [MIM:604537]. LCA designates a clinicallyand genetically heterogeneous group of childhood retinaldegenerations, generally inherited in an autosomal recessivemanner. Affected infants have little or no retinal photoreceptorfunction as tested by electroretinography. LCA represents the mostcommon genetic cause of congenital visual impairment in infantsand children.

Defects in LCAT are the cause of lecithin-cholesterolacyltransferase deficiency (LCATD) [MIM:245900], also called Norumdisease. LCATD is a disorder of lipoprotein metabolismcharacterized by inadequate esterification of plasmaticcholesterol. Two clinical forms are recognized: familial LCATdeficiency and fish-eye disease. Familial LCAT deficiency isassociated with a complete absence of alpha and beta LCATactivities and results in esterification anomalies involving bothHDL (alpha-LCAT activity) and LDL (beta-LCAT activity). It causesa typical triad of diffuse corneal opacities, target cellhemolytic anemia, and proteinuria with renal failure.

Defects in LCAT are a cause of fish-eye disease (FED)[MIM:136120], also known as dyslipoproteinemic corneal dystrophyor alpha-LCAT deficiency. FED is due to a partial LCAT deficiencythat affects only alpha-LCAT activity. It is characterized by lowplasma HDL and corneal opacities due to accumulation ofcholesterol deposits in the cornea ('fish-eye').

Note=A chromosomal aberration involving LCK is found inleukemias. Translocation t(1,7)(p34,q34) with TCRB.

Defects in LDB3 are the cause of cardiomyopathy dilatedtype 1C (CMD1C) [MIM:601493]. Dilated cardiomyopathy is a disordercharacterized by ventricular dilation and impaired systolicfunction, resulting in congestive heart failure and arrhythmia.Patients are at risk of premature death.

Defects in LDB3 are the cause of left ventricular non-compaction type 3 (LVNC3) [MIM:601493]. Left ventricular non-compaction is characterized by numerous prominent trabeculationsand deep intertrabecular recesses in hypertrophied and hypokineticsegments of the left ventricle.

Defects in LDB3 are the cause of myopathy myofibrillarZASP-related (MFM-ZASP) [MIM:609452]. A neuromuscular disordercharacterized by distal and proximal muscle weakness with signs ofcardiomyopathy and neuropathy.

Defects in LDHA are the cause of glycogen storage diseasetype 11 (GSD11) [MIM:612933]. A metabolic disorder that results inexertional myoglobinuria, pain, cramps and easy fatigue.

Note=Defects in LDHB result in deficiency of lactatedehydrogenase, a condition with no clear symptomatic consequences.Lactate dehydrogenase deficiency can probably be considered a non-disease.

Defects in LDLR are the cause of familialhypercholesterolemia (FH) [MIM:143890], a common autosomal semi-dominant disease that affects about 1 in 500 individuals. Thereceptor defect impairs the catabolism of LDL, and the resultantelevation in plasma LDL-cholesterol promotes deposition ofcholesterol in the skin (xanthelasma), tendons (xanthomas), andcoronary arteries (atherosclerosis).

Defects in LEP may be a cause of obesity (OBESITY)[MIM:601665]. It is a condition characterized by an increase ofbody weight beyond the limitation of skeletal and physicalrequirements, as the result of excessive accumulation of body fat.

Defects in LFNG are the cause of spondylocostaldysostosis type 3 (SCDO3) [MIM:609813]. An autosomal recessivecondition of variable severity associated with vertebral and ribsegmentation defects. The main skeletal malformations includefusion of vertebrae, hemivertebrae, fusion of certain ribs, andother rib malformations. Deformity of the chest and spine (severescoliosis, kyphoscoliosis and lordosis) is a natural consequenceof the malformation and leads to a dwarf-like appearance. As thethorax is small, infants frequently have respiratory insufficiencyand repeated respiratory infections resulting in life-threateningcomplications in the first year of life.

Defects in LEFTY2 are the cause of left-right axismalformations (L-R axis malformation) [MIM:601877]. The defectincludes left pulmonary isomerism, with cardiac anomaliescharacterized by complete atrioventricular canal defect andhypoplastic left ventricle, and interrupted inferior vena cava.

Defects in LGI1 are the cause of lateral temporal lobeepilepsy autosomal dominant (ADLTE) [MIM:600512], also known asautosomal dominant partial epilepsy with auditory features(ADPEAF). ADLTE is a form of epilepsy characterized by partialseizures, usually preceded by auditory signs.

Defects in LHX3 are the cause of pituitary hormonedeficiency combined type 3 (CPHD3) [MIM:221750], also known ascombined pituitary hormone deficiency with rigid cervical spine orsensorineural deafness with pituitary dwarfism. CPHD ischaracterized by a complete deficit in all but one(adrenocorticotropin) anterior pituitary hormone and a rigidcervical spine leading to limited head rotation.

Defects in LHX4 are the cause of pituitary hormonedeficiency combined type 4 (CPHD4) [MIM:262700], also known asshort stature pituitary and cerebellar defects and small sellaturcica. The disorder is characterized by short stature, pituitaryand cerebellar defects, and small transverse depression crossingthe midline on the superior surface of the body of the sphenoidbone which houses the pituitary gland.

Note=A chromosomal aberration involving LHX4 may be acause of acute lymphoblastic leukemia. Translocationt(1,14)(q25,q32) with IGHG1.

Defects in LIPA are the cause of Wolman disease (WOD)[MIM:278000]. WOD is a severe manifestation of LIPA deficiency,leading to the accumulation of cholesteryl esters andtriglycerides in most tissues of the body. WOD occurs in infancyand is nearly always fatal before the age of 1 year.

Defects in LIPA are the cause of cholesteryl esterstorage disease (CESD) [MIM:278000]. CESD is a mild manifestationof LIPA deficiency, leading to the accumulation of cholesterylesters and triglycerides in most tissues of the body. It ischaracterized by late-onset.

Defects in LIFR are the cause of Stueve-Wiedemannsyndrome (SWS) [MIM:601559], also knowns as Schwartz-Jampelsyndrome type 2 (SJS2). SWS is a severe autosomal recessivecondition and belongs to the group of the bent-bone dysplasias.SWS is characterized by bowing of the lower limbs, with internalcortical thickening, wide metaphyses with abnormal trabecularpattern, and camptodactyly. Additional features include feedingand swallowing difficulties, as well as respiratory distress andhyperthermic episodes, which cause death in the first months oflife. The rare survivors develop progressive scoliosis,spontaneous fractures, bowing of the lower limbs, with prominentjoints and dysautonomia symptoms, including temperatureinstability, absent corneal and patellar reflexes, and smoothtongue.

Note=A chromosomal aberration involving LIFR is found insalivary gland pleiomorphic adenomas, the most common benignepithelial tumors of the salivary gland. Translocationt(5,8)(p13,q12) with PLAG1.

Note=LIMK1 is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.

Defects in LIPC are the cause of hepatic lipasedeficiency (HL deficiency) [MIM:151670].

Defects in LIPH are the cause of hypotrichosis localizedautosomal recessive type 2 (LAH2) [MIM:604379], also known asalopecia universalis congenita Mari type. A conditioncharacterized by the presence of less than the normal amount ofhair. Affected individuals have sparse or absent scalp, axillaryand body hair and sparse eyebrows and eyelashes.

Defects in LIPH are the cause of woolly hair autosomalrecessive type 2 (ARWH2) [MIM:604379]. A hair shaft disordercharacterized by fine and tightly curled hair. Compared to normalcurly hair that is observed in some populations, woolly hair growsslowly and stops growing after a few inches. Under lightmicroscopy, woolly hair shows some structural anomalies, includingtrichorrexis nodosa and tapered ends. Some individuals may presentwith hypotrichosis.

Defects in LIPI may be a cause of susceptibility tofamilial hypertriglyceridemia (FHTR)[MIM:145750]. Familialhypertriglyceridemia is a common inherited disorder in which theconcentration of very low density lipoprotein (VLDL) is elevatedin the plasma. This leads to increased risk of heart disease,obesity, and pancreatitis.

Defects in LPL are the cause of lipoprotein lipasedeficiency (LPL deficiency) [MIM:238600], also known as familialchylomicronemia or hyperlipoproteinemia type I. LPL deficiencychylomicronemia is a recessive disorder usually manifesting inchildhood. On a normal diet, patients often present with abdominalpain, hepatosplenomegaly, lipemia retinalis, eruptive xanthomata,and massive hypertriglyceridemia, sometimes complicated with acutepancreatitis.

Defects in PAFAH1B1 are the cause of lissencephaly type 1(LIS1) [MIM:607432], also known as classic lissencephaly. LIS1 ischaracterized by agyria or pachgyria and disorganization of theclear neuronal lamination of normal six-layered cortex. The cortexis abnormally thick and poorly organized with 4 primitive layers.LIS1 is associated with enlarged and dysmorphic ventricles andoften hypoplasia of the corpus callosum.

Defects in PAFAH1B1 are the cause of subcortical bandheterotopia (SBH) [MIM:607432]. SBH is a mild brain malformationof the lissencephaly spectrum. It is characterized by bilateraland symmetric ribbons of gray matter found in the central whitematter between the cortex and the ventricular surface.

Defects in PAFAH1B1 are a cause of Miller-Diekerlissencephaly syndrome (MDLS) [MIM:247200]. MDLS is a contiguousgene deletion syndrome of chromosome 17p13.3, characterized byclassical lissencephaly and distinct facial features. Additionalcongenital malformations can be part of the condition.

Defects in LITAF are the cause of Charcot-Marie-Toothdisease type 1C (CMT1C) [MIM:601098]. CMT1C is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of theperipheral nervous system. Charcot-Marie-Tooth disease isclassified in two main groups on the basis of electrophysiologicproperties and histopathology: primary peripheral demyelinatingneuropathy or CMT1, and primary peripheral axonal neuropathy orCMT2. Neuropathies of the CMT1 group are characterized by severelyreduced nerve conduction velocities (less than 38 m/sec),segmental demyelination and remyelination with onion bulbformations on nerve biopsy, slowly progressive distal muscleatrophy and weakness, absent deep tendon reflexes, and hollowfeet.

Note=Defects in LITAF may be involved in extramammaryPaget disease (EMPD) carcinogenesis. EMPD is a cancerous diseaserepresenting about 8% of all malignant skin cancers, it usuallyappears in the anogenital area and can be fatal by metastasizingto internal organs when left untreated for a long time. Theclinical features are usually those of eczematous eruptions withweeping and crust formation.

Defects in LMAN1 are THE cause of factor V and factorVIII combined deficiency type 1 (F5F8D1) [MIM:227300], also knownas multiple coagulation factor deficiency I (MCFD1). F5F8D1 is anautosomal recessive blood coagulation disorder characterized bybleeding symptoms similar to those in hemophilia orparahemophilia, that are caused by single deficiency of FV orFVIII, respectively. The most common symptoms are epistaxis,menorrhagia, and excessive bleeding during or after trauma. Plasmalevels of coagulation factors V and VIII are in the range of 5 to30% of normal.

Defects in LMBRD1 are the cause of methylmalonic aciduriaand homocystinuria type cblF (MMAFHC) [MIM:277380], also known ashomocystinuria-megaloblastic anemia complementation type F. MMAFHCis a disorder of cobalamin metabolism characterized by decreasedlevels of the coenzymes adenosylcobalamin (AdoCbl) andmethylcobalamin (MeCbl). It is due to accumulation of freecobalamin in lysosomes, thus hindering its conversion tocofactors. Clinical features include developmental delay,stomatitis, glossitis, seizures and methylmalonic aciduriaresponsive to vitamin B12.

Defects in LMBR1 are associated with preaxial polydactylytype 2 (PPD2) [MIM:174500], also known as polydactyly oftriphalangeal thumb. Polydactyly consists of duplication of thedistal phalanx. The thumb in PPD2 is usually opposable andpossesses a normal metacarpal. The mutations do not change thenormal expression of LMBR1, but alter the expression of SHH bydisrupting a long-range, cis-regulatory element of that gene.

Defects in LMBR1 are the cause of acheiropody (ACHP)[MIM:200500]. Acheiropody is a very rare condition characterizedby bilateral congenital amputations of the hands and feet. Thespecific malformative phenotype consists of a complete amputationof the distal epiphysis of the humerus, amputation of the tibialdiaphysis, and aplasia of the radius, ulna, fibula, and of all thebones of the hands and feet. This syndrome of autosomal recessiveinheritance has only been observed in Brazil so far.

Defects in LMBR1 are a cause of syndactyly type 4 (SDYT4)[MIM:186200]. SDYT4 is a very rare congenital distal limbmalformation characterized by complete bilateral syndactyly(involving all digits 1 to 5). A frequent association withpolydactyly (with six metacarpals and six digits) has beenreported. Feet are affected occasionally. The condition isinherited as an autosomal dominant trait.

Defects in LMF1 are the cause of combined lipasedeficiency (CLD) [MIM:246650]. CLD is characterized by repeatedepisodes of pancreatitis, tuberous xanthomas and lipodystrophy andis caused by deficiency of both lipoprotein lipase (LPL) andhepatic triglyceride lipase (HTGL).

Defects in LMNA are the cause of Emery-Dreifuss musculardystrophy type 2 (EDMD2) [MIM:181350]. A degenerative myopathycharacterized by weakness and atrophy of muscle withoutinvolvement of the nervous system, early contractures of theelbows, Achilles tendons and spine, and cardiomyopathy associatedwith cardiac conduction defects.

Defects in LMNA are the cause of cardiomyopathy dilatedtype 1A (CMD1A) [MIM:115200]. Dilated cardiomyopathy is a disordercharacterized by ventricular dilation and impaired systolicfunction, resulting in congestive heart failure and arrhythmia.Patients are at risk of premature death.

Defects in LMNA are the cause of familial partiallipodystrophy type 2 (FPLD2) [MIM:151660], also known as familialpartial lipodystrophy Dunnigan type. A disorder characterized bythe loss of subcutaneous adipose tissue in the lower parts of thebody (limbs, buttocks, trunk). It is accompanied by anaccumulation of adipose tissue in the face and neck causing adouble chin, fat neck, or cushingoid appearance. Adipose tissuemay also accumulate in the axillae, back, labia majora, andintraabdominal region. Affected patients are insulin-resistant andmay develop glucose intolerance and diabetes mellitus after age 20years, hypertriglyceridemia, and low levels of high densitylipoprotein cholesterol.

Defects in LMNA are the cause of limb-girdle musculardystrophy type 1B (LGMD1B) [MIM:159001]. LGMD1B is an autosomaldominant degenerative myopathy with age-related atrioventricularcardiac conduction disturbances, dilated cardiomyopathy, and theabsence of early contractures. LGMD1B is characterized by slowlyprogressive skeletal muscle weakness of the hip and shouldergirdles. Muscle biopsy shows mild dystrophic changes.

Defects in LMNA are the cause of Charcot-Marie-Toothdisease type 2B1 (CMT2B1) [MIM:605588]. CMT2B1 is a form ofCharcot-Marie-Tooth disease, the most common inherited disorder ofthe peripheral nervous system. Charcot-Marie-Tooth disease isclassified in two main groups on the basis of electrophysiologicproperties and histopathology: primary peripheral demyelinatingneuropathy or CMT1, and primary peripheral axonal neuropathy orCMT2. Neuropathies of the CMT2 group are characterized by signs ofaxonal regeneration in the absence of obvious myelin alterations,normal or slightly reduced nerve conduction velocities, andprogressive distal muscle weakness and atrophy. CMT2B1 inheritanceis autosomal recessive.

Defects in LMNA are the cause of Hutchinson-Gilfordprogeria syndrome (HGPS) [MIM:176670]. HGPS is a rare geneticdisorder characterized by features reminiscent of marked prematureaging. Note=HGPS is caused by the toxic accumulation of a mutantform of lamin-A/C. This mutant protein, called progerin, acts toderegulate mitosis and DNA damage signaling, leading to prematurecell death and senescence. Progerin lacks the conservedZMPSTE24/FACE1 cleavage site and therefore remains permanentlyfarnesylated. Thus, although it can enter the nucleus andassociate with the nuclear envelope, it cannot incorporatenormally into the nuclear lamina.

Defects in LMNA are the cause of cardiomyopathy dilatedwith hypergonadotropic hypogonadism (CMDHH) [MIM:212112]. Adisorder characterized by the association of genital anomalies,hypergonadotropic hypogonadism and dilated cardiomyopathy.Patients can present other variable clinical manifestationsincluding mental retardation, skeletal anomalies, scleroderma-likeskin, graying and thinning of hair, osteoporosis. Dilatedcardiomyopathy is characterized by ventricular dilation andimpaired systolic function, resulting in congestive heart failureand arrhythmia.

Defects in LMNA are the cause of mandibuloacral dysplasiawith type A lipodystrophy (MADA) [MIM:248370]. A disordercharacterized by mandibular and clavicular hypoplasia,acroosteolysis, delayed closure of the cranial suture, progeroideappearance, partial alopecia, soft tissue calcinosis, jointcontractures, and partial lipodystrophy with loss of subcutaneousfat from the extremities. Adipose tissue in the face, neck andtrunk is normal or increased.

Defects in LMNA are a cause of lethal tight skincontracture syndrome (LTSCS) [MIM:275210], also known asrestrictive dermopathy (RD). Lethal tight skin contracturesyndrome is a rare disorder mainly characterized by intrauterinegrowth retardation, tight and rigid skin with erosions, prominentsuperficial vasculature and epidermal hyperkeratosis, facialfeatures (small mouth, small pinched nose and micrognathia),sparse/absent eyelashes and eyebrows, mineralization defects ofthe skull, thin dysplastic clavicles, pulmonary hypoplasia,multiple joint contractures and an early neonatal lethal course.Liveborn children usually die within the first week of life. Theoverall prevalence of consanguineous cases suggested an autosomalrecessive inheritance.

Defects in LMNA are the cause of heart-hand syndromeSlovenian type (HHS-Slovenian) [MIM:610140]. Heart-hand syndrome(HHS) is a clinically and genetically heterogeneous disordercharacterized by the co-occurrence of a congenital cardiac diseaseand limb malformations.

Defects in LMNA are the cause of muscular dystrophycongenital LMNA-related (CMD-LMNA) [MIM:613205]. It is a form ofcongenital muscular dystrophy. Patients present at birth, orwithin the first few months of life, with hypotonia, muscleweakness and often with joint contractures.

Defects in LMNB1 are the cause of leukodystrophydemyelinating autosomal dominant adult-onset (ADLD) [MIM:169500].ADLD is a slowly progressive and fatal demyelinatingleukodystrophy, presenting in the fourth or fifth decade of life.Clinically characterized by early autonomic abnormalities,pyramidal and cerebellar dysfunction, and symmetric demyelinationof the CNS. It differs from multiple sclerosis and otherdemyelinating disorders in that neuropathology shows preservationof oligodendroglia in the presence of subtotal demyelination andlack of astrogliosis.

Defects in LMNB2 are a cause of Barraquer-Simons syndrome(BaSiS) [MIM:608709], also known as partial acquired lipodystrophy(APL). BaSiS is a rare childhood disease characterized by loss ofsubcutaneous fat from the face and trunk. Fat deposition on thepelvic girdle and lower limbs is normal or excessive. Mostfrequently, onset between 5 and 15 years of age. Most affectedsubjects are females and some show no other abnormality, but manydevelop glomerulonephritis, diabetes mellitus, hyperlipidemia, andcomplement deficiency. Mental retardation in some cases. BaSiS isa sporadic disorder of unknown etiology.

Defects in LMX1B are the cause of nail-patella syndrome(NPS) [MIM:161200], also known as onychoosteodysplasia. NPS is adisease that cause abnormal skeletal patterning and renaldysplasia.

Defects in ALOXE3 are a cause of non-bullous congenitalichthyosiform erythroderma (NCIE) [MIM:242100]. NCIE is a non-bullous ichthyosis, a skin disorder characterized by abnormalcornification of the epidermis. Most affected individuals are bornwith a tight, shiny, translucent covering called collodionmembrane. The collodion membrane subsequently evolves intogeneralized scaling and intense redness of the skin. Clinicalfeatures are milder than in lamellar ichthyoses and demonstrate agreater variability in the intensity of erythema, size and type ofscales. In contrast to lamellar ichthyoses, scales are usuallywhite, fine and powdery, and palms and soles are severelyaffected. Patients suffer from palmoplantar keratoderma, oftenwith painful fissures, digital contractures, and loss of pulpvolume.

Defects in LOXHD1 are the cause of deafness autosomalrecessive type 77 (DFNB77) [MIM:613079]. A form of non-syndromicdeafness characterized by preserved low-frequency hearing, and atrend toward mild to moderate mid-frequency and high-frequencyhearing loss during childhood and adolescence. Hearing lossprogresses to become moderate to severe at mid and highfrequencies during adulthood.

Genetic variations in LOXL1 are a cause of susceptibilityto exfoliation syndrome (XFS) [MIM:177650], also calledexfoliation glaucoma (XFG). XFS is a disorder characterized byaccumulation of abnormal fibrillar deposits in the anteriorsegment of the eye. In addition to being a cause of glaucoma andglaucomatous optic neuropathy, exfoliation syndrome has also beenassociated with lens zonule weakness, cataract formation, andsystemic vascular complications due to deposition of exfoliationmaterial in extraocular tissues. Note=Susceptibility toexfoliation syndrome is conferred by a risk haplotype thatincludes two LOXL1 coding non-synonymous SNPs (Arg141Leu andGly153Asp) and one intronic SNP. Arg141Leu and Gly153Asp aresufficient to confer disease susceptibility in some populations.

Defects in LPAR6 are the cause of woolly hair autosomalrecessive type 1 (ARWH1) [MIM:278150]. A hair shaft disordercharacterized by fine and tightly curled hair. Compared to normalcurly hair that is observed in some populations, woolly hair growsslowly and stops growing after a few inches. Under lightmicroscopy, woolly hair shows some structural anomalies, includingtrichorrexis nodosa and tapered ends.

Defects in LPAR6 are the cause of hypotrichosis localizedautosomal recessive type 3 (LAH3) [MIM:611452]. A conditioncharacterized by the presence of less than the normal amount ofhair. Affected individuals show progressive hair loss, thinning ofscalp hair since early childhood, sparse body hair, and sparseeyebrows and eyelashes in some cases.

Defects in LCT are the cause of congenital lactasedeficiency (COLACD) [MIM:223000], also known as hereditaryalactasia or disaccharide intolerance II. Congenital lactasedeficiency is a an autosomal recessive, rare and severegastrointestinal disorder. It is characterized by watery diarrheain infants fed with breast milk or other lactose-containingformulas. An almost total lack of LCT activity is found in jejunalbiopsy material of patients with congenital lactase deficiency.Opposite to congenital lactase deficiency, adult-typehypolactasia, also known as lactose intolerance, is the mostcommon enzyme deficiency worldwide. It is caused by developmentaldown-regulation of lactase activity during childhood or earlyadulthood. The decline of lactase activity is a normalphysiological phenomenon, however, the majority of NorthernEuropeans have the ability to maintain lactase activity and digestlactose throughout life (lactase persistence). The down-regulationof lactase activity operates at the transcriptional level and itis associated with a noncoding variation in the MCM6 gene, locatedin the upstream vicinity of LCT.

Defects in LPIN1 are a cause of autosomal recessive acuterecurrent myoglobinuria (ARARM) [MIM:268200], also known as acuterecurrent rhabdomyolysis. Recurrent myoglobinuria is characterizedby recurrent attacks of rhabdomyolysis (necrosis or disintegrationof skeletal muscle) associated with muscle pain and weakness andfollowed by excretion of myoglobin in the urine. Renal failure mayoccasionally occur. Onset is usually in early childhood under theage of 5 years.

Defects in LPIN2 are the cause of Majeed syndrome(MAJEEDS) [MIM:609628]. An autosomal recessive syndromecharacterized by chronic recurrent multifocal osteomyelitis thatis of early onset with a lifelong course, congenitaldyserythropoietic anemia that presents as hypochromic, microcyticanemia during the first year of life and ranges from mild totransfusion-dependent, and transient inflammatory dermatosis,often manifesting as Sweet syndrome (neutrophilic skininfiltration).

Defects in LRPPRC are the cause of Leigh syndrome French-Canadian type (LSFC) [MIM:220111]. Leigh syndrome is a severeneurological disorder characterized by bilaterally symmetricalnecrotic lesions in subcortical brain regions that is commonlyassociated with systemic cytochrome c oxidase (COX) deficiency. Inthe Saguenay-Lac Saint Jean region of Quebec province in Canada, abiochemically distinct form of Leigh syndrome with COX deficiencyhas been described. Patients have been observed to have adevelopmental delay, hypotonia, mild facial dysmorphism, chronicwell-compensated metabolic acidosis, and high mortality due toepisodes of severe acidosis and coma. Enzyme activity was close tonormal in kidney and heart, 50% of normal in fibroblasts andskeletal muscle, and nearly absent in brain and liver. LSFCpatients show reduced (<30%) levels of LRPPRC in both fibroblastand liver mitochondria and a specifically reduced translation ofCOX subunits MT-CO1/COXI and MT-CO3 (COXIII).

Note=A chromosomal aberration involving LPP is associatedwith a subclass of benign mesenchymal tumors known as lipomas.Translocation t(3,12)(q27-q28,q13-q15) with HMGA2 is shown inlipomas.

Note=A chromosomal aberration involving LPP is associatedwith pulmonary chondroid hamartomas. Translocation t(3,12)(q27-q28,q14-q15) with HMGA2 is detected in pulmonary chondroidhamartomas.

Note=A chromosomal aberration involving LPP is associatedwith parosteal lipomas. Translocation t(3,12)(q28,q14) with HMGA2is also shown in one parosteal lipoma.

Note=A chromosomal aberration involving LPP is associatedwith acute monoblastic leukemia. Translocation t(3,11)(q28,q23)with MLL is associated with acute monoblastic leukemia.

Defects in LRAT are a cause of Leber congenital amaurosistype 14 (LCA14) [MIM:613341]. It is a severe dystrophy of theretina, typically becoming evident in the first years of life.Visual function is usually poor and often accompanied bynystagmus, sluggish or near-absent pupillary responses,photophobia, high hyperopia and keratoconus.

Defects in LRRC50 are the cause of primary ciliarydyskinesia type 13 (CILD13) [MIM:613193]. A disorder characterizedby abnormalities of motile cilia. Respiratory infections leadingto chronic inflammation and bronchiectasis are recurrent, due todefects in the respiratory cilia, reduced fertility is oftenobserved in male patients due to abnormalities of sperm tails.Half of the patients exhibit randomization of left-right bodyasymmetry and situs inversus, due to dysfunction of monocilia atthe embryonic node. Primary ciliary dyskinesia associated withsitus inversus is referred to as Kartagener syndrome. Atultrastructural level, CILD13 is characterized by a markedreduction or absence of both dynein arms from the cilia.

Defects in LRRC8A are the cause of agammaglobulinemiatype 5 (AGM5) [MIM:613506]. It is a primary immunodeficiencycharacterized by profoundly low or absent serum antibodies and lowor absent circulating B cells due to an early block of B-celldevelopment. Affected individuals develop severe infections in thefirst years of life. Note=A chromosomal aberration involving LRRC8has been found in a patient with congenital agammaglobulinemia.Translocation t(9,20)(q33.2,q12). The translocation truncates theLRRC8 gene, resulting in deletion of the eighth, ninth, and halfof the seventh LRR domains.

Defects in LRP2 are the cause of Donnai-Barrow syndrome(DBS) [MIM:222448], also known as faciooculoacousticorenalsyndrome (FOAR syndrome). DBS is a rare autosomal recessivedisorder characterized by major malformations including agenesisof the corpus callosum, congenital diaphragmatic hernia, facialdysmorphology, ocular anomalies, sensorineural hearing loss anddevelopmental delay. The FOAR syndrome was first described ascomprising facial anomalies, ocular anomalies, sensorineuralhearing loss, and proteinuria. DBS and FOAR were first describedas distinct disorders but the classic distinguishing featuresbetween the 2 disorders were presence of proteinuria and absenceof diaphragmatic hernia and corpus callosum anomalies in FOAR.Early reports noted that the 2 disorders shared many phenotypicfeatures and may be identical. Although there is variability inthe expression of some features (e.g. agenesis of the corpuscallosum and proteinuria), DBS and FOAR are now considered torepresent the same entity.

Defects in LRP5 are the cause of vitreoretinopathyexudative type 4 (EVR4) [MIM:601813]. EVR4 is a disorder of theretinal vasculature characterized by an abrupt cessation of growthof peripheral capillaries, leading to an avascular peripheralretina. This may lead to compensatory retinal neovascularization,which is thought to be induced by hypoxia from the initialavascular insult. New vessels are prone to leakage and rupturecausing exudates and bleeding, followed by scarring, retinaldetachment and blindness. Clinical features can be highlyvariable, even within the same family. Patients with mild forms ofthe disease are asymptomatic, and their only disease relatedabnormality is an arc of avascular retina in the extreme temporalperiphery. EVR4 inheritance can be autosomal dominant orrecessive.

Genetic variations in LRP5 are a cause of susceptibilityto osteoporosis (OSTEOP) [MIM:166710], also known as senileosteoporosis or postmenopausal osteoporosis. Osteoporosis ischaracterized by reduced bone mass, disruption of bonemicroarchitecture without alteration in the composition of bone.Osteoporotic bones are more at risk of fracture.

Defects in LRP5 are the cause of osteoporosis-pseudoglioma syndrome (OPPG) [MIM:259770], also known asosteogenesis imperfecta ocular form. OPPG is a recessive disordercharacterized by very low bone mass and blindness. Individualywith OPPG are prone to develop bone fractures and deformations andhave various eye abnormalities, including phthisis bulbi, retinaldetachments, falciform folds or persistent vitreal vasculature.

Defects in LRP5 are a cause of high bone mass trait (HBM)[MIM:601884]. HBM is a rare phenotype characterized byexceptionally dense bones. HBM individuals show otherwise acompletely normal skeletal structure and no other unusual clinicalfindings.

Defects in LRP5 are a cause of endosteal hyperostosisWorth type (WENHY) [MIM:144750], also known as autosomal dominantosteosclerosis. WENHY is an autosomal dominant sclerosing bonedysplasia clinically characterized by elongation of the mandible,increased gonial angle, flattened forehead, and the presence of aslowly enlarging osseous prominence of the hard palate (toruspalatinus). Serum calcium, phosphorus and alkaline phosphataselevels are normal. Radiologically, it is characterized by earlythickening of the endosteum of long bones, the skull and of themandible. With advancing age, the trabeculae of the metaphysisbecome thickened. WENHY becomes clinically and radiologicallyevident by adolescence, does not cause deformity except in theskull and mandible, and is not associated with bone pain orfracture. Affected patients have normal height, proportion,intelligence and longevity.

Defects in LRP5 are the cause of osteopetrosis autosomaldominant type 1 (OPTA1) [MIM:607634]. Osteopetrosis is a raregenetic disease characterized by abnormally dense bone, due todefective resorption of immature bone. The disorder occurs in twoforms: a severe autosomal recessive form occurring in utero,infancy, or childhood, and a benign autosomal dominant formoccurring in adolescence or adulthood. OPTA1 is characterized bygeneralized osteosclerosis most pronounced in the cranial vault.Patients are often asymptomatic, but some suffer from pain andhearing loss. It appears to be the only type of osteopetrosis notassociated with an increased fracture rate.

Defects in LRP5 are the cause of van Buchem disease type2 (VBCH2)[MIM:607636]. VBCH2 is an autosomal dominant sclerosingbone dysplasia characterized by cranial osteosclerosis, thickenedcalvaria and cortices of long bones, enlarged mandible and normalserum alkaline phosphatase levels.

Defects in LRP6 are the cause of autosomal dominantcoronary artery disease type 2 (ADCAD2) [MIM:610947].

Defects in LRP8 are a cause of myocardial infarction type1 (MCI1) [MIM:608446]. A condition defined by the irreversiblenecrosis of heart muscle secondary to prolonged ischemia.

Defects in LRRK2 are the cause of Parkinson disease type8 (PARK8) [MIM:607060]. A slowly progressive neurodegenerativedisorder characterized by bradykinesia, rigidity, resting tremor,postural instability, neuronal loss in the substantia nigra, andthe presence of neurofibrillary MAPT (tau)-positive and Lewybodies in some patients.

Defects in LHB are a cause of hypogonadism LHB-related(HGON-LHB) [MIM:152780]. Hypogonadism is characterized byinfertility and pseudohermaphroditism.

Defects in LHCGR are a cause of familial male precociouspuberty (FMPP) [MIM:176410], also known as testotoxicosis. In FMPPthe receptor is constitutively activated.

Defects in LHCGR are the cause of luteinizing hormoneresistance (LHR) [MIM:238320], also known as Leydig cellhypoplasia in males. LHR is an autosomal recessive disordercharacterized by unresponsiveness to luteinizing hormone,defective sexual development in males, and defective folliculardevelopment and ovulation, amenorrhea and infertility in females.Two forms of the disorder have been defined in males. Type 1 is asevere form characterized by complete 46,XY malepseudohermaphroditism, low testosterone and high luteinizinghormone levels, total lack of responsiveness to luteinizing andchorionic gonadotropin hormones, lack of breast development, andabsent development of secondary male sex characteristics. Type 2,a milder form, displays a broader range of phenotypic expressionranging from micropenis to severe hypospadias.

Defects in LTBP2 are the cause of primary congenitalglaucoma type 3D (GLC3D) [MIM:613086]. An autosomal recessive formof primary congenital glaucoma (PCG). PCG is characterized bymarked increase of intraocular pressure at birth or earlychildhood, large ocular globes (buphthalmos) and corneal edema. Itresults from developmental defects of the trabecular meshwork andanterior chamber angle of the eye that prevent adequate drainageof aqueous humor.

Defects in LTBP2 are the cause of microspherophakia(MCSPH) [MIM:251750]. It is a rare disease characterized bysmaller and more spherical lenses than normal bilaterally, anincreased anteroposterior thickness of the lens and highly myopiceyes. Lens dislocation or subluxation may occur, leading todefective accommodation.

Defects in LTBP3 are the cause of tooth agenesisselective type 6 (STHAG6) [MIM:613097]. A form of selective toothagenesis, a common anomaly characterized by the congenital absenceof one or more teeth. Selective tooth agenesis without associatedsystemic disorders has sometimes been divided into 2 types:oligodontia, defined as agenesis of 6 or more permanent teeth, andhypodontia, defined as agenesis of less than 6 teeth. The numberin both cases does not include absence of third molars (wisdomteeth). Some individuals affected by tooth agenesis selective type6 have short stature.

Defects in LTBP4 are the cause of Urban-Rifkin-Davissyndrome (URDS) [MIM:613177], also known as Cutis laxa with severepulmonary gastrointestinal and urinary abnormalities. URDS is asyndrome characterized by disrupted pulmonary, gastrointestinal,urinary, musculoskeletal, craniofacial and dermal development.Clinical features include cutis laxa, mild cardiovascular lesions,respiratory distress with cystic and atelectatic changes in thelungs, and diverticulosis, tortuosity and stenosis at variouslevels of the intestinal tract. Craniofacial features includemicroretrognathia, flat midface, receding forehead and widefontanelles.

Defects in LTC4S are the cause of leukotriene C4 synthasedeficiency (LTC4 synthase deficiency) [MIM:246530]. LTC4 synthasedeficiency is a fatal neurometabolic developmental disorder. It isassociated with muscular hypotonia, psychomotor retardation,failure to thrive, and microcephaly.

Defects in LAMTOR2 are the cause of immunodeficiency dueto defect in MAPBP-interacting protein (ID-MAPBPIP) [MIM:610798].This form of primary immunodeficiency syndrome includes congenitalneutropenia, partial albinism, short stature and B-cell andcytotoxic T-cell deficiency.

Defects in ALOX12B are a cause of non-bullous congenitalichthyosiform erythroderma (NCIE) [MIM:242100]. NCIE is a non-bullous ichthyosis, a skin disorder characterized by abnormalcornification of the epidermis. Most affected individuals are bornwith a tight, shiny, translucent covering called collodionmembrane. The collodion membrane subsequently evolves intogeneralized scaling and intense redness of the skin. Clinicalfeatures are milder than in lamellar ichthyoses and demonstrate agreater variability in the intensity of erythema, size and type ofscales. In contrast to lamellar ichthyoses, scales are usuallywhite, fine and powdery, and palms and soles are severelyaffected. Patients suffer from palmoplantar keratoderma, oftenwith painful fissures, digital contractures, and loss of pulpvolume.

Defects in GAA are the cause of glycogen storage diseasetype 2 (GSD2) [MIM:232300], also called acid alpha-glucosidase(GAA) deficiency or acid maltase deficiency (AMD). GSD2 is ametabolic disorder with a broad clinical spectrum. The severeinfantile form, or Pompe disease, presents at birth with massiveaccumulation of glycogen in muscle, heart and liver.Cardiomyopathy and muscular hypotonia are the cardinal features ofthis form whose life expectancy is less than two years. Thejuvenile and adult forms present as limb-girdle muscular dystrophybeginning in the lower limbs. Final outcome depends on respiratorymuscle failure. Patients with the adult form can be free ofclinical symptoms for most of their life but finally develop aslowly progressive myopathy.

Defects in SELP may be a cause of susceptibility toischemic stroke (ISCHSTR) [MIM:601367], also known ascerebrovascular accident or cerebral infarction. A stroke is anacute neurologic event leading to death of neural tissue of thebrain and resulting in loss of motor, sensory and/or cognitivefunction. Ischemic strokes, resulting from vascular occlusion, isconsidered to be a highly complex disease consisting of a group ofheterogeneous disorders with multiple genetic and environmentalrisk factors.

Note=A chromosomal aberration involving LYL1 may be acause of a form of T-cell acute lymphoblastic leukemia (T-ALL).Translocation t(7,19)(q35,p13) with TCRB.

Defects in LOX may be a cause of cutis laxa autosomalrecessive type 1 (ARCL1) [MIM:219100].

Defects in LYZ are a cause of amyloidosis type 8 (AMYL8)[MIM:105200], also known as systemic non-neuropathic amyloidosisor Ostertag-type amyloidosis. AMYL8 is a hereditary generalizedamyloidosis due to deposition of apolipoprotein A1, fibrinogen andlysozyme amyloids. Viscera are particularly affected. There is noinvolvement of the nervous system. Clinical features include renalamyloidosis resulting in nephrotic syndrome, arterialhypertension, hepatosplenomegaly, cholestasis, petechial skinrash.

Defects in LYST are the cause of Chediak-Higashi syndrome(CHS) [MIM:214500]. CHS is a rare autosomal recessive disordercharacterized by hypopigmentation, severe immunologic deficiency,a bleeding tendency, neurologic abnormalities, abnormalintracellular transport to and from the lysosome, and giantinclusion bodies in a variety of cell types. Most patients die atan early age unless they receive an allogeneic hematopoietic stemcell transplant (SCT).

Defects in DMGDH are the cause of DMGDH deficiency(DMGDHD) [MIM:605850]. DMGDHD is a disorder characterized by fishodor, muscle fatigue with increased serum creatine kinase.Biochemically it is characterized by an increase of N,N-dimethylglycine (DMG) in serum and urine.

Defects in MAN2B1 are the cause of lysosomal alpha-mannosidosis (AM) [MIM:248500]. AM is a lysosomal storage diseasecharacterized by accumulation of unbranched oligosaccharidechains. This accumulation is expressed histologically ascytoplasmic vacuolation predominantly in the CNS andparenchymatous organs. Depending on the clinical findings at theage of onset, a severe infantile (type I) and a mild juvenile(type II) form of alpha-mannosidosis are recognized. There isconsiderable variation in the clinical expression with mentalretardation, recurrent infections, impaired hearing and Hurler-like skeletal changes being the most consistent abnormalities.

Note=A chromosomal aberration involving MACROD1 is foundin acute leukemia. Translocation t(11,21)(q13,q22) that forms aRUNX1-MACROD1 fusion protein.

Note=A chromosomal aberration involving MAF is found insome forms of multiple myeloma (MM). Translocationt(14,16)(q32.3,q23) with an IgH locus.

Defects in MAF are the cause of cataract pulverulentjuvenile-onset MAF-related (CAPJOM) [MIM:610202]. A form ofcataract with nuclear or cortical pulverulent opacities.Pulverulent cataracts are characterized by a dust-like,'pulverised' appearance of the opacities which can be found in anypart of the lens. The phenotype shows significant intra- andinterfamilial variation, both in the distribution of the cataractand the degree of opacification. Some patients with cataractpulverulent juvenile-onset can present microcornea and bilateraliris colobomas in addition to cataract.

Defects in MAF are the cause of cataract congenitalcerulean type 4 (CCA4) [MIM:610202]. A cerulean form of congenitalcataract. Cerulean cataracts are characterized by peripheralbluish and white opacifications organized in concentric layerswith occasional central lesions arranged radially. The opacitiesare observed in the superficial layers of the fetal nucleus aswell as the adult nucleus of the lens. Involvement is usuallybilateral. Visual acuity is only mildly reduced in childhood. Inadulthood, the opacifications may progress, making lens extractionnecessary. Histologically the lesions are described as fusiformcavities between lens fibers which contain a deeply staininggranular material. Although the lesions may take on variouscolors, a dull blue is the most common appearance and isresponsible for the designation cerulean cataract.

Defects in MAGEL2 may be a cause of the Prader-Willisyndrome (PWS) which is a contiguous gene syndrome resulting frominactivity of the paternal copies of a number of genes on 15q11,through deletion or disruption of these genes or maternaluniparental disomy 15. The PWS syndrome is characterized bymuscular hypotonia, mental retardation, short stature, obesity,hypogonadotropic hypogonadism, and small hands and feet.

Defects in MAGT1 are the cause of mental retardation X-linked type 95 (MRX95) [MIM:300716]. Mental retardation ischaracterized by significantly sub-average general intellectualfunctioning associated with impairments in adaptative behavior andmanifested during the developmental period. In contrast tosyndromic or specific X-linked mental retardation which alsopresent with associated physical, neurological and/or psychiatricmanifestations, intellectual deficiency is the only primarysymptom of non-syndromic X-linked mental retardation.

Defects in MARVELD2 are the cause of deafness autosomalrecessive type 49 (DFNB49) [MIM:610153]. DFNB49 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Note=A chromosomal aberration involving MALT1 isrecurrent in low-grade mucosa-associated lymphoid tissue (MALTlymphoma). Translocation t(11,18)(q21,q21) with BIRC2. Thistranslocation is found in approximately 50% of cytogeneticallyabnormal low-grade MALT lymphoma.

Defects in MAMLD1 are a cause of X-linked hypospadiastype 2 (HYSP2) [MIM:300758]. Hypospadias is a common malformationin which the urethra opens on the ventral side of the penis. It isconsidered a complex disorder with both genetic and environmentalfactors involved in the pathogenesis. Hypospadias can occur aloneon an apparently multifactorial basis or as part of syndromes.

Note=A chromosomal aberration involving MAML2 is found inmucoepidermoid carcinomas, benign Warthin tumors and clear cellhidradenomas. Translocation t(11,19)(q21,p13) with CRTC1/MECT1.The fusion protein consists of the N-terminus of CRTC1 joined tothe C-terminus of MAML2. The reciprocal fusion protein consistingof the N-terminus of MAML2 joined to the C-terminus of CRTC1 hasbeen detected in a small number of mucoepidermoid carcinomas.

Defects in LEMD3 are the cause of Buschke-Ollendorffsyndrome (BOS) [MIM:166700], also known as dermatoosteopoikilosisor disseminated dermatofibrosis with osteopoikilosis ordermatofibrosis lenticularis disseminata with osteopoikilosis orosteopathia condensans disseminata. BOS refers to the associationof osteopoikilosis with disseminated connective-tissue nevi.Osteopoikilosis is a skeletal dysplasia characterized by asymmetric but unequal distribution of multiple hyperostotic areasin different parts of the skeleton. Both elastic-type nevi(juvenile elastoma) and collagen-type nevi (dermatofibrosislenticularis disseminata) have been described in BOS. Skin or bonylesions can be absent in some family members, whereas otherrelatives may have both.

Defects in LEMD3 are a cause of melorheostosis (MEL)[MIM:155950]. Melorheostosis is a rare mesenchymal dysplasia andone of the sclerosing bone disorders. It is caused by adevelopmental error, with a sclerotomal distribution, frequentlyinvolving one limb. It may be asymptomatic, but pain, stiffnesswith limitation of motion, leg-length discrepancy and limbdeformity may occur.

Note=Defects in MANBA are the cause of a mild disorderthat affects peripheral and central nervous system myelin.

Defects in MANBA are the cause of lysosomal beta-mannosidosis (LYSBMAN) [MIM:248510]. Beta-mannosidosis is anautosomal recessive lysosomal storage disease of glycoproteincatabolism. Clinical features are heterogeneous with a wide rangeof symptoms and age of onset. The disease is associated with arange of neurological involvement, including various degrees ofmental retardation in most of the cases, hearing loss and speechimpairment, hypotonia, epilepsy and peripheral neuropathy.Affected individuals have a profound reduction in beta-mannosidaseactivity in plasma, fibroblasts and leukocytes.

Note=MASP2 deficiency is associated with susceptibilityto infections and with the development of immunologic disease.

Note=The MAS oncogene has a weak focus-inducing activityin transfected NIH 3T3 cells.

Defects in MATN3 are the cause of multiple epiphysealdysplasia type 5 (EDM5) [MIM:607078]. EDM is a generalizedskeletal dysplasia associated with significant morbidity. Jointpain, joint deformity, waddling gait, and short stature are themain clinical signs and symptoms. EDM is broadly categorized intothe more severe Fairbank and the milder Ribbing types. EDM5 isrelatively mild and clinically variable. It is primarilycharacterized by delayed and irregular ossification of theepiphyses and early-onset osteoarthritis.

Defects in MATN3 are the cause of spondyloepimetaphysealdysplasia MATN3-related (SEMD-MATN3) [MIM:608728]. A bone diseasecharacterized by disproportionate early-onset dwarfism, bowing ofthe lower limbs, lumbar lordosis and normal hands. Skeletalabnormalities include short, wide and stocky long bones withsevere epiphyseal and metaphyseal changes, hypoplastic iliac bonesand flat, ovoid vertebral bodies.

Genetic variations in MATN3 are associated withsusceptibility to osteoarthritis type 2 (OS2) [MIM:140600], alsocalled osteoarthritis of distal interphalangeal joints (OADIP) orhand osteoarthritis (HOA). Osteoarthritis is a degenerativedisease of the joints characterized by degradation of the hyalinearticular cartilage and remodeling of the subchondral bone withsclerosis. Clinical symptoms include pain and joint stiffnessoften leading to significant disability and joint replacement. Inthe hand, osteoarthritis can develop in the distal interphalangealand the first carpometacarpal (base of thumb) and proximalinterphalangeal joints. Patients with osteoarthritis may have one,a few, or all of these sites affected.

Defects in MATR3 are the cause of myopathy distal type 2(MPD2) [MIM:606070], also called vocal cord and pharyngealdysfunction with distal myopathy (VCPDM). MPD2 is a musculardisorder characterized by distal weakness, with onset in hands andfeet, associated with vocal cord and pharyngeal weakness causing anasal voice and swallowing disorders.

Defects in MBD5 are the cause of mental retardationautosomal dominant type 1 (MRD1) [MIM:156200]. Mental retardationis characterized by significantly sub-average general intellectualfunctioning associated with impairments in adaptative behavior andmanifested during the developmental period.

Note=There is an association between low levels of MBL2and a defect of opsonization which results in susceptibility tofrequent and chronic infections.

Plays a role in the pathogenesis of dystrophia myotonicatype 1 (DM1) [MIM:160900]. A muscular disorder characterized bymyotonia, muscle wasting in the distal extremities, cataract,hypogonadism, defective endocrine functions, male baldness andcardiac arrhythmias. Note=In muscle cells from DM1 patients, MBNL1is sequestered by DMPK RNAs containing CUG triplet repeatexpansions. MBNL1 binding is proportional to repeat lengthconsistent with the direct correlation between the length ofrepeat expansion and disease severity.

Note=The reduction in the surface charge of citrullinatedand/or methylated MBP could result in a weakened attachment to themyelin membrane. This mechanism could be operative indemyelinating diseases such as chronical multiple sclerosis (MS),and fulminating MS (Marburg disease).

Defects in MBTPS2 are the cause of ichthyosisfollicularis-atrichia-photophobia syndrome (IFAPS) [MIM:308205]. Asyndrome characterized by a peculiar triad of follicularichthyosis, total or subtotal atrichia, and photophobia of varyingdegree. Histopathologically, the epidermal granular layer isgenerally well-preserved or thickened at the infundibulum. Hairfollicles are poorly developed and tend to be surrounded by aninflammatory infiltrate. A subgroup of patients is described withlamellar rather than follicular ichthyosis. Non-consistentfeatures may include growth and psychomotor retardation,aganglionic megacolon, seizures and nail dystrophy.

Defects in MBTPS2 are a cause of keratosis follicularisspinulosa decalvans X-linked (KFSDX) [MIM:308800]. A rare disorderaffecting the skin and the eye. Affected men show thickening ofthe skin of the neck, ears, and extremities, especially the palmsand soles, loss of eyebrows, eyelashes and beard, thickening ofthe eyelids with blepharitis and ectropion, and cornealdegeneration.

Defects in MC4R are a cause of obesity (OBESITY)[MIM:601665]. It is a condition characterized by an increase ofbody weight beyond the limitation of skeletal and physicalrequirements, as the result of excessive accumulation of body fat.

Defects in SLC25A20 are the cause of carnitine-acylcarnitine translocase deficiency (CACT deficiency)[MIM:212138]. It is an autosomal recessive deficiency inmitochondrial oxidation of fatty acids. It is usually lethalwithin a few hours or days after birth. Symptoms characterizingits normally severe clinical phenotype include fatty hepatomegalywith abnormal liver function, cardiomyopathy, muscle weakness andepisodes of life-threatening coma, which eventually lead to death.

Defects in MCCC1 are the cause of methylcrotonoyl-CoAcarboxylase deficiency type 1 (MCC1 deficiency) [MIM:210200]. MCC1deficiency is an autosomal recessive disorder of leucinecatabolism. The phenotype is variable, ranging from neonatal onsetwith severe neurological involvement to asymptomatic adults. Thereis a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, usually incombination with a severe secondary carnitine deficiency.

Defects in MCCC2 are the cause of methylcrotonoyl-CoAcarboxylase deficiency type 2 (MCC2 deficiency) [MIM:210210]. MCC2deficiency is an autosomal recessive disorder of leucinecatabolism. The phenotype is variable, ranging from neonatal onsetwith severe neurological involvement to asymptomatic adults. Thereis a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, usually incombination with a severe secondary carnitine deficiency.

Defects in MCEE are a cause of methylmalonyl-CoAepimerase deficiency (MCEE deficiency) [MIM:251120], also known asmethylmalonyl-CoA racemase deficiency or methylmalonic aciduriatype 3. MCEE deficiency is an autosomal recessive inborn error ofamino acid metabolism, involving valine, threonine, isoleucine andmethionine. This organic aciduria may present in the neonatalperiod with life-threatening metabolic acidosis, hyperammonemia,feeding difficulties, pancytopenia and coma.

Note=MCF2 and DBL represent two activated versions of thesame proto-oncogene.

Defects in MCFD2 are a cause of factor V and factor VIIIcombined deficiency type 2 (F5F8D2) [MIM:613625], also known asmultiple coagulation factor deficiency 2 (MCFD2). F5F8D2 is ablood coagulation disorder characterized by bleeding symptomssimilar to those in hemophilia or parahemophilia, that are causedby single deficiency of FV or FVIII, respectively. The most commonsymptoms are epistaxis, menorrhagia, and excessive bleeding duringor after trauma. Plasma levels of coagulation factors V and VIIIare in the range of 5 to 30% of normal.

Defects in MCOLN1 are the cause of mucolipidosis type IV(MLIV) [MIM:252650], also known as sialolipidosis. MLIV is anautosomal recessive lysosomal storage disorder characterized bysevere psychomotor retardation and ophthalmologic abnormalities,including corneal opacity, retinal degeneration and strabismus.Storage bodies of lipids and water-soluble substances are seen byelectron microscopy in almost every cell type of the patients.Most patients are unable to speak or walk independently and reacha maximal developmental level of 1-2 years. All patients haveconstitutive achlorhydia associated with a secondary elevation ofserum gastrin levels. MLIV may be due to a defect in sortingand/or transport along the late endocytic pathway. MLIV is foundat relatively high frequency among Ashkenazi Jews.

Defects in MCPH1 are the cause of microcephaly primarytype 1 (MCPH1) [MIM:251200], also known as true microcephaly ormicrocephaly vera. Microcephaly is defined as a head circumferencemore than 3 standard deviations below the age-related mean. Brainweight is markedly reduced and the cerebral cortex isdisproportionately small. Despite this marked reduction in size,the gyral pattern is relatively well preserved, with no majorabnormality in cortical architecture. Primary microcephaly isfurther defined by the absence of other syndromic features orsignificant neurological deficits. This entity is inherited asautosomal recessive trait.

Defects in CD46 are a cause of susceptibility tohemolytic uremic syndrome atypical type 2 (AHUS2) [MIM:612922]. Anatypical form of hemolytic uremic syndrome. It is a complexgenetic disease characterized by microangiopathic hemolyticanemia, thrombocytopenia, renal failure and absence of episodes ofenterocolitis and diarrhea. In contrast to typical hemolyticuremic syndrome, atypical forms have a poorer prognosis, withhigher death rates and frequent progression to end-stage renaldisease. Note=Susceptibility to the development of atypicalhemolytic uremic syndrome can be conferred by mutations in variouscomponents of or regulatory factors in the complement cascadesystem. Other genes may play a role in modifying the phenotype.Patients with CD46 mutations seem to have an overall betterprognosis compared to patients carrying CFH mutations.

Defects in NR3C2 are a cause of autosomal dominantpseudohypoaldosteronism type I (AD-PHA1) [MIM:177735]. PHA1 ischaracterized by urinary salt wasting, resulting from target organunresponsiveness to mineralocorticoids. There are 2 forms of PHA1:the autosomal dominant form that is mild, and the recessive formwhich is more severe and due to defects in any of the epithelialsodium channel subunits. In AD-PHA1 the target organ defect isconfined to kidney. Clinical expression can vary from asymptomaticto moderate. It may be severe at birth, but symptoms remit withage. Familial and sporadic cases have been reported.

Defects in NR3C2 are a cause of early-onset hypertensionwith severe exacerbation in pregnancy (EOHSEP) [MIM:605115].Inheritance is autosomal dominant. The disease is characterized bythe onset of severe hypertension before the age of 20, and bysuppression of aldosterone secretion.

Defects in MED13L are a cause of transposition of thegreat arteries, dextro-looped (DTGA) [MIM:608808]. DTGA consistsof complete inversion of the great vessels, so that the aortaincorrectly arises from the right ventricle and the pulmonaryartery incorrectly arises from the left ventricle. This createscompletely separate pulmonary and systemic circulatory systems, anarrangement that is incompatible with life. Patients often haveatrial and/or ventricular septal defects or other types ofshunting that allow some mixing between the circulations in orderto support life minimally, but surgical intervention is alwaysrequired.

Note=A chromosomal aberration involving MED13L is foundin a patient with transposition of the great arteries, dextro-looped and mental retardation. Translocation t(12,17)(q24.1,q21).

Note=Defects in MAD1L1 are involved in the developmentand/or progression of various types of cancer.

Note=Seems to be amplified in certain tumors (includingsoft tissue sarcomas, osteosarcomas and gliomas). A higherfrequency of splice variants lacking p53 binding domain sequenceswas found in late-stage and high-grade ovarian and bladdercarcinomas. Four of the splice variants show loss of p53 binding.

Genetic variations in ABCB1 are associated withsusceptibility to inflammatory bowel disease type 13 (IBD13)[MIM:612244]. Inflammatory bowel disease is characterized by achronic relapsing intestinal inflammation. It is subdivided intoCrohn disease and ulcerative colitis phenotypes. Crohn disease mayinvolve any part of the gastrointestinal tract, but mostfrequently the terminal ileum and colon. Bowel inflammation istransmural and discontinuous, it may contain granulomas or beassociated with intestinal or perianal fistulas. In contrast, inulcerative colitis, the inflammation is continuous and limited torectal and colonic mucosal layers, fistulas and granulomas are notobserved. Both diseases include extraintestinal inflammation ofthe skin, eyes, or joints. Crohn disease and ulcerative colitisare commonly classified as autoimmune diseases.

Defects in ABCB4 are the cause of progressive familialintrahepatic cholestasis type 3 (PFIC3) [MIM:602347]. PFIC3 is anautosomal recessive liver disorder presenting with early onsetcholestasis that progresses to cirrhosis and liver failure beforeadulthood. It is characterized by elevated serum gamma-glutamyltransferase levels.

Defects in ABCB4 are a cause of intrahepatic cholestasisof pregnancy (ICP) [MIM:147480], also known as obstetriccholestasis. ICP is a multifactorial liver disorder of pregnancy.It presents during the second or, more commonly, the thirdtrimestre of pregnancy with intense pruritus which becomes moresevere with advancing gestation and cholestasis. Cholestasisresults from abnormal biliary transport from the liver into thesmall intestine. ICP causes fetal distress, spontaneous prematuredelivery and intrauterine death. ICP patients have spontaneous andprogressive disappearance of cholestasis after delivery.

Defects in ABCB4 are a cause of gallbladder disease type1 (GBD1) [MIM:600803]. It is one of the major digestive diseases.Gallstones composed of cholesterol (cholelithiasis) are the commonmanifestations in western countries. Most people with gallstones,however, remain asymptomatic through their lifetimes.

Note=A chromosomal aberration involving MDS1 is found ina form of acute myeloid leukemia (AML). Translocation t(3,21) withAML1.

Note=A chromosomal aberration involving MDS2 is a causeof myelodysplastic syndrome (MDS). Translocationt(1,12)(p36.1,p13) with ETV6.

Defects in MECP2 may be a cause of Angelman syndrome (AS)[MIM:105830], also known as happy puppet syndrome. AS is aneurodevelopmental disorder characterized by severe mentalretardation, absent speech, ataxia, sociable affect and dysmorphicfacial features. AS and Rett syndrome have overlapping clinicalfeatures.

Defects in MECP2 are the cause of mental retardationsyndromic X-linked type 13 (MRXS13) [MIM:300055]. Mentalretardation is a mental disorder characterized by significantlysub-average general intellectual functioning associated withimpairments in adaptative behavior and manifested during thedevelopmental period. MRXS13 patients manifest mental retardationassociated with other variable features such as spasticity,episodes of manic depressive psychosis, increased tone andmacroorchidism.

Defects in MECP2 are the cause of Rett syndrome (RTT)[MIM:312750]. RTT is an X-linked dominant disease, it is aprogressive neurologic developmental disorder and one of the mostcommon causes of mental retardation in females. Patients appear todevelop normally until 6 to 18 months of age, then gradually losespeech and purposeful hand movements and develop microcephaly,seizures, autism, ataxia, intermittent hyperventilation, andstereotypic hand movements. After initial regression, thecondition stabilizes and patients usually survive into adulthood.

Defects in MECP2 may be the cause of susceptibilityautism X-linked type 3 (AUTSX3) [MIM:300496]. AUTSX3 is apervasive developmental disorder (PDD), prototypicallycharacterized by impairments in reciprocal social interaction andcommunication, restricted and stereotyped patterns of interestsand activities, and the presence of developmental abnormalities by3 years of age.

Defects in MECP2 are the cause of encephalopathy neonatalsevere due to MECP2 mutations (ENS-MECP2) [MIM:300673]. Note=TheMECP2 gene is mutated in Rett syndrome, a severeneurodevelopmental disorder that almost always occurs in females.Although it was first thought that MECP2 mutations causing Rettsyndrome were lethal in males, later reports identified a severeneonatal encephalopathy in surviving male sibs of patients withRett syndrome. Additional reports have confirmed a severephenotype in males with Rett syndrome-associated MECP2 mutations.

Defects in MECP2 are the cause of mental retardationsyndromic X-linked Lubs type (MRXSL) [MIM:300260]. Mentalretardation is characterized by significantly below averagegeneral intellectual functioning associated with impairments inadaptative behavior and manifested during the developmentalperiod. MRXSL patients manifest mental retardation associated withvariable features. They include swallowing dysfunction andgastroesophageal reflux with secondary recurrent respiratoryinfections, hypotonia, mild myopathy and characteristic faciessuch as downslanting palpebral fissures, hypertelorism and a shortnose with a low nasal bridge. Note=Increased dosage of MECP2 dueto gene duplication appears to be responsible for the mentalretardation phenotype.

Defects in MED12 are the cause of Opitz-Kaveggia syndrome(OKS) [MIM:305450], also known as FG syndrome type 1 (FGS1) or FGsyndrome (FGS). OKS is an X-linked disorder characterized bymental retardation, relative macrocephaly, hypotonia andconstipation.

Defects in MED12 are the cause of Lujan-Fryns syndrome(LUJFRYS) [MIM:309520], also known as X-linked mental retardationwith marfanoid habitus. Clinically, Lujan-Fryns syndrome can bedistinguished from Opitz-Kaveggia syndrome by tall stature,hypernasal voice, hyperextensible digits and high nasal root.

Defects in MED17 are the cause of microcephaly postnatalprogressive with seizures and brain atrophy (MCPHSBA)[MIM:613668]. It is a disorder characterized by postnatalprogressive microcephaly and severe developmental retardationassociated with cerebral and cerebellar atrophy. Infants manifestswallowing difficulties leading to failure to thrive, jitteriness,poor visual fixation, truncal arching, seizures. There is noacquisition of developmental milestones and patients suffer frommarked spasticity and profound retardation. Progressivemicrocephaly becomes evident few months after birth.

Defects in MED25 are the cause of Charcot-Marie-Toothdisease type 2B2 (CMT2B2) [MIM:605589]. It is a recessive axonalform of Charcot-Marie-Tooth disease, a disorder of the peripheralnervous system, characterized by progressive weakness and atrophy,initially of the peroneal muscles and later of the distal musclesof the arms. Charcot-Marie-Tooth disease is classified in two maingroups on the basis of electrophysiologic properties andhistopathology: primary peripheral demyelinatingneuropathies(designated CMT1 when they are dominantly inherited)and primary peripheral axonal neuropathies (CMT2). Neuropathies ofthe CMT2 group are characterized by signs of axonal regenerationin the absence of obvious myelin alterations, normal or slightlyreduced nerve conduction velocities, and progressive distal muscleweakness and atrophy. Nerve conduction velocities are normal orslightly reduced.

Defects in MEF2A might be a cause of autosomal dominantcoronary artery disease 1 with myocardial infarction (ADCAD1)[MIM:608320].

Defects in MEF2C are the cause of mental retardation-stereotypic movements-epilepsy and/or cerebral malformations(MRSME) [MIM:613443]. It is a disorder characterized by severemental retardation, absent speech, hypotonia, poor eye contact andstereotypic movements. Dysmorphic features include high broadforehead with variable small chin, short nose with antevertednares, large open mouth, upslanted palpebral fissures andprominent eyebrows. Some patients have seizures.

Defects in MEFV are the cause of familial Mediterraneanfever autosomal recessive (ARFMF) [MIM:249100]. ARFMF is aninherited disorder characterized by recurrent episodic fever,serosal inflammation and pain in the abdomen, chest or joints.ARFMF is frequently complicated by amyloidosis, which leads torenal failure and can be prophylactically treated with colchicine.ARFMF primarily affects ancestral ethnic groups living around theMediterranean basin: North African Jews, Armenians, Arabs andTurks. The disease is also distributed in other populationsincluding Greeks, Cypriots, Italians and Spanish, although at alower prevalence.

Defects in MEFV are the cause of familial Mediterraneanfever autosomal dominant (ADFMF) [MIM:134610]. ADFMF ischaracterized by periodic fever, serosal inflammation and pain inthe abdomen, chest or joints as seen also in the autosomalrecessive form of the disease. It is associated with renalamyloidosis and characterized by colchicine unresponsiveness.

Defects in MEIS1 could be a cause of susceptibility torestless legs syndrome type 7 (RLS7) [MIM:612853]. Restless legssyndrome (RLS) is a neurologic sleep/wake disorder characterizedby uncomfortable and unpleasant sensations in the legs that appearat rest, usually at night, inducing an irresistible desire to movethe legs. The disorder results in nocturnal insomnia and chronicsleep deprivation.

Defects in MLPH are a cause of Griscelli syndrome type 3(GS3) [MIM:609227]. GS3 is a rare autosomal recessive disordercharacterized by pigmentary dilution of the skin and hair, thepresence of large clumps of pigment in hair shafts, and anaccumulation of melanosomes in melanocytes, without other clinicalmanifestations.

Defects in MEN1 are the cause of familial multipleendocrine neoplasia type I (MEN1) [MIM:131100]. Autosomal dominantdisorder characterized by tumors of the parathyroid glands,gastro-intestinal endocrine tissue, the anterior pituitary andother tissues. Cutaneous lesions and nervous-tissue tumors canexist. Prognosis in MEN1 patients is related to hormonalhypersecretion by tumors, such as hypergastrinemia causing severepeptic ulcer disease (Zollinger-Ellison syndrome, ZES), primaryhyperparathyroidism, and acute forms of hyperinsulinemia.

Defects in MEN1 are the cause of familial isolatedhyperparathyroidism (FIHP) [MIM:145000], also known ashyperparathyroidism type 1 (HRPT1). FIHP is an autosomal dominantdisorder characterized by hypercalcemia, elevated parathyroidhormone (PTH) levels, and uniglandular or multiglandularparathyroid tumors.

Defects in NF2 are the cause of neurofibromatosis 2 (NF2)[MIM:101000], also known as central neurofibromatosis. NF2 is agenetic disorder characterized by bilateral vestibular schwannomas(formerly called acoustic neuromas), schwannomas of other cranialand peripheral nerves, meningiomas, and ependymomas. It isinherited in an autosomal dominant fashion with full penetrance.Affected individuals generally develop symptoms of eighth-nervedysfunction in early adulthood, including deafness and balancedisorder. Although the tumors of NF2 are histologically benign,their anatomic location makes management difficult, and patientssuffer great morbidity and mortality.

Defects in NF2 are a cause of schwannomatosis (SCHWA)[MIM:162091], also known as congenital cutaneousneurilemmomatosis. Schwannomas are benign tumors of the peripheralnerve sheath that usually occur singly in otherwise normalindividuals. Multiple schwannomas in the same individual suggestan underlying tumor-predisposition syndrome. The most common suchsyndrome is NF2. The hallmark of NF2 is the development ofbilateral vestibular-nerve schwannomas, but two-thirds or more ofall NF2-affected individuals develop schwannomas in otherlocations, and dermal schwannomas may precede vestibular tumors inNF2-affected children. There have been several reports ofindividuals with multiple schwannomas who do not show evidence ofvestibular schwannoma. Clinical report suggests thatschwannomatosis is a clinical entity distinct from other forms ofneurofibromatosis.

Defects in MERTK are a cause of retinitis pigmentosa (RP)[MIM:268000]. RP that leads to degeneration of retinalphotoreceptor cells. Patients typically have night visionblindness and loss of midperipheral visual field. As theircondition progresses, they lose their far peripheral visual fieldand eventually central vision as well.

Defects in MESP2 are the cause of spondylocostaldysostosis type 2 (SCDO2) [MIM:608681]. An autosomal recessivecondition of variable severity associated with vertebral and ribsegmentation defects. The main skeletal malformations includefusion of vertebrae, hemivertebrae, fusion of certain ribs, andother rib malformations. Deformity of the chest and spine (severescoliosis, kyphoscoliosis and lordosis) is a natural consequenceof the malformation and leads to a dwarf-like appearance. As thethorax is small, infants frequently have respiratory insufficiencyand repeated respiratory infections resulting in life-threateningcomplications in the first year of life.

Defects in MTR are the cause of methylcobalamindeficiency type G (cblG) [MIM:250940], also known ashomocystinuria-megaloblastic anemia complementation type G. It isan autosomal recessive inherited disease that causes mentalretardation, macrocytic anemia, and homocystinuria. Milddeficiency in MS activity could be associated with mildhyperhomocysteinemia, a risk factor for cardiovascular disease andpossibly neural tube defects. MS mutations could also be involvedin tumorigenesis.

Defects in MTR may be a cause of susceptibility tofolate-sensitive neural tube defects (folate-sensitive NTD)[MIM:601634]. The most common NTDs are open spina bifida(myelomeningocele) and anencephaly. Genetic defects in MTR mayaffect the risk of spina bifida via the maternal rather than theembryonic genotype.

Defects in MAT1A are the cause of methionineadenosyltransferase deficiency (MATD) [MIM:250850], also calledMAT I/III deficiency. MATD is an inborn error of metabolismresulting in isolated hypermethioninemia. Most patients have noclinical abnormalities, although some neurologic symptoms may bepresent in rare cases with severe loss of methionineadenosyltransferase activity.

Note=Activation of MET after rearrangement with the TPRgene produces an oncogenic protein.

Note=Defects in MET may be associated with gastriccancer.

Defects in MET are a cause of hepatocellular carcinoma(HCC) [MIM:114550].

Defects in MET are a cause of renal cell carcinomapapillary (RCCP) [MIM:605074]. It is a subtype of renal cellcarcinoma tending to show a tubulo-papillary architecture formedby numerous, irregular, finger-like projections of connectivetissue. Renal cell carcinoma is a heterogeneous group of sporadicor hereditary carcinoma derived from cells of the proximal renaltubular epithelium. It is subclassified into common renal cellcarcinoma (clear cell, non-papillary carcinoma), papillary renalcell carcinoma, chromophobe renal cell carcinoma, collecting ductcarcinoma with medullary carcinoma of the kidney, and unclassifiedrenal cell carcinoma.

Note=A common allele in the promoter region of the METshows genetic association with susceptibility to autism in somefamilies. Functional assays indicate a decrease in MET promoteractivity and altered binding of specific transcription factorcomplexes.

Note=MET activating mutations may be involved in thedevelopment of a highly malignant, metastatic syndrome known ascancer of unknown primary origin (CUP) or primary occultmalignancy. Systemic neoplastic spread is generally a late eventin cancer progression. However, in some instances, distantdissemination arises at a very early stage, so that metastasesreach clinical relevance before primary lesions. Sometimes, theprimary lesions cannot be identified in spite of the progresses inthe diagnosis of malignancies.

Note=Genetic variations in MEX3C may be associated withsusceptibility to essential hypertension.

Genetic variation in MCF2L2 may be associated withsusceptibility to noninsulin-dependent diabetes mellitus (NIDDM)[MIM:125853], also known as diabetes mellitus type 2.

MFAP4 is deleted in the Smith-Magenis syndrome (SMS)[MIM:182290].

Note=A chromosomal aberration involving MFHAS1 may be acause of B-cell lymphoma. Translocation t(8,14)(p23.1,q21) with acryptic exon named '14q21 element'. The resulting fusion proteinnamed 'chimeric MASL1' is tumorigenic in nude mice.

Defects in MFN2 are the cause of Charcot-Marie-Toothdisease type 2A2 (CMT2A2) [MIM:609260]. CMT2A2 is a form ofCharcot-Marie-Tooth disease, the most common inherited disorder ofthe peripheral nervous system. Charcot-Marie-Tooth disease isclassified in two main groups on the basis of electrophysiologicproperties and histopathology: primary peripheral demyelinatingneuropathy or CMT1, and primary peripheral axonal neuropathy orCMT2. Neuropathies of the CMT2 group are characterized by signs ofaxonal regeneration in the absence of obvious myelin alterations,normal or slightly reduced nerve conduction velocities, andprogressive distal muscle weakness and atrophy.

Defects in MFN2 are the cause of Charcot-Marie-Toothdisease type 6 (CMT6) [MIM:601152], also referred to as autosomaldominant hereditary motor and sensory neuropathy VI (HMSN6). CMT6is an autosomal dominant form of axonal CMT associated with opticatrophy.

Defects in MFRP are the cause of nanophthalmos 2 (NNO2)[MIM:609549]. NNO2 is a rare autosomal recessive disorder of eyedevelopment characterized by extreme hyperopia and smallfunctional eyes.

Defects in MFRP are the cause of microphthalmia isolatedtype 5 (MCOP5) [MIM:611040]. Microphthalmia is a clinicallyheterogeneous disorder of eye formation, ranging from small sizeof a single eye to complete bilateral absence of ocular tissues.Ocular abnormalities like opacities of the cornea and lens,scaring of the retina and choroid, cataract and otherabnormalities like cataract may also be present. MCOP5 ischaracterized by posterior microphthalmia, retinitis pigmentosa,foveoschisis and optic disc drusen.

Defects in MFSD8 are the cause of neuronal ceroidlipofuscinosis type 7 (CLN7) [MIM:610951]. A form of lateinfantile neuronal ceroid lipofuscinosis. CNL are a clinically andgenetically heterogeneous group of neurodegenerative disorderscharacterized by the intracellular accumulation of autofluorescentlipopigment storage material in different patternsultrastructurally. The patterns most often observed CLN7 are mixedcombinations of granular, curvilinear, fingerprint, andrectilinear profiles. The clinical course includes progressivedementia, seizures, and progressive visual failure.

Defects in MGAT2 are the cause of congenital disorder ofglycosylation type 2A (CDG2A) [MIM:212066], also known ascarbohydrate-deficient glycoprotein syndrome type II. CDGs are afamily of severe inherited diseases caused by a defect in proteinN-glycosylation. They are characterized by under-glycosylatedserum proteins. These multisystem disorders present with a widevariety of clinical features, such as disorders of the nervoussystem development, psychomotor retardation, dysmorphic features,hypotonia, coagulation disorders, and immunodeficiency. The broadspectrum of features reflects the critical role of N-glycoproteinsduring embryonic development, differentiation, and maintenance ofcell functions.

Defects in MGP are the cause of Keutel syndrome (KS)[MIM:245150]. KS is an autosomal recessive disorder characterizedby abnormal cartilage calcification, peripheral pulmonary stenosisneural hearing loss and midfacial hypoplasia.

Note=Anti-MICA antibodies and ligand shedding areinvolved in the progression of monoclonal gammopathy ofundetermined significance (MGUS)to multiple myeloma.

Genetic variations in MICA may be a cause ofsusceptibility to psoriasis type 1 (PSORS1) [MIM:177900].Psoriasis is a common, chronic inflammatory disease of the skinwith multifactorial etiology. It is characterized by red, scalyplaques usually found on the scalp, elbows and knees. Theselesions are caused by abnormal keratinocyte proliferation andinfiltration of inflammatory cells into the dermis and epidermis.

Genetic variation in MICA is a cause of susceptibility topsoriatic arthritis (PSORAS) [MIM:607507]. PSORAS is aninflammatory, seronegative arthritis associated with psoriasis. Itis a heterogeneous disorder ranging from a mild, non-destructivedisease to a severe, progressive, erosive arthropathy. Five typesof psoriatic arthritis have been defined: asymmetricaloligoarthritis characterized by primary involvement of the smalljoints of the fingers or toes, asymmetrical arthritis whichinvolves the joints of the extremities, symmetrical polyarthritischaracterized by a rheumatoidlike pattern that can involve hands,wrists, ankles, and feet, arthritis mutilans, which is a rare butdeforming and destructive condition, arthritis of the sacroiliacjoints and spine (psoriatic spondylitis).

Genetic variations in MICA are a cause of susceptibilityto rheumatoid arthritis (RA) [MIM:180300]. It is a systemicinflammatory disease with autoimmune features and a complexgenetic component. It primarily affects the joints and ischaracterized by inflammatory changes in the synovial membranesand articular structures, widespread fibrinoid degeneration of thecollagen fibers in mesenchymal tissues, and by atrophy andrarefaction of bony structures. Note=The MICB*004 allele isasociated with rheumatoid arthritis.

Note=Genetic variation in MICB is associated withcytomegalovirus and herpes simplex virus I seropositivity and thismay be associated with schizophrenia risk.

Genetic variations in MIF are associated withsusceptibility to rheumatoid arthritis systemic juvenile (RASJ)[MIM:604302]. An inflammatory articular disorder with systemic-onset beginning before the age of 16. It represents a subgroup ofjuvenile arthritis associated with severe extraarticular featuresand occasionally fatal complications. During active phases of thedisorder, patients display a typical daily spiking fever, anevanescent macular rash, lymphadenopathy, hepatosplenomegaly,serositis, myalgia and arthritis.

Defects in NDUFAF2 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinical disorders,from lethal neonatal disease to adult-onset neurodegenerativedisorders. Phenotypes include macrocephaly with progressiveleukodystrophy, non-specific encephalopathy, cardiomyopathy,myopathy, liver disease, Leigh syndrome, Leber hereditary opticneuropathy, and some forms of Parkinson disease.

Note=Defects in MINPP1 may be involved in follicularthyroid tumors development.

Note=A chromosomal aberration involving MIPOL1 is foundin a patient with mirror-image polydactyly of hands and feetwithout other anomalies (MIP). Translocation t(2,14)(p23.3,q13).MIP is a very rare congenital anomaly characterized by mirror-image duplication of digits. MIP is occasionally associated withdimelia of the ulna and fibula, tibial and/or fibular hypoplasia,nasal abnormality and other malformations. Most MIP cases aresporadic, but very rare parent-child transmissions observed infamilial cases suggest an autosomal mode of inheritance.

Defects in MIP are a cause of cataract autosomal dominant[MIM:604219]. Cataract is an opacification of the crystalline lensof the eye that frequently results in visual impairment orblindness. Opacities vary in morphology, are often confined to aportion of the lens, and may be static or progressive. In general,the more posteriorly located and dense an opacity, the greater theimpact on visual function. Cataract is the most common treatablecause of visual disability in childhood.

Defects in AMH are the cause of persistent Muellerianduct syndrome type 1 (PMDS1) [MIM:261550]. PMDS1 is a form of malepseudohermaphroditism characterized by a failure of Muellerianduct regression in otherwise normal males.

Defects in MITF are the cause of Waardenburg syndrometype 2A (WS2A) [MIM:193510]. It is a dominant inherited disordercharacterized by sensorineural hearing loss and patches ofdepigmentation. The features show variable expression andpenetrance.

Defects in MITF are a cause of Waardenburg syndrome type2 with ocular albinism (WS2-OA) [MIM:103470]. It is an ocularalbinism with sensorineural deafness.

Defects in MITF are the cause of Tietz syndrome (TIETZS)[MIM:103500]. It is an autosomal dominant disorder characterizedby generalized hypopigmentation and profound, congenital,bilateral deafness. Penetrance is complete.

Defects in MAPK10 are a cause of epileptic encephalopathyLennox-Gastaut type (EELG) [MIM:606369]. Epilepticencephalopathies of the Lennox-Gastaut group are childhoodepileptic disorders characterized by severe psychomotor delay andseizures. Note=A chromosomal aberration involving MAPK10 has beenfound in a single patient. Translocation t(Y,4)(q11.2,q21) whichcauses MAPK10 truncation.

Defects in MKKS are the cause of McKusick-Kaufmansyndrome (MKKS) [MIM:236700]. MKKS is an autosomal recessivedevelopmental disorder. It is characterized by hydrometrocolpos,postaxial polydactyly and congenital heart defects.

Defects in MKKS are the cause of Bardet-Biedl syndrometype 6 (BBS6) [MIM:209900]. Bardet-Biedl syndrome (BBS) is agenetically heterogeneous, autosomal recessive disordercharacterized by usually severe pigmentary retinopathy, earlyonset obesity, polydactyly, hypogenitalism, renal malformation andmental retardation. Secondary features include diabetes mellitus,hypertension and congenital heart disease. A relatively highincidence of BBS is found in the mixed Arab populations of Kuwaitand in Bedouin tribes throughout the Middle East, most likely dueto the high rate of consaguinity in these populations and afounder effect.

Defects in MKS1 are the cause of Meckel syndrome type 1(MKS1) [MIM:249000]. MKS1 is an autosomal recessive disordercharacterized by a combination of renal cysts and variablyassociated features including developmental anomalies of thecentral nervous system (typically encephalocele), hepatic ductaldysplasia and cysts, and polydactyly.

Defects in MKS1 are the cause of Bardet-Biedl syndrometype 13 (BBS13) [MIM:209900]. Bardet-Biedl syndrome (BBS) is agenetically heterogeneous, autosomal recessive disordercharacterized by usually severe pigmentary retinopathy, earlyonset obesity, polydactyly, hypogenitalism, renal malformation andmental retardation. Secondary features include diabetes mellitus,hypertension and congenital heart disease. A relatively highincidence of BBS is found in the mixed Arab populations of Kuwaitand in Bedouin tribes throughout the Middle East, most likely dueto the high rate of consaguinity in these populations and afounder effect.

Defects in TMEM67 are the cause of Meckel syndrome type 3(MKS3) [MIM:607361]. MKS3 is an autosomal recessive disordercharacterized by a combination of renal cysts and variablyassociated features including developmental anomalies of thecentral nervous system (typically encephalocele), hepatic ductaldysplasia and cysts, and polydactyly.

Defects in TMEM67 are the cause of Joubert syndrome type6 (JBTS6) [MIM:610688]. JBTS is an autosomal recessive disorderpresenting with cerebellar ataxia, oculomotor apraxia, hypotonia,neonatal breathing abnormalities and psychomotor delay.Neuroradiologically, it is characterized by cerebellar vermianhypoplasia/aplasia, thickened and reoriented superior cerebellarpeduncles, and an abnormally large interpeduncular fossa, givingthe appearance of a molar tooth on transaxial slices (molar toothsign). Additional variable features include retinal dystrophy andrenal disease.

Note=Genetic variations in TMEM67 may act as a modifierof the expression of Bardet-Biedl syndrome in patients who havemutations in other genes. Heterozygosity for a complex mutation inthe TMEM67 gene coding for a protein with 2 in cis changes, andhomozygosity for a truncating mutation of the CEP290 gene has beenfound in a patient with Bardet-Biedl syndrome type 14.

Defects in TMEM67 are a cause of COACH syndrome (COACHS)[MIM:216360]. It is a disorder characterized by mentalretardation, ataxia due to cerebellar hypoplasia, and hepaticfibrosis. Patients present the molar tooth sign, a midbrain-hindbrain malformation pathognomonic for Joubert syndrome andrelated disorders. Other features, such as coloboma and renalcysts, may be variable.

Defects in TMEM67 are the cause of nephronophthisis type11 (NPHP11) [MIM:613550]. NPHP11 is a disorder characterized bythe association of nephronophthisis with hepatic fibrosis.Nephronophthisis is a progressive tubulo-interstitial kidneydisorder histologically characterized by modifications of thetubules with thickening of the basement membrane, interstitialfibrosis and, in the advanced stages, medullary cysts. Typicalclinical features are chronic renal failure, anemia, polyuria,polydipsia, isosthenuria, and growth retardation. Associationswith extrarenal symptoms, especially ocular lesions, are frequent.

Defects in MLC1 are a cause of leukoencephalopathymegalencephalic with subcortical cysts (MLC) [MIM:604004]. MLC isa syndrome of cerebral leukoencephalopathy and megalencephalycharacterized by ataxia, spasticity, seizures, delay in motordevelopment and mild mental retardation. The brain appears swollenon magnetic resonance imaging, with diffuse white-matterabnormalities and the invariable presence of subcortical cysts infrontal and temporal lobes.

Note=A chromosomal aberration involving MLF1 is a causeof myelodysplastic syndrome (MDS). Translocation t(3,5)(q25.1,q34)with NPM1/NPM.

Defects in MLH1 are the cause of hereditary non-polyposiscolorectal cancer type 2 (HNPCC2) [MIM:609310]. Mutations in morethan one gene locus can be involved alone or in combination in theproduction of the HNPCC phenotype (also called Lynch syndrome).Most families with clinically recognized HNPCC have mutations ineither MLH1 or MSH2 genes. HNPCC is an autosomal, dominantlyinherited disease associated with marked increase in cancersusceptibility. It is characterized by a familial predispositionto early onset colorectal carcinoma (CRC) and extra-coloniccancers of the gastrointestinal, urological and femalereproductive tracts. HNPCC is reported to be the most common formof inherited colorectal cancer in the Western world, and accountsfor 15% of all colon cancers. Cancers in HNPCC originate withinbenign neoplastic polyps termed adenomas. Clinically, HNPCC isoften divided into two subgroups. Type I: hereditarypredisposition to colorectal cancer, a young age of onset, andcarcinoma observed in the proximal colon. Type II: patients havean increased risk for cancers in certain tissues such as theuterus, ovary, breast, stomach, small intestine, skin, and larynxin addition to the colon. Diagnosis of classical HNPCC is based onthe Amsterdam criteria: 3 or more relatives affected by colorectalcancer, one a first degree relative of the other two, 2 or moregeneration affected, 1 or more colorectal cancers presentingbefore 50 years of age, exclusion of hereditary polyposissyndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can beused to describe families who do not or only partially fulfill theAmsterdam criteria, but in whom a genetic basis for colon canceris strongly suspected.

Defects in MLH1 are a cause of mismatch repair cancersyndrome (MMRCS) [MIM:276300], also known as Turcot syndrome orbrain tumor-polyposis syndrome 1 (BTPS1). MMRCS is an autosomaldominant disorder characterized by malignant tumors of the brainassociated with multiple colorectal adenomas. Skin featuresinclude sebaceous cysts, hyperpigmented and cafe au lait spots.

Defects in MLH1 are a cause of Muir-Torre syndrome(MuToS) [MIM:158320], also abbreviated MTS. MuToS is a rareautosomal dominant disorder characterized by sebaceous neoplasmsand visceral malignancy.

Note=Defects in MLH1 may contribute to lobular carcinomain situ (LCIS), a non-invasive neoplastic disease of the breast.

Defects in MLH1 are a cause of susceptibility toendometrial cancer (ENDMC) [MIM:608089].

Note=Some epigenetic changes can be transmitted unchangedthrough the germline (termed 'epigenetic inheritance'). Evidencethat this mechanism occurs in humans is provided by theidentification of individuals in whom 1 allele of the MLH1 gene isepigenetically silenced throughout the soma (implying a germlineevent). These individuals are affected by HNPCC but does not haveidentifiable mutations in MLH1, even though it is silenced, whichdemonstrates that an epimutation can phenocopy a genetic disease.

Defects in MLH3 are the cause of hereditary non-polyposiscolorectal cancer type 7 (HNPCC7) [MIM:604395]. Mutations in morethan one gene locus can be involved alone or in combination in theproduction of the HNPCC phenotype (also called Lynch syndrome).Most families with clinically recognized HNPCC have mutations ineither MLH1 or MSH2 genes. HNPCC is an autosomal, dominantlyinherited disease associated with marked increase in cancersusceptibility. It is characterized by a familial predispositionto early onset colorectal carcinoma (CRC) and extra-coloniccancers of the gastrointestinal, urological and femalereproductive tracts. HNPCC is reported to be the most common formof inherited colorectal cancer in the Western world, and accountsfor 15% of all colon cancers. Cancers in HNPCC originate withinbenign neoplastic polyps termed adenomas. Clinically, HNPCC isoften divided into two subgroups. Type I: hereditarypredisposition to colorectal cancer, a young age of onset, andcarcinoma observed in the proximal colon. Type II: patients havean increased risk for cancers in certain tissues such as theuterus, ovary, breast, stomach, small intestine, skin, and larynxin addition to the colon. Diagnosis of classical HNPCC is based onthe Amsterdam criteria: 3 or more relatives affected by colorectalcancer, one a first degree relative of the other two, 2 or moregeneration affected, 1 or more colorectal cancers presentingbefore 50 years of age, exclusion of hereditary polyposissyndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can beused to describe families who do not or only partially fulfill theAmsterdam criteria, but in whom a genetic basis for colon canceris strongly suspected.

Defects in MLH3 are a cause of colorectal cancer (CRC)[MIM:114500].

Note=Chromosomal aberrations involving MLL are a cause ofacute leukemias. Translocation t(1,11)(q21,q23) with MLLT11/AF1Q,translocation t(3,11)(p21,q23) with NCKIPSD/AF3p21, translocationt(3,11)(q25,q23) with GMPS, translocation t(4,11)(q21,q23) withAFF1/MLLT2/AF4, insertion ins(5,11)(q31,q13q23) with AFF4/AF5Q31,translocation t(5,11)(q12,q23) with AF5-alpha/CENPK, translocationt(6,11)(q27,q23) with MLLT4/AF6, translocation t(9,11)(p22,q23)with MLLT3/AF9, translocation t(10,11)(p11.2,q23) with ABI1,translocation t(10,11)(p12,q23) with MLLT10/AF10,t(11,15)(q23,q14) with CASC5 and ZFYVE19, translocationt(11,17)(q23,q21) with MLLT6/AF17, translocationt(11,19)(q23,p13.3) with ELL, translocation t(11,19)(q23,p13.3)with MLLT1/ENL, translocation t(11,19)(q23,p23) with GAS7,translocation t(X,11)(q13,q23) with FOXO4/AFX1. Translocationt(3,11)(q28,q23) with LPP. Translocation t(10,11)(q22,q23) withTET1. Translocation t(9,11)(q34,q23) with DAB2IP. Translocationt(4,11)(p12,q23) with FRYL. Fusion proteins MLL-MLLT1, MLL-MLLT3and MLL-ELL interact with PPP1R15A and, on the contrary to unfusedMLL, inhibit PPP1R15A-induced apoptosis.

Note=A chromosomal aberration involving MLL may be acause of chronic neutrophilic leukemia. Translocationt(4,11)(q21,q23) with SEPT11.

Defects in MLL2 are the cause of Kabuki syndrome (KABS)[MIM:147920]. It is a congenital mental retardation syndrome withadditional features, including postnatal dwarfism, a peculiarfacies characterized by long palpebral fissures with eversion ofthe lateral third of the lower eyelids, a broad and depressednasal tip, large prominent earlobes, a cleft or high-archedpalate, scoliosis, short fifth finger, persistence of fingerpads,radiographic abnormalities of the vertebrae, hands, and hipjoints, and recurrent otitis media in infancy.

Defects in MYL2 are the cause of cardiomyopathy familialhypertrophic type 10 (CMH10) [MIM:608758]. Familial hypertrophiccardiomyopathy is a hereditary heart disorder characterized byventricular hypertrophy, which is usually asymmetric and ofteninvolves the interventricular septum. The symptoms includedyspnea, syncope, collapse, palpitations, and chest pain. They canbe readily provoked by exercise. The disorder has inter- andintrafamilial variability ranging from benign to malignant formswith high risk of cardiac failure and sudden cardiac death.

Defects in MYL2 are the cause of cardiomyopathy familialhypertrophic with mid-left ventricular chamber type 2 (MVC2)[MIM:608758]. MVC2 is a very rare variant of familial hypertrophiccardiomyopathy, characterized by mid-left ventricular chamberthickening.

Defects in MMAA are the cause of methylmalonic aciduriatype cblA (MMAA) [MIM:251100], also known as methylmalonicaciduria type A or vitamin B12-responsive methylmalonicaciduria ofcblA complementation type. MMAA is a disorder of methylmalonateand cobalamin metabolism due to defective synthesis ofadenosylcobalamin. Inheritance is autosomal recessive.

Defects in MMAB are the cause of methylmalonic aciduriatype cblB (MMAB) [MIM:251110], also known as methylmalonicaciduria type B or vitamin B12-responsive methylmalonicaciduria ofcblB complementation type. MMAB is a disorder of methylmalonateand cobalamin metabolism due to defective synthesis ofadenosylcobalamin. Inheritance is autosomal recessive.

Defects in MMACHC are the cause of methylmalonic aciduriaand homocystinuria type cblC (MMACHC) [MIM:277400]. MMACHC is adisorder of cobalamin metabolism characterized by decreased levelsof the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin(MeCbl). Affected individuals may have developmental, hematologic,neurologic, metabolic, ophthalmologic, and dermatologic clinicalfindings. Although considered a disease of infancy or childhood,some individuals develop symptoms in adulthood.

Defects in MMADHC are the cause of methylmalonic aciduriaand homocystinuria type cblD (MMADHC) [MIM:277410]. MMADHC is adisorder of cobalamin metabolism characterized by decreased levelsof the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin(MeCbl). Clinical features include developmental delay, hyotonia,mental retardation, seizures, megaloblastic anemia. Some patientsmanifest combined methylmalonic aciduria and homocystinuria(referred to as cblD original), some have only isolatedhomocystinuria (cblD variant 1), and others have onlymethylmalonic aciduria (cblD variant 2).

Defects in MMP13 are the cause of spondyloepimetaphysealdysplasia Missouri type (SEMD-MO) [MIM:602111]. A bone diseasecharacterized by moderate to severe metaphyseal changes, mildepiphyseal involvement, rhizomelic shortening of the lower limbswith bowing of the femora and/or tibiae, coxa vara, genu varum andpear-shaped vertebrae in childhood. Epimetaphyseal changes improvewith age.

Defects in MMP13 are the cause of metaphysealanadysplasia type 1 (MANDP1) [MIM:602111]. Metaphysealanadysplasia consists of an abnormal bone developmentcharacterized by severe skeletal changes that, in contrast withthe progressive course of most other skeletal dysplasias, resolvespontaneously with age. Clinical characteristics are evident fromthe first months of life and include slight shortness of statureand a mild varus deformity of the legs. Patients attain a normalstature in adolescence and show improvement or complete resolutionof varus deformity of the legs and rhizomelic micromelia.

May play a role in pathological processes participatingin rheumatoid arthritis (RA)-associated joint tissue destruction.Autoantigen anti-MMP19 are frequent in RA patients.

Defects in MMP20 are the cause of amelogenesis imperfectahypomaturation type 2A2 (AI2A2) [MIM:612529]. AI2A2 is anautosomal recessive defect of enamel formation. The disorderinvolves both primary and secondary dentitions. The teeth have ashiny agar jelly appearance and the enamel is softer than normal.Brown pigment is present in middle layers of enamel.

Defects in MMP2 are the cause of Torg-Winchester syndrome(TWS) [MIM:259600], also known as multicentric osteolysisnodulosis and arthropathy (MONA). TWS is an autosomal recessiveosteolysis syndrome. It is severe with generalized osteolysis andosteopenia. Subcutaneous nodules are usually absent. Torg-Winchester syndrome has been associated with a number ofadditional features including coarse face, corneal opacities,patches of thickened, hyperpigmented skin, hypertrichosis and gumhypertrophy. However, these features are not always present andhave occasionally been observed in other osteolysis syndromes.

Defects in MMP9 may be a cause of susceptibility tointervertebral disc disease (IDD) [MIM:603932], also known aslumbar disk herniation (LDH). IDD is one of the most commonmusculo-skeletal disorders and the predominant cause of low-backpain and unilateral leg pain.

Defects in MMP9 are the cause of metaphyseal anadysplasiatype 2 (MANDP2) [MIM:613073]. Metaphyseal anadysplasia consists ofan abnormal bone development characterized by severe skeletalchanges that, in contrast with the progressive course of mostother skeletal dysplasias, resolve spontaneously with age.Clinical characteristics are evident from the first months of lifeand include slight shortness of stature and a mild varus deformityof the legs. Patients attain a normal stature in adolescence andshow improvement or complete resolution of varus deformity of thelegs and rhizomelic micromelia.

Note=Deficiency in multimerin-1 due to proteolyticdegradation within the platelet alpha granules is associated withan autosomal dominant bleeding disorder (factor V Quebec).

Defects in ALDH6A1 are the cause of methylmalonatesemialdehyde dehydrogenase deficiency (MMSDH deficiency)[MIM:603178]. This is characterized by elevated beta-alanine, 3-hydroxypropionic acid, and both isomers of 3-amino and 3-hydroxyisobutyric acids in urine organic acids.

Defects in MNX1 are a cause of Currarino syndrome(CURRAS) [MIM:176450]. The triad of a presacral tumor, sacralagenesis and anorectal malformation constitutes the Currarinosyndrome which is caused by dorsal-ventral patterning defectsduring embryonic development. The syndrome occurs in the majorityof patients as an autosomal dominant trait.

Defects in MOCS2 are the cause of molybdenum cofactordeficiency type B (MOCOD type B) [MIM:252150], an autosomalrecessive disease which leads to the pleiotropic loss of allmolybdoenzyme activities and is characterized by severeneurological damage, neonatal seizures and early childhood death.The initiator codon is mutated which results in a complete loss ofthe protein.

Defects in MOCS2 are the cause of molybdenum cofactordeficiency type B (MOCOD type B) [MIM:252150]. MOCOD type B is anautosomal recessive disease which leads to the pleiotropic loss ofall molybdoenzyme activities and is characterized by severeneurological damage, neonatal seizures and early childhood death.

Defects in MOCOS are the cause of xanthinuria type 2(XU2) [MIM:603592]. Xanthinuria is characterized by excretion ofvery large amounts of xanthine in the urine and a tendency to formxanthine stones. Uric acid is strikingly diminished in serum andurine. In addition, patient suffering of XU2 cannot metabolizeallopurinol into oxypurinol due to dual deficiency of xanthinedehydrogenase and aldehyde oxidase.

Defects in MOCS1 are the cause of molybdenum cofactordeficiency type A (MOCOD type A) [MIM:252150], an autosomalrecessive disease which leads to the pleiotropic loss of allmolybdoenzyme activities and is characterized by severeneurological damage, neonatal seizures and early childhood death.

Defects in MOGS are the cause of type IIb congenitaldisorder of glycosylation (CDGIIb) [MIM:606056], also known asglucosidase I deficiency. CDGIIb is characterized by markedgeneralized hypotonia and hypomotility of the neonate, dysmorphicfeatures, including a prominent occiput, short palpebral fissures,retrognathia, high arched palate, generalized edema, andhypoplastic genitalia. Symptoms of the infant includedhepatomegaly, hypoventilation, feeding problems and seizures. Theclinical course was progressive and the infant did not survivemore than a few months.

Defects in SLC16A12 are a cause of cataract juvenile withmicrocornea and glucosuria (CJMG) [MIM:612018]. Renal glucosuriais defined by elevated glucose level in the urine withouthyperglycemia and without evidence of morphological renalanomalies.

Defects in SLC16A1 are the cause of symptomaticdeficiency in lactate transport (SDLT) [MIM:245340], also known aserythrocyte lactate transporter defect. Deficiency of lactatetransporter may result in an acidic intracellular environmentcreated by muscle activity with consequent degeneration of muscleand release of myoglobin and creatine kinase. This defect mightcompromise extreme performance in otherwise healthy individuals.

Defects in SLC16A1 are the cause of familialhyperinsulinemic hypoglycemia type 7 (HHF7) [MIM:610021], alsoknown as exercise-induced hyperinsulinemic hypoglycemia. HHF7 is adominantly inherited hypoglycemic disorder characterized byinappropriate insulin secretion during anaerobic exercise or onpyruvate load.

Defects in MAP2K1 are a cause of cardiofaciocutaneoussyndrome (CFC syndrome) [MIM:115150], also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctivefacial appearance, heart defects and mental retardation. Heartdefects include pulmonic stenosis, atrial septal defects andhypertrophic cardiomyopathy. Some affected individuals presentwith ectodermal abnormalities such as sparse, friable hair,hyperkeratotic skin lesions and a generalized ichthyosis-likecondition. Typical facial features are similar to Noonan syndrome.They include high forehead with bitemporal constriction,hypoplastic supraorbital ridges, downslanting palpebral fissures,a depressed nasal bridge, and posteriorly angulated ears withprominent helices. The inheritance of CFC syndrome is autosomaldominant.

Defects in MAP2K2 are a cause of cardiofaciocutaneoussyndrome (CFC syndrome) [MIM:115150], also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctivefacial appearance, heart defects and mental retardation. Heartdefects include pulmonic stenosis, atrial septal defects andhypertrophic cardiomyopathy. Some affected individuals presentwith ectodermal abnormalities such as sparse, friable hair,hyperkeratotic skin lesions and a generalized ichthyosis-likecondition. Typical facial features are similar to Noonan syndrome.They include high forehead with bitemporal constriction,hypoplastic supraorbital ridges, downslanting palpebral fissures,a depressed nasal bridge, and posteriorly angulated ears withprominent helices. The inheritance of CFC syndrome is autosomaldominant.

Note=Defects in MAP2K3 may be involved in colon cancer.

Defects in SLC25A3 are a cause of mitochondrial phosphatecarrier deficiency (MPCD) [MIM:610773]. MPCD is a fatal disorderof oxidative phosphorylation. Patients have lactic acidosis,hypertrophic cardiomyopathy and muscular hypotonia and die withinthe first year of life.

Defects in MPI are the cause of congenital disorder ofglycosylation type 1B (CDG1B) [MIM:602579], also known ascarbohydrate-deficient glycoprotein syndrome type Ib (CDGS1B).Congenital disorders of glycosylation are metabolic deficienciesin glycoprotein biosynthesis that usually cause severe mental andpsychomotor retardation. They are characterized by under-glycosylated serum glycoproteins. CDG1B is clinicallycharacterized by protein-losing enteropathy.

Defects in MPDU1 are the cause of congenital disorder ofglycosylation type 1F (CDG1F) [MIM:609180]. CDGs are a family ofsevere inherited diseases caused by a defect in protein N-glycosylation. They are characterized by under-glycosylated serumproteins. These multisystem disorders present with a wide varietyof clinical features, such as disorders of the nervous systemdevelopment, psychomotor retardation, dysmorphic features,hypotonia, coagulation disorders, and immunodeficiency. The broadspectrum of features reflects the critical role of N-glycoproteinsduring embryonic development, differentiation, and maintenance ofcell functions.

Defects in MPV17 are the cause of mitochondrial DNAdepletion syndrome type 6 (MTDPS6) [MIM:256810]. A diseasecharacterized by infantile onset of progressive liver failure,often leading to death in the first year of life, peripheralneuropathy, corneal scarring, acral ulceration and osteomyelitisleading to autoamputation, cerebral leukoencephalopathy, failureto thrive, and recurrent metabolic acidosis with intercurrentinfections.

Defects in MRAP are the cause of glucocorticoiddeficiency type 2 (GCCD2) [MIM:607398], also known as familialglucocorticoid deficiency type 2 (FGD2). GCCD2 is an autosomalrecessive disorder due to congenital insensitivity or resistanceto adrenocorticotropin (ACTH). It is characterized by progressiveprimary adrenal insufficiency, without mineralocorticoiddeficiency.

Defects in MRE11A are a cause of ataxia telangiectasia-like disorder (ATLD) [MIM:604391]. ATLD is a disease with the sameclinical feature than ataxia-telangiectasia but with a somewhatmilder clinical course.

Defects in ABCC2 are the cause of Dubin-Johnson syndrome(DJS) [MIM:237500]. DJS is an autosomal recessive disordercharacterized by conjugated hyperbilirubinemia, an increase in theurinary excretion of coproporphyrin isomer I, deposition ofmelanin-like pigment in hepatocytes, and prolonged retention ofsulfobromophthalein, but otherwise normal liver function.

Defects in ABCC6 are the cause of pseudoxanthomaelasticum (PXE) [MIM:264800]. PXE is a disorder characterized bycalcification of elastic fibers in skin, arteries and retina thatresults in dermal lesions with associated laxity and loss ofelasticity, arterial insufficiency and retinal hemorrhages leadingto macular degeneration. PXE is caused in the overwhelmingmajority of cases by homozygous or compound heterozygous mutationsin the ABCC6 gene (autosomal recessive PXE). Individuals carryingheterozygous mutations express limited manifestations of thepseudoxanthoma elasticum phenotype (autosomal dominant PXE).

Defects in MSH2 are the cause of hereditary non-polyposiscolorectal cancer type 1 (HNPCC1) [MIM:120435]. Mutations in morethan one gene locus can be involved alone or in combination in theproduction of the HNPCC phenotype (also called Lynch syndrome).Most families with clinically recognized HNPCC have mutations ineither MLH1 or MSH2 genes. HNPCC is an autosomal, dominantlyinherited disease associated with marked increase in cancersusceptibility. It is characterized by a familial predispositionto early onset colorectal carcinoma (CRC) and extra-coloniccancers of the gastrointestinal, urological and femalereproductive tracts. HNPCC is reported to be the most common formof inherited colorectal cancer in the Western world. Cancers inHNPCC originate within benign neoplastic polyps termed adenomas.Clinically, HNPCC is often divided into two subgroups. Type I:hereditary predisposition to colorectal cancer, a young age ofonset, and carcinoma observed in the proximal colon. Type II:patients have an increased risk for cancers in certain tissuessuch as the uterus, ovary, breast, stomach, small intestine, skin,and larynx in addition to the colon. Diagnosis of classical HNPCCis based on the Amsterdam criteria: 3 or more relatives affectedby colorectal cancer, one a first degree relative of the othertwo, 2 or more generation affected, 1 or more colorectal cancerspresenting before 50 years of age, exclusion of hereditarypolyposis syndromes. The term "suspected HNPCC" or "incompleteHNPCC" can be used to describe families who do not or onlypartially fulfill the Amsterdam criteria, but in whom a geneticbasis for colon cancer is strongly suspected. MSH2 mutations maypredispose to hematological malignancies and multiple cafe-au-laitspots.

Defects in MSH2 are a cause of Muir-Torre syndrome(MuToS) [MIM:158320], also abbreviated MTS. MuToS is a rareautosomal dominant disorder characterized by sebaceous neoplasmsand visceral malignancy.

Defects in MSH2 are a cause of susceptibility toendometrial cancer (ENDMC) [MIM:608089].

Defects in MSH2 are a cause of hereditary non-polyposiscolorectal cancer type 8 (HNPCC8) [MIM:613244]. HNPCC is a diseaseassociated with marked increase in cancer susceptibility. It ischaracterized by a familial predisposition to early-onsetcolorectal carcinoma (CRC) and extra-colonic tumors of thegastrointestinal, urological and female reproductive tracts. HNPCCis reported to be the most common form of inherited colorectalcancer in the Western world. Clinically, HNPCC is often dividedinto two subgroups. Type I is characterized by hereditarypredisposition to colorectal cancer, a young age of onset, andcarcinoma observed in the proximal colon. Type II is characterizedby increased risk for cancers in certain tissues such as theuterus, ovary, breast, stomach, small intestine, skin, and larynxin addition to the colon. Diagnosis of classical HNPCC is based onthe Amsterdam criteria: 3 or more relatives affected by colorectalcancer, one a first degree relative of the other two, 2 or moregeneration affected, 1 or more colorectal cancers presentingbefore 50 years of age, exclusion of hereditary polyposissyndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can beused to describe families who do not or only partially fulfill theAmsterdam criteria, but in whom a genetic basis for colon canceris strongly suspected. Note=HNPCC8 results from heterozygousdeletion of 3-prime exons of EPCAM and intergenic regions directlyupstream of MSH2, resulting in transcriptional read-through andepigenetic silencing of MSH2 in tissues expressing EPCAM.

Defects in MSH3 are a cause of susceptibility toendometrial cancer (ENDMC) [MIM:608089].

Defects in MSH6 are the cause of hereditary non-polyposiscolorectal cancer type 5 (HNPCC5) [MIM:600678]. Mutations in morethan one gene locus can be involved alone or in combination in theproduction of the HNPCC phenotype (also called Lynch syndrome).Most families with clinically recognized HNPCC have mutations ineither MLH1 or MSH2 genes. HNPCC is an autosomal, dominantlyinherited disease associated with marked increase in cancersusceptibility. It is characterized by a familial predispositionto early onset colorectal carcinoma (CRC) and extra-coloniccancers of the gastrointestinal, urological and femalereproductive tracts. HNPCC is reported to be the most common formof inherited colorectal cancer in the Western world. Cancers inHNPCC originate within benign neoplastic polyps termed adenomas.Clinically, HNPCC is often divided into two subgroups. Type I:hereditary predisposition to colorectal cancer, a young age ofonset, and carcinoma observed in the proximal colon. Type II:patients have an increased risk for cancers in certain tissuessuch as the uterus, ovary, breast, stomach, small intestine, skin,and larynx in addition to the colon. Diagnosis of classical HNPCCis based on the Amsterdam criteria: 3 or more relatives affectedby colorectal cancer, one a first degree relative of the othertwo, 2 or more generation affected, 1 or more colorectal cancerspresenting before 50 years of age, exclusion of hereditarypolyposis syndromes. MSH6 mutations appear to be associated withatypical HNPCC and in particular with development of endometrialcarcinoma or atypical endometrial hyperplasia, the presumedprecursor of endometrial cancer. Defects in MSH6 are also found infamilial colorectal cancers (suspected or incomplete HNPCC) thatdo not fulfill the Amsterdam criteria for HNPCC.

Defects in MSH6 are a cause of susceptibility toendometrial cancer (ENDMC) [MIM:608089].

Genetic variations in MC1R are a cause of susceptibilityto cutaneous malignant melanoma type 5 (CCM5) [MIM:613099].Malignant melanoma is a malignant neoplasm of melanocytes, arisingde novo or from a pre-existing benign nevus, which occurs mostoften in the skin but also may involve other sites.

Note=Chromosomal aberrations involving MSI2 maycontribute to disease progression in chronic myeloid leukemia.Translocation t(7,17)(p15,q23) with HOXA9, translocationt(7,17)(q32-34,q23).

Note=Antibodies against MSLN are detected in patientswith mesothelioma and ovarian cancer.

Defects in MSMB are the cause of susceptibility toprostate cancer hereditary type 13 (HPC13) [MIM:611928]. It is acondition associated with familial predisposition to cancer of theprostate. Most prostate cancers are adenocarcinomas that developin the acini of the prostatic ducts. Other rare histopathologictypes of prostate cancer that occur in approximately 5% ofpatients include small cell carcinoma, mucinous carcinoma,prostatic ductal carcinoma, transitional cell carcinoma, squamouscell carcinoma, basal cell carcinoma, adenoid cystic carcinoma(basaloid), signet-ring cell carcinoma and neuroendocrinecarcinoma.

Defects in MSRB3 are the cause of deafness autosomalrecessive type 74 (DFNB74) [MIM:613718]. A form of non-syndromicsensorineural deafness characterized by prelingual, bilateral,profound hearing loss. Sensorineural deafness results from damageto the neural receptors of the inner ear, the nerve pathways tothe brain, or the area of the brain that receives soundinformation. Note=A nonsense mutation affecting exclusivelymitochondrial isoform 2 is sufficient to produce hearing loss.

Defects in MSX1 are the cause of tooth agenesis selectivetype 1 (STHAG1) [MIM:106600]. A form of selective tooth agenesis,a common anomaly characterized by the congenital absence of one ormore teeth. Selective tooth agenesis without associated systemicdisorders has sometimes been divided into 2 types: oligodontia,defined as agenesis of 6 or more permanent teeth, and hypodontia,defined as agenesis of less than 6 teeth. The number in both casesdoes not include absence of third molars (wisdom teeth). Toothagenesis selective type 1 can be associated with orofacial cleftin some patients.

Note=MSX1 is deleted in some patients with Wolf-Hirschhorn syndrome (WHS). WHS results from sub-telomericdeletions in the short arm of chromosome 4.

Defects in MSX1 are the cause of Witkop syndrome (WITS)[MIM:189500]. WITS is a form of ectodermal dyslasia also calledtooth-and-nail syndrome or dysplasia of nails with hypodontia.Ectodermal dysplasias (EDs) constitute a heterogeneous group ofdevelopmental disorders affecting tissues of ectodermal origin.EDs are characterized by abnormal development of two or moreectodermal structures such as hair, teeth, nails and sweat glands,with or without any additional clinical sign. Each combination ofclinical features represents a different type of ectodermaldysplasia. Witkop syndrome is characterized by abnormalitieslargely limited largely to teeth (some of which are missing) andnails (which are poorly formed early in life, especiallytoenails). This condition is distinguished from anhidroticectodermal dysplasia by autosomal dominant inheritance and littleinvolvement of hair and sweat glands. The teeth are not asseverely affected.

Defects in MSX1 are the cause of non-syndromic orofacialcleft type 5 (OFC5) [MIM:608874], also called non-syndromic cleftlip with or without cleft palate 5. Non-syndromic orofacial cleftis a common birth defect consisting of cleft lips with or withoutcleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides andrange in severity from a simple notch in the upper lip to acomplete opening in the lip extending into the floor of thenostril and involving the upper gum.

Defects in MSX2 are the cause of parietal foramina 1(PFM1) [MIM:168500], also known as foramina parietalia permagna(FPP). PFM1 is an autosomal dominant disease characterized by ovaldefects of the parietal bones caused by deficient ossificationaround the parietal notch, which is normally obliterated duringthe fifth fetal month.

Defects in MSX2 are the cause of parietal foramina withcleidocranial dysplasia (PFMCCD) [MIM:168550], also known ascleidocranial dysplasia with parietal foramina. PFMCCD combinesskull defects in the form of enlarged parietal foramina anddeficient ossification of the clavicles.

Defects in MSX2 are the cause of craniosynostosis type 2(CRS2) [MIM:604757], also known as craniosynostosis Boston-type(CSB). CRS2 is an autosomal dominant disorder characterized by thepremature fusion of calvarial sutures. The craniosynostosisphenotype is either fronto-orbital recession, or frontal bossing,or turribrachycephaly, or cloverleaf skull. Associated featuresinclude severe headache, high incidence of visual problems (myopiaor hyperopia), and short first metatarsals. Intelligence isnormal.

Note=Overexpressed in T-cell leukemia bearing a t(X,14)translocation.

Note=Detected in T-cell leukemia bearing a t(X,14)translocation. Plays a key role in T-cell prolymphocytic leukemia.

Note=A chromosomal aberration involving CBFA2T3 is foundin therapy-related myeloid malignancies. Translocationt(16,21)(q24,q22) that forms a RUNX1-CBFA2T3 fusion protein.

Note=A chromosomal aberration involving RUNX1T1 is acause of acute myeloid leukemia (AML-M2). Translocationt(8,21)(q22,q22) with RUNX1/AML1.

Defects in RUNX1T1 may be a cause of colorectal cancer(CRC) [MIM:114500].

Defects in MTHFR are the cause ofmethylenetetrahydrofolate reductase deficiency (MTHFRD)[MIM:236250]. MTHFRD is autosomal recessive disorder with a widerange of features including homocysteinuria, homocysteinemia[MIM:603174], developmental delay, severe mental retardation,perinatal death, psychiatric disturbances, and later-onsetneurodegenerative disorders.

Defects in MTHFR may be a cause of susceptibility toischemic stroke (ISCHSTR) [MIM:601367], also known ascerebrovascular accident or cerebral infarction. A stroke is anacute neurologic event leading to death of neural tissue of thebrain and resulting in loss of motor, sensory and/or cognitivefunction. Ischemic strokes, resulting from vascular occlusion, isconsidered to be a highly complex disease consisting of a group ofheterogeneous disorders with multiple genetic and environmentalrisk factors.

Defects in MTHFR may be a cause of susceptibility tofolate-sensitive neural tube defects (folate-sensitive NTD)[MIM:601634]. The most common NTDs are open spina bifida(myelomeningocele) and anencephaly.

Defects in MTM1 are the cause of centronuclear myopathyX-linked (XCNM) [MIM:310400], also known as X-linked myotubularmyopathy (XLMTM) or myotubular myopathy type 1 (MTM1).Centronuclear myopathies are congenital muscle disorderscharacterized by progressive muscular weakness and wastinginvolving mainly limb girdle, trunk, and neck muscles. It may alsoaffect distal muscles. Weakness may be present during childhood oradolescence or may not become evident until the third decade oflife. Ptosis is a frequent clinical feature. The most prominenthistopathologic features include high frequency of centrallylocated nuclei in muscle fibers not secondary to regeneration,radial arrangement of sarcoplasmic strands around the centralnuclei, and predominance and hypotrophy of type 1 fibers.

Defects in MTMR2 are the cause of Charcot-Marie-Toothdisease type 4B1 (CMT4B1) [MIM:601382]. CMT4B1 is a recessive,severe form of Charcot-Marie-Tooth disease, the most commoninherited disorder of the peripheral nervous system. Charcot-Marie-Tooth disease is classified in two main groups on the basisof electrophysiologic properties and histopathology: primaryperipheral demyelinating neuropathy and primary peripheral axonalneuropathy. Demyelinating CMT neuropathies are characterized byseverely reduced nerve conduction velocities (less than 38 m/sec),segmental demyelination and remyelination with onion bulbformations on nerve biopsy, slowly progressive distal muscleatrophy and weakness, absent deep tendon reflexes, and hollowfeet. By convention, autosomal recessive forms of demyelinatingCharcot-Marie-Tooth disease are designated CMT4.

Defects in SBF2 are the cause of Charcot-Marie-Toothdisease type 4B2 (CMT4B2) [MIM:604563]. CMT4B2 is a recessive formof Charcot-Marie-Tooth disease, the most common inherited disorderof the peripheral nervous system. Charcot-Marie-Tooth disease isclassified in two main groups on the basis of electrophysiologicproperties and histopathology: primary peripheral demyelinatingneuropathy and primary peripheral axonal neuropathy. DemyelinatingCMT neuropathies are characterized by severely reduced nerveconduction velocities (less than 38 m/sec), segmentaldemyelination and remyelination with onion bulb formations onnerve biopsy, slowly progressive distal muscle atrophy andweakness, absent deep tendon reflexes, and hollow feet. Byconvention, autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4. CMT4B2 is characterizedby abnormal folding of myelin sheaths.

Defects in MTMR14 may be a cause of centronuclearmyopathy autosomal dominant (ADCNM) [MIM:160150], also known asautosomal dominant myotubular myopathy. Centronuclear myopathiesare congenital muscle disorders characterized by progressivemuscular weakness and wasting involving mainly limb girdle, trunk,and neck muscles. It may also affect distal muscles. Weakness maybe present during childhood or adolescence or may not becomeevident until the third decade of life. Ptosis is a frequentclinical feature. The most prominent histopathologic featuresinclude high frequency of centrally located nuclei in musclefibers not secondary to regeneration, radial arrangement ofsarcoplasmic strands around the central nuclei, and predominanceand hypotrophy of type 1 fibers.

Defects in MTTP are the cause of abetalipoproteinemia(ABL) [MIM:200100]. ABL is an autosomal recessive disorder oflipoprotein metabolism. Affected individuals produce virtually nocirculating apolipoprotein B-containing lipoproteins(chylomicrons, VLDL, LDL, lipoprotein(A)). Malabsorption of theantioxidant vitamin E occurs, leading to spinocerebellar andretinal degeneration.

Defects in MTRR are the cause of methylcobalamindeficiency type E (cblE) [MIM:236270], also known as vitamin B12-responsive homocystinuria or homocystinuria-megaloblastic anemiacomplementation type E. Patients who are defective in reductiveactivation of methionine synthase exhibit megaloblastic anemia,developmental delay, hypomethioninemia, and hyperhomocysteinemia,a risk factor in cardiovascular disease and neural tube defects.It is an autosomal recessive disease.

Defects in MTRR may be a cause of susceptibility tofolate-sensitive neural tube defects (folate-sensitive NTD)[MIM:601634]. The most common NTDs are open spina bifida(myelomeningocele) and anencephaly. Genetic defects in MTRR mayaffect the risk of spina bifida via the maternal rather than theembryonic genotype.

Defects in TRMU are a cause of acute infantile liverfailure (AILF) [MIM:613070]. AILF is a transient disorder ofhepatic function. In addition to elevated liver enzymes, jaundice,vomiting, coagulopathy, and hyperbilirubinemia, the presence ofincreased serum lactate is consistent with a defect inmitochondrial respiratory function. Patients who survive theinitial acute episode can recover and show normal development.

Defects in MTUS1 may be a cause of hepatocellularcarcinoma (HCC) [MIM:114550].

Genetic variations in MUC7 are associated withsusceptibility to asthma (ASTHMA) [MIM:600807]. The most commonchronic disease affecting children and young adults. It is acomplex genetic disorder with a heterogeneous phenotype, largelyattributed to the interactions among many genes and between thesegenes and the environment. It is characterized by recurrentattacks of paroxysmal dyspnea, with weezing due to spasmodiccontraction of the bronchi.

Defects in MUSK is a cause of autosomal recessivecongenital myasthenic syndrome (CMS) [MIM:608931]. Congenitalmyasthenic syndromes are inherited disorders of neuromusculartransmission that stem from mutations in presynaptic, synaptic, orpostsynaptic proteins. MUSK mutations lead to decreased agrin-dependent AChR aggregation, a critical step in the formation ofthe neuromuscular junction.

Defects in MUT are the cause of methylmalonic aciduriatype mut (MMAM) [MIM:251000]. MMAM is an often fatal disorder oforganic acid metabolism. Common clinical features includelethargy, vomiting, failure to thrive, hypotonia, neurologicaldeficit and early death. Two forms of the disease aredistinguished by the presence (mut-) or absence (mut0) of residualenzyme activity. Mut0 patients have more severe neurologicalmanifestations of the disease than do MUT- patients. MMAM isunresponsive to vitamin B12 therapy.

Defects in MUTYH are a cause of colorectal adenomatouspolyposis autosomal recessive (CAPAR) [MIM:608456]. It is acondition characterized by the development of multiple colorectaladenomatous polyps, benign neoplasms derived from glandularepithelium. Some affecetd individuals may develop colorectalcarcinoma.

Defects in MUTYH are a cause of gastric cancer (GASC)[MIM:613659]. A malignant disease which starts in the stomach, canspread to the esophagus or the small intestine, and can extendthrough the stomach wall to nearby lymph nodes and organs. It alsocan metastasize to other parts of the body. The term gastriccancer or gastric carcinoma refers to adenocarcinoma of thestomach that accounts for most of all gastric malignant tumors.Two main histologic types are recognized, diffuse type andintestinal type carcinomas. Diffuse tumors are poorlydifferentiated infiltrating lesions resulting in thickening of thestomach. In contrast, intestinal tumors are usually exophytic,often ulcerating, and associated with intestinal metaplasia of thestomach, most often observed in sporadic disease.

Defects in MXI1 may be a cause of susceptibility toprostate cancer (PC) [MIM:176807]. It is a malignancy originatingin tissues of the prostate. Most prostate cancers areadenocarcinomas that develop in the acini of the prostatic ducts.Other rare histopathologic types of prostate cancer that occur inapproximately 5% of patients include small cell carcinoma,mucinous carcinoma, prostatic ductal carcinoma, transitional cellcarcinoma, squamous cell carcinoma, basal cell carcinoma, adenoidcystic carcinoma (basaloid), signet-ring cell carcinoma andneuroendocrine carcinoma.

Note=Amplification of the N-MYC gene is associated with avariety of human tumors, most frequently neuroblastoma, where thelevel of amplification appears to increase as the tumorprogresses.

Defects in MYCN are the cause of microcephaly-oculo-digito-esophageal-duodenal syndrome (MODED) [MIM:164280], alsoknown as oculodigitoesophagoduodenal syndrome (ODED).Microcephaly-oculo-digito-esophageal-duodenal syndrome ischaracterized by variable combinations of esophageal and duodenalatresias, microcephaly, learning disability and limbmalformations. Cardiac and renal malformations, vertebralanomalies, and deafness have also been described.

Defects in MYCN are the cause of microcephaly and digitalabnormalities with normal intelligence (MCPHDANI) [MIM:602585].

Note=Overexpression of MYC is implicated in the etiologyof a variety of hematopoietic tumors.

Note=A chromosomal aberration involving MYC may be acause of a form of B-cell chronic lymphocytic leukemia.Translocation t(8,12)(q24,q22) with BTG1.

Defects in MYC are a cause of Burkitt lymphoma (BL)[MIM:113970]. A form of undifferentiated malignant lymphomacommonly manifested as a large osteolytic lesion in the jaw or asan abdominal mass. Note=Chromosomal aberrations involving MYC areusually found in Burkitt lymphoma. Translocations t(8,14), t(8,22)or t(2,8) which juxtapose MYC to one of the heavy or light chainimmunoglobulin gene loci.

Defects in MYD88 are the cause of MYD88 deficiency(MYD88D) [MIM:612260], also known as recurrent pyogenic bacterialinfections due to MYD88 deficiency. Patients suffer from autosomalrecessive, life-threatening, often recurrent pyogenic bacterialinfections, including invasive pneumococcal disease, and diebetween 1 and 11 months of age. Surviving patients are otherwisehealthy, with normal resistance to other microbes, and theirclinical status improved with age.

Defects in MYF6 may be a cause of centronuclear myopathyautosomal dominant (ADCNM) [MIM:160150], also known as autosomaldominant myotubular myopathy. Centronuclear myopathies arecongenital muscle disorders characterized by progressive muscularweakness and wasting involving mainly limb girdle, trunk, and neckmuscles. It may also affect distal muscles. Weakness may bepresent during childhood or adolescence or may not become evidentuntil the third decade of life. Ptosis is a frequent clinicalfeature. The most prominent histopathologic features include highfrequency of centrally located nuclei in muscle fibers notsecondary to regeneration, radial arrangement of sarcoplasmicstrands around the central nuclei, and predominance and hypotrophyof type 1 fibers.

Note=A chromosomal aberration involving MYH11 is found inacute myeloid leukemia of M4EO subtype. Pericentric inversioninv(16)(p13,q22). The inversion produces a fusion proteinconsisting of the 165 N-terminal residues of CBF-beta (PEPB2) andthe tail region of MYH11.

Defects in MYH11 are the cause of aortic aneurysmfamilial thoracic type 4 (AAT4) [MIM:132900], also known asfamilial thoracic aortic aneurysm and dissection (TAAD). Aneurysmsand dissections of the aorta usually result from degenerativechanges in the aortic wall. Thoracic aortic aneurysms anddissections are primarily associated with a characteristichistologic appearance known as 'medial necrosis' or 'Erdheimcystic medial necrosis' in which there is degeneration andfragmentation of elastic fibers, loss of smooth muscle cells, andan accumulation of basophilic ground substance. Patients with AAT4show marked aortic stiffness. Pathological aortas show large areasof medial degeneration with very low smooth muscle cells content.

Defects in MYH14 are the cause of deafness autosomaldominant type 4 (DFNA4) [MIM:600652]. DFNA4 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in MYH2 are the cause of inclusion body myopathytype 3 (IBM3) [MIM:605637]. Hereditary inclusion body myopathiesconstitute a group of neuromuscular disorders characterized byslowly progressive distal and proximal weakness and a typicalmuscle pathology including rimmed vacuoles and filamentousinclusions. IBM3 is a variant of hereditary inclusion bodymyopathies and is characterized by autosomal dominant myopathywith joint contracture, ophthalmoplegia and rimmed vacuoles.Morphological analysis of muscle biopsies from patients indicatethat the type 2A fibers frequently were abnormal, whereas otherfiber types appeared normal.

Defects in MYH3 are the cause of distal arthrogryposistype 2A (DA2A) [MIM:193700], also known as Freeman-Sheldonsyndrome (FSS). Distal arthrogryposis is a clinically andgenetically heterogeneous group of disorders characterized by boneanomalies and joint contractures of the hands and feet, causingmedially overlapping fingers, clenched fists, ulnar deviation offingers, camptodactyly and positional foot deformities. It is adisorder of primary limb malformation without primary neurologicor muscle disease. DA2A is the most severe form of distalarthrogryposis. Affected individuals have contractures of theorofacial muscles, characterized by microstomia with pouting lips,H-shaped dimpling of the chin, deep nasolabial folds, andblepharophimosis. Dysphagia, failure to thrive, growth deficit,and life-threatening respiratory complications (caused bystructural anomalies of the oropharynx and upper airways) arefrequent. Inheritance is autosomal dominant.

Defects in MYH3 are the cause of distal arthrogryposistype 2B (DA2B) [MIM:601680], also known as Sheldon-Hall syndrome(SHS) or arthrogryposis multiplex congenita distal type 2B(AMCD2B). DA2B is a form of inherited multiple congenitalcontractures. Affected individuals have vertical talus, ulnardeviation in the hands, severe camptodactyly, and a distinctiveface characterized by a triangular shape, prominent nasolabialfolds, small mouth and a prominent chin. DA2B is the most commonof the distal arthrogryposis syndromes. It is similar to DA2A butthe facial contractures are less dramatic.

Defects in MYH6 are the cause of atrial septal defecttype 3 (ASD3) [MIM:160710]. ASD3 is a congenital heartmalformation characterized by incomplete closure of the wallbetween the atria resulting in blood flow from the left to theright atria.

Defects in MYH6 are the cause of cardiomyopathy familialhypertrophic type 14 (CMH14) [MIM:613251]. It is a hereditaryheart disorder characterized by ventricular hypertrophy, which isusually asymmetric and often involves the interventricular septum.The symptoms include dyspnea, syncope, collapse, palpitations,andchest pain. They can be readily provoked by exercise. The disorderhas inter- and intrafamilial variability ranging from benign tomalignant forms with high risk of cardiac failure and suddencardiac death.

Defects in MYH6 are the cause of cardiomyopathy dilatedtype 1EE (CMD1EE) [MIM:613252]. It is a disorder characterized byventricular dilation and impaired systolic function, resulting incongestive heart failure and arrhythmia. Patients are at risk ofpremature death.

Defects in MYH7 are the cause of cardiomyopathy familialhypertrophic type 1 (CMH1) [MIM:192600]. Familial hypertrophiccardiomyopathy is a hereditary heart disorder characterized byventricular hypertrophy, which is usually asymmetric and ofteninvolves the interventricular septum. The symptoms includedyspnea, syncope, collapse, palpitations, and chest pain. They canbe readily provoked by exercise. The disorder has inter- andintrafamilial variability ranging from benign to malignant formswith high risk of cardiac failure and sudden cardiac death.

Defects in MYH7 are the cause of myopathy myosin storage(MYOMS) [MIM:608358]. In this disorder, muscle biopsy shows type 1fiber predominance and increased interstitial fat and connectivetissue. Inclusion bodies consisting of the beta cardiac myosinheavy chain are present in the majority of type 1 fibers, but notin type 2 fibers.

Defects in MYH7 are the cause of scapuloperoneal myopathyMYH7-related (SPMM) [MIM:181430], also known as scapuloperonealsyndrome myopathic type. SPMM is a progressive muscular atrophiabeginning in the lower legs and affecting the shoulder regionearlier and more severely than distal arm.

Defects in MYH7 are a cause of cardiomyopathy dilatedtype 1S (CMD1S) [MIM:613426]. Dilated cardiomyopathy is a disordercharacterized by ventricular dilation and impaired systolicfunction, resulting in congestive heart failure and arrhythmia.Patients are at risk of premature death.

Defects in MYH7 are the cause of myopathy distal type 1(MPD1) [MIM:160500]. MPD1 is a muscular disorder characterized byearly-onset selective weakness of the great toe and ankledorsiflexors, followed by weakness of the finger extensors. Mildproximal weakness occasionally develops years later after theonset of the disease.

Defects in MYH8 are a cause of Carney complex variant(CACOV) [MIM:608837]. Carney complex is a multiple neoplasiasyndrome characterized by spotty skin pigmentation, cardiac andother myxomas, endocrine tumors, and psammomatous melanoticschwannomas. Familial cardiac myxomas are associated with spottypigmentation of the skin and other phenotypes, including primarypigmented nodular adrenocortical dysplasia, extracardiac(frequently cutaneous) myxomas, schwannomas, and pituitary,thyroid, testicular, bone, ovarian, and breast tumors. Cardiacmyxomas do not develop in all patients with the Carney complex,but affected patients have at least two features of the complex orone feature and a clinically significant family history.

Defects in MYH8 are a cause of trismus-pseudocamptodactyly syndrome (TPCS) [MIM:158300]. Trismus-pseudocamptodactyly syndrome is a hereditary distal arthrogryposischaracterized by an inability to open the mouth fully (trismus)and pseudocamptodactyly in which wrist dorsiflexion, but notvolarflexion, produces involuntary flexion contracture of distaland proximal interphalangeal joints. Such hand and jawcontractures are caused by shortened flexor muscle-tendon units.Similar lower-limb contractures also produce foot deformity. Thetrismus-pseudocamptodactyly syndrome is a morbid autosomaldominant trait with variable expressivity but high penetrance. Inthese patients, trismus complicates dental care, feeding duringinfancy, and intubation for anesthesia, and thepseudocamptodactyly impairs manual dexterity, with consequentoccupational and social disability. Many patients require surgicalcorrection of contractures.

Defects in MYH9 are the cause of May-Hegglin anomaly(MHA) [MIM:155100]. MHA is an autosomal dominantmacrothrombocytopenia characterized by thrombocytopenia, giantplatelets and leukokyte inclusions appearing as highly parallelparacrystalline bodies.

Defects in MYH9 are the cause of Sebastian syndrome (SBS)[MIM:605249]. SBS is an autosomal dominant macrothrombocytopeniacharacterized by thrombocytopenia, giant platelets and leukocyteinclusions that are smaller and less organized than in May-Hegglinanomaly.

Defects in MYH9 are the cause of Fechtner syndrome (FTNS)[MIM:153640]. FTNS is an autosomal dominant macrothrombocytopeniacharacterized by thrombocytopenia, giant platelets and leukocyteinclusions that are small and poorly organized. Additionally, FTNSis distinguished by Alport-like clinical features of sensorineuraldeafness, cataracts and nephritis.

Defects in MYH9 are the cause of Alport syndrome withmacrothrombocytopenia (APSM) [MIM:153650]. APSM is an autosomaldominant disorder characterized by the association of ocularlesions, sensorineural hearing loss and nephritis (Alportsyndrome) with platelet defects.

Defects in MYH9 are the cause of Epstein syndrome (EPS)[MIM:153650]. EPS is an autosomal dominant disorder characterizedby the association of macrothrombocytopathy, sensorineural hearingloss and nephritis.

Defects in MYH9 are the cause of deafness autosomaldominant type 17 (DFNA17) [MIM:603622]. DFNA17 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information. DFNA17 is characterized by progressive hearingimpairment and cochleosaccular degeneration.

Defects in MYH9 are the cause of macrothrombocytopeniawith progressive sensorineural deafness (MPSD) [MIM:600208]. MPSDis an autosomal dominant disorder characterized by the associationof macrothrombocytopathy and progressive sensorineural hearingloss without renal dysfunction.

Note=Subjects with mutations in the motor domain of MYH9present with severe thrombocytopenia and develop nephritis anddeafness before the age of 40 years, while those with mutations inthe tail domain have a much lower risk of noncongenitalcomplications and significantly higher platelet counts. Theclinical course of patients with mutations in the four mostfrequently affected residues of MYH9 (responsible for 70% of MYH9-related cases) were evaluated. Mutations at residue 1933 do notinduce kidney damage or cataracts and cause deafness only in theelderly, those in position 702 result in severe thrombocytopeniaand produce nephritis and deafness at a juvenile age, whilealterations at residue 1424 or 1841 result in intermediateclinical pictures.

Note=Genetic variations in MYH9 are associated with non-diabetic end stage renal disease (ESRD).

Defects in MYL3 are the cause of cardiomyopathy familialhypertrophic type 8 (CMH8) [MIM:608751]. Familial hypertrophiccardiomyopathy is a hereditary heart disorder characterized byventricular hypertrophy, which is usually asymmetric and ofteninvolves the interventricular septum. The symptoms includedyspnea, syncope, collapse, palpitations, and chest pain. They canbe readily provoked by exercise. The disorder has inter- andintrafamilial variability ranging from benign to malignant formswith high risk of cardiac failure and sudden cardiac death. CMH8inheritance can be autosomal dominant or recessive.

Defects in MYL3 are the cause of cardiomyopathy familialhypertrophic with mid-left ventricular chamber type 1 (MVC1)[MIM:608751]. MVC1 is a very rare variant of familial hypertrophiccardiomyopathy, characterized by mid-left ventricular chamberthickening.

Defects in MYLK2 are a cause of cardiomyopathy familialhypertrophic (CMH) [MIM:192600], also designated FHC or HCM.Familial hypertrophic cardiomyopathy is a hereditary heartdisorder characterized by ventricular hypertrophy, which isusually asymmetric and often involves the interventricular septum.The symptoms include dyspnea, syncope, collapse, palpitations, andchest pain. They can be readily provoked by exercise. The disorderhas inter- and intrafamilial variability ranging from benign tomalignant forms with high risk of cardiac failure and suddencardiac death.

Defects in MYO15A are the cause of deafness autosomalrecessive type 3 (DFNB3) [MIM:600316]. DFNB3 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in MYO1A are the cause of deafness autosomaldominant type 48 (DFNA48) [MIM:607841]. DFNA48 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in MYO3A are the cause of deafness autosomalrecessive type 30 (DFNB30) [MIM:607101]. DFNB30 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in MYO5A are a cause of Griscelli syndrome type 1(GS1) [MIM:214450], also known as Griscelli syndrome with primaryneurologic impairment. Griscelli syndrome is a rare autosomalrecessive disorder that results in pigmentary dilution of the skinand hair, the presence of large clumps of pigment in hair shafts,silvery-gray hair and accumulation of melanosomes in melanocytes.GS1 patients show developmental delay, hypotonia and mentalretardation, without apparent immune abnormalities.

Defects in MYO5A are a cause of Griscelli syndrome type 3(GS3) [MIM:609227]. GS3 is characterized by pigmentary dilution ofthe skin and hair, the presence of large clumps of pigment in hairshafts, silvery-gray hair and accumulation of melanosomes inmelanocytes, without other clinical manifestations.

Defects in MYO5A are a cause of Elejalde syndrome(ELEJAS) [MIM:256710], also known as neuroectodermalmelanolysosomal disease. Elejalde syndrome is an autosomalrecessive condition characterized by skin hypopigmentation, thepresence of large clumps of pigment in hair shafts, silvery-grayhair, accumulation of melanosomes in melanocytes and primaryneurological abnormalities. Elejalde syndrome may be the sameentity as Griscelli syndrome type 1.

Defects in MYO5B are a cause of diarrhea type 2 (DIAR2)[MIM:251850]. DIAR2 is characterized by onset of intractable life-threatening watery diarrhea during infancy. Two forms arerecognized: early-onset MVID with diarrhea beginning in theneonatal period, and late-onset, with first symptoms appearingafter 3 or 4 months of life.

Defects in MYO6 are the cause of deafness autosomaldominant type 22 (DFNA22) [MIM:606346]. DFNA22 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information. DFNA22 is progressive and postlingual, withonset during childhood. By the age of approximately 50 years,affected individuals invariably have profound sensorineuraldeafness.

Defects in MYO6 are the cause of deafness autosomalrecessive type 37 (DFNB37) [MIM:607821].

Defects in MYO6 are the cause of deafness sensorineuralwith hypertrophic cardiomyopathy (DFNHCM) [MIM:606346].

Defects in MYO7A are the cause of Usher syndrome type 1B(USH1B) [MIM:276900]. USH is a genetically heterogeneous conditioncharacterized by the association of retinitis pigmentosa andsensorineural deafness. Age at onset and differences in auditoryand vestibular function distinguish Usher syndrome type 1 (USH1),Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3).USH1 is characterized by profound congenital sensorineuraldeafness, absent vestibular function and prepubertal onset ofprogressive retinitis pigmentosa leading to blindness.

Defects in MYO7A are the cause of deafness autosomalrecessive type 2 (DFNB2) [MIM:600060], also called neurosensorynon-syndromic recessive deafness 2 (NSRD2). DFNB2 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in MYO7A are the cause of deafness autosomaldominant type 11 (DFNA11) [MIM:601317].

Genetic variation in MYO9B is the cause of susceptibilityto celiac disease type 4 (CELIAC4) [MIM:609753]. It is amultifactorial disorder of the small intestine that is influencedby both environmental and genetic factors. It is characterized bymalabsorption resulting from inflammatory injury to the mucosa ofthe small intestine after the ingestion of wheat gluten or relatedrye and barley proteins. In its classic form, celiac disease ischaracterized in children by malabsorption and failure to thrive.

Defects in MYOC are the cause of primary open angleglaucoma type 1A (GLC1A) [MIM:137750]. Primary open angle glaucoma(POAG) is characterized by a specific pattern of optic nerve andvisual field defects. The angle of the anterior chamber of the eyeis open, and usually the intraocular pressure is increased. Thedisease is asymptomatic until the late stages, by which timesignificant and irreversible optic nerve damage has already takenplace.

Defects in MYOC may also contribute to primary congenitalglaucoma type 3A (GLC3A) [MIM:231300]. Defects in MYOC maycontribute to this phenotype via digenic inheritance. GLC3A is anautosomal recessive form of primary congenital glaucoma (PCG). PCGis characterized by marked increase of intraocular pressure atbirth or early choldhood, large ocular globes (buphthalmos) andcorneal edema. It results from developmental defects of thetrabecular meshwork and anterior chamber angle of the eye thatprevent adequate drainage of aqueous humor.

Note=A chromosomal aberration involving PDE4DIP may bethe cause of a myeloproliferative disorder (MBD) associated witheosinophilia. Translocation t(1,5)(q23,q33) that forms a PDE4DIP-PDGFRB fusion protein.

Defects in MYOT are the cause of limb-girdle musculardystrophy type 1A (LGMD1A) [MIM:159000]. LGMD1A is an autosomaldominant degenerative myopathy with onset within a mean age of 28years. LGMD1A is characterized by progressive skeletal muscleweakness of the hip and shoulder girdles, later progressing toinclude distal weakness, as well as a distinctive dysarthricpattern of speech. Affected muscle exhibits disorganization andstreaming of the Z-line.

Defects in MYOT are the cause of myopathy myofibrillarmyotylin-related (MFM-MYOT) [MIM:609200]. A neuromuscular disordercharacterized by progressive skeletal muscle weakness greaterdistally than proximally, tight heel cords, hyporeflexia,cardiomyopathy and peripheral neuropathy in some patients.Affected muscle exhibits disorganization and streaming of the Z-line, presence of large hyaline structures, excessive accumulationof myotilin and other ectopically expressed proteins and prominentcongophilic deposits.

Defects in MYOT are the cause of spheroid body myopathy(SBM) [MIM:182920]. SBM is an autosomal dominant form ofmyofibrillar myopathy (MFM), characterized by slowly progressingproximal muscle weakness and dysarthric nasal speech. There is noevidence of cardiomyopathy. Muscle biopsy shows spheroid bodieswithin the type I muscle fibers.

Defects in MPZ are the cause of Charcot-Marie-Toothdisease type 1B (CMT1B) [MIM:118200]. CMT1B is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of theperipheral nervous system. Charcot-Marie-Tooth disease isclassified in two main groups on the basis of electrophysiologicproperties and histopathology: primary peripheral demyelinatingneuropathy or CMT1, and primary peripheral axonal neuropathy orCMT2. Neuropathies of the CMT1 group are characterized by severelyreduced nerve conduction velocities (less than 38 m/sec),segmental demyelination and remyelination with onion bulbformations on nerve biopsy, slowly progressive distal muscleatrophy and weakness, absent deep tendon reflexes, and hollowfeet.

Defects in MPZ are the cause of Charcot-Marie-Toothdisease type 2I (CMT2I) [MIM:607677]. CMT2I is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of theperipheral nervous system. Charcot-Marie-Tooth disease isclassified in two main groups on the basis of electrophysiologicproperties and histopathology: primary peripheral demyelinatingneuropathy or CMT1, and primary peripheral axonal neuropathy orCMT2. Neuropathies of the CMT2 group are characterized by signs ofaxonal regeneration in the absence of obvious myelin alterations,normal or slightly reduced nerve conduction velocities, andprogressive distal muscle weakness and atrophy. CMT2I ischaracterized by late onset (range 47 to 60 years).

Defects in MPZ are the cause of Charcot-Marie-Toothdisease type 2J (CMT2J) [MIM:607736]. CMT2J is a form of Charcot-Marie-Tooth disease characterized by the association of axonalperipheral neuropathy with hearing loss and pupillaryabnormalities such as Adie pupil. Inheritance is autosomaldominant.

Defects in MPZ are the cause of Adie pupil (ADIEP)[MIM:103100]. A stationary, benign disorder characterized bytonic, sluggishly reacting pupil and hypoactive or absent tendonreflexes. Adie pupil is a characteristic of Charcot-Marie-Toothdisease type 2J.

Defects in MPZ may be the cause of Charcot-Marie-Toothdisease dominant intermediate type D (CMTDID) [MIM:607791]. CMTDIDis a form of Charcot-Marie-Tooth disease characterized by featuresintermediate between demyelinating and axonal peripheralneuropathies, and motor median nerve conduction velocities rangingfrom 25 to 45 m/sec.

Defects in MPZ are a cause of Dejerine-Sottas syndrome(DSS) [MIM:145900], also known as Dejerine-Sottas neuropathy (DSN)or hereditary motor and sensory neuropathy III (HMSN3). DSS is asevere degenerating neuropathy of the demyelinating Charcot-Marie-Tooth disease category, with onset by age 2 years. DSS ischaracterized by motor and sensory neuropathy with very slow nerveconduction velocities, increased cerebrospinal fluid proteinconcentrations, hypertrophic nerve changes, delayed age of walkingas well as areflexia. There are both autosomal dominant andautosomal recessive forms of Dejerine-Sottas syndrome.

Defects in MPZ are a cause of congenital hypomyelinationneuropathy (CHN) [MIM:605253]. CHN is characterized clinically byearly onset of hypotonia, areflexia, distal muscle weakness, andvery slow nerve conduction velocities.

Defects in MPZ are a cause of Roussy-Levy syndrome(ROULS) [MIM:180800], also known as Roussy-Levy hereditaryareflexic dystasia. This autosomal dominant disorder resemblesCharcot-Marie-Tooth disease type 1 in that it presents with footdeformity, weakness and atrophy of distal limb muscles, especiallythe peronei, and absent tendon reflexes. The phenotype differs,however, in that it includes static tremor of the upper limbs andgait ataxia.

Defects in MYBPC3 are the cause of cardiomyopathyfamilial hypertrophic type 4 (CMH4) [MIM:115197]. Familialhypertrophic cardiomyopathy is a hereditary heart disordercharacterized by ventricular hypertrophy, which is usuallyasymmetric and often involves the interventricular septum. Thesymptoms include dyspnea, syncope, collapse, palpitations, andchest pain. They can be readily provoked by exercise. The disorderhas inter- and intrafamilial variability ranging from benign tomalignant forms with high risk of cardiac failure and suddencardiac death.

Defects in PLP1 are the cause of leukodystrophyhypomyelinating type 1 (HLD1) [MIM:312080], also known asPelizaeus-Merzbacher disease. HLD1 is an X-linked recessivedysmyelinating disorder of the central nervous system in whichmyelin is not formed properly. It is characterized clinically bynystagmus, spastic quadriplegia, ataxia, and developmental delay.

Defects in PLP1 are the cause of spastic paraplegia X-linked type 2 (SPG2) [MIM:312920]. SPG2 is characterized byspastic gait and hyperreflexia. In some patients, complicatingfeatures include nystagmus, dysarthria, sensory disturbance,mental retardation, optic atrophy.

Note=Chromosomal aberrations involving MYST3 may be acause of acute myeloid leukemias. Translocation t(8,16)(p11,p13)with CREBBP, translocation t(8,22)(p11,q13) with EP300. MYST3-CREBBP may induce leukemia by inhibiting RUNX1-mediatedtranscription. Inversion inv(8)(p11,q13) generates the MYST3-NCOA2oncogene, which consists of the N-terminus part of MYST3/MOZ andthe C-terminus part of NCOA2/TIF2. MYST3-NCOA2 binds to CREBBP anddisrupts its function in transcription activation.

Note=A chromosomal aberration involving MYST3 is a causeof therapy-related myelodysplastic syndrome. Translocationt(2,8)(p23,p11.2) with ASXL2 generates a MYST3-ASXL2 fusionprotein.

Note=A chromosomal aberration involving MYST4 may be acause acute myeloid leukemias. Translocation t(10,16)(q22,p13)with CREBBP.

Defects in NAGA are the cause of Schindler disease(SCHIND) [MIM:609241]. Schindler disease is a form of NAGAdeficiency characterized by early onset neuroaxonal dystrophy andneurological signs (convulsion during fever, epilepsy, psychomotorretardation and hypotonia). NAGA deficiency is typicallyclassified in three main phenotypes: NAGA deficiency type I(Schindler disease or Schindler disease type I) with severemanifestations, NAGA deficiency type II (Kanzazi disease orSchindler disease type II) which is mild, NAGA deficiency type III(Schindler disease type III) characterized by mild-to-moderateneurologic manifestations. NAGA deficiency results in theincreased urinary excretion of glycopeptides and oligosaccharidescontaining alpha-N-acetylgalactosaminyl moieties. Inheritance isautosomal recessive.

Defects in NAGA are the cause of Kanzaki disease (KANZD)[MIM:609242], also known as NAGA deficiency type II or Schindlerdisease type II. Kanzaki disease is an autosomal recessivedisorder characterized by late onset, angiokeratoma corporisdiffusum and mild intellectual impairment.

Defects in NAGS are the cause of N-acetylglutamatesynthase deficiency (NAGSD) [MIM:237310]. NAGSD is a rareautosomal recessively inherited metabolic disorder leading tosevere neonatal or late onset hyperammonemia without increasedexcretion of orotic acid. Clinical symptoms are somnolence,tachypnea, feeding difficulties, a severe neurologic presentationcharacterized by uncontrollable movements, developmental delay,visual impairment, failure to thrive and hyperammonemiaprecipitated by the introduction of high-protein diet or febrileillness.

Defects in NLRP12 are the cause of familial coldautoinflammatory syndrome type 2 (FCAS2) [MIM:611762]. FCAS arerare autosomal dominant systemic inflammatory diseasescharacterized by episodes of rash, arthralgia, fever andconjunctivitis after generalized exposure to cold.

Genetic variations in NLRP1 are associated withsusceptibility to vitiligo (VTLG) [MIM:193200]. VTLG is apigmentary disorder of the skin characterized by circumscribeddepigmented macules and patches, commonly on extensor aspects ofextremities, on the face or neck and in skin folds. It is aprogressive disorder in which some or all of the melanocytes inthe affected skin are selectively destroyed. It is amultifactorial disorder with a complex etiology probably includingautoimmune mechanisms, and is associated with an elevated risk ofother autoimmune diseases.

Genetic variations in NLRP1 gene are associated withsusceptibility to vitiligo-associated multiple autoimmune diseasetype 1 (VAMAS1) [MIM:606579]. VAMAS1 is an autoimmune disordercharacterized by the association of vitiligo with severalautoimmune and autoinflammatory diseases including autoimmunethyroid disease, rheumatoid arthritis and systemic lupuserythematosus.

Defects in NLRP3 are the cause of familial coldautoinflammatory syndrome type 1 (FCAS1) [MIM:120100], also knownas familial cold urticaria. FCAS are rare autosomal dominantsystemic inflammatory diseases characterized by episodes of rash,arthralgia, fever and conjunctivitis after generalized exposure tocold.

Defects in NLRP3 are a cause of Muckle-Wells syndrome(MWS) [MIM:191900], also known as urticaria-deafness-amyloidosissyndrome. MWS is a hereditary periodic fever syndromecharacterized by fever, chronic recurrent urticaria, arthralgias,progressive sensorineural deafness, and reactive renalamyloidosis. The disease may be severe if generalized amyloidosisoccurs.

Defects in NLRP3 are the cause of chronic infantileneurologic cutaneous and articular syndrome (CINCA) [MIM:607115],also known as neonatal onset multisystem inflammatory disease(NOMID). CINCA is a rare congenital inflammatory disordercharacterized by a triad of neonatal onset of cutaneous symptoms,chronic meningitis and joint manifestations with recurrent feverand inflammation.

Defects in NLRP7 are the cause of hydatidiform mole(HYDM) [MIM:231090]. HYDM is an abnormal human pregnancy with noembryo and cystic degeneration of placental villi.

Note=A chromosomal aberration disrupting NAV3 has beenfound in patients with Sezary syndrome. Translocationt(12,18)(q21,q21.2).

Defects in CYB5R3 are the cause of methemoglobinemiaCYB5R3-related (METHB-CYB5R3) [MIM:250800]. A form ofmethemoglobinemia, a hematologic disease characterized by thepresence of excessive amounts of methemoglobin in blood cells,resulting in decreased oxygen carrying capacity of the blood,cyanosis and hypoxia. There are two types of methemoglobinemiaCYB5R3-related. In type 1, the defect affects the soluble form ofthe enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type 2, the defect affects boththe soluble and microsomal forms of the enzyme and is thusgeneralized, affecting red cells, leukocytes and all body tissues.Type 2 methemoglobinemia is associated with mental deficiency andother neurologic symptoms.

Defects in NBN are the cause of Nijmegen breakagesyndrome (NBS) [MIM:251260]. NBS is an autosomal recessivesyndrome characterized by chromosomal instability, radiationsensitivity, microcephaly, growth retardation, immunodeficiencyand predisposition to cancer, particularly to lymphoidmalignancies.

Defects in NBN are a cause of susceptibility to breastcancer (BC) [MIM:114480]. A common malignancy originating frombreast epithelial tissue. Breast neoplasms can be distinguished bytheir histologic pattern. Invasive ductal carcinoma is by far themost common type. Breast cancer is etiologically and geneticallyheterogeneous. Important genetic factors have been indicated byfamilial occurrence and bilateral involvement. Mutations at morethan one locus can be involved in different families or even inthe same case.

Defects in NBN may be associated with aplastic anemia(AA) [MIM:609135]. A form of anemia in which the bone marrow failsto produce adequate numbers of peripheral blood elements. It ischaracterized by peripheral pancytopenia and marrow hypoplasia.

Note=Defects in NBN might play a role in the pathogenesisof childhood acute lymphoblastic leukemia (ALL).

Defects in NCF1 are the cause of chronic granulomatousdisease autosomal recessive cytochrome-b-positive type 1 (CGD1)[MIM:233700]. Chronic granulomatous disease is a geneticallyheterogeneous disorder characterized by the inability ofneutrophils and phagocytes to kill microbes that they haveingested. Patients suffer from life-threatening bacterial/fungalinfections.

Defects in NCF2 are a cause of chronic granulomatousdisease autosomal recessive cytochrome-b-positive type 2 (CGD2)[MIM:233710]. Chronic granulomatous disease is a geneticallyheterogeneous disorder characterized by the inability ofneutrophils and phagocytes to kill microbes that they haveingested. Patients suffer from life-threatening bacterial/fungalinfections.

Note=A chromosomal aberration involving NCOA1 is a causeof rhabdomyosarcoma. Translocation t(2,2)(q35,p23) with PAX3generates the NCOA1-PAX3 oncogene consisting of the N-terminuspart of PAX3 and the C-terminus part of NCOA1. The fusion proteinacts as a transcriptional activator. Rhabdomyosarcoma is the mostcommon soft tissue carcinoma in childhood, representing 5-8% ofall malignancies in children.

Note=Chromosomal aberrations involving NCOA2 may be acause of acute myeloid leukemias. Inversion inv(8)(p11,q13)generates the MYST3-NCOA2 oncogene, which consists of the N-terminus part of MYST3/MOZ and the C-terminus part of NCOA2/TIF2.MYST3-NCOA2 binds to CREBBP and disrupts its function intranscription activation.

Defects in NCOA4 are a cause of thyroid papillarycarcinoma (TPC) [MIM:188550]. TPC is a common tumor of the thyroidthat typically arises as an irregular, solid or cystic mass fromotherwise normal thyroid tissue. Papillary carcinomas aremalignant neoplasm characterized by the formation of numerous,irregular, finger-like projections of fibrous stroma that iscovered with a surface layer of neoplastic epithelial cells.Note=A chromosomal aberration involving NCOA4 is found in thyroidpapillary carcinomas. Inversion inv(10)(q11.2,q11.2) generates theRET/NCOA4 (PTC3) oncogene that has been found in sporadic andradiation-associated post-Chernobyl thyroid papillary carcinomas.

Defects in POR are the cause of adrenal hyperplasiavariant type (AHV) [MIM:201750], also known as Antley-Bixlersyndrome-like phenotype with disordered steroidogenesis. AHV is arare variant of congenital adrenal hyperplasia. It is an autosomalrecessive disorder with apparent combined P450C17 and P450C21deficiency. Affected girls are born with ambiguous genitalia, buttheir circulating androgens are low and virilization does notprogress. Conversely, affected boys are sometimes bornundermasculinized. Boys and girls can also present with bonemalformations, in some cases resembling the pattern seen inpatients with Antley-Bixler syndrome.

Defects in POR are a cause of isolated disorderedsteroidogenesis (IDS) [MIM:201750].

Defects in NEUROD1 are the cause of maturity-onsetdiabetes of the young type 6 (MODY6) [MIM:606394]. MODY is a formof diabetes that is characterized by an autosomal dominant mode ofinheritance, onset in childhood or early adulthood (usually before25 years of age), a primary defect in insulin secretion andfrequent insulin-independence at the beginning of the disease.

Defects in NDP are the cause of Norrie disease (ND)[MIM:310600], also known as atrophia bulborum hereditaria orEpiskopi blindness. ND is a recessive disorder characterized byvery early childhood blindness due to degenerative andproliferative changes of the neuroretina. Approximately 50% ofpatients show some form of progressive mental disorder, often withpsychotic features, and about one-third of patients developsensorineural deafness in the second decade. In addition, somepatients have more complex phenotypes, including growth failureand seizure.

Defects in NDP are the cause of vitreoretinopathyexudative type 2 (EVR2) [MIM:305390]. EVR2 is a disorder of theretinal vasculature characterized by an abrupt cessation of growthof peripheral capillaries, leading to an avascular peripheralretina. This may lead to compensatory retinal neovascularization,which is thought to be induced by hypoxia from the initialavascular insult. New vessels are prone to leakage and rupturecausing exudates and bleeding, followed by scarring, retinaldetachment and blindness. Clinical features can be highlyvariable, even within the same family. Patients with mild forms ofthe disease are asymptomatic, and their only disease relatedabnormality is an arc of avascular retina in the extreme temporalperiphery.

Defects in NDRG1 are the cause of Charcot-Marie-Toothdisease type 4D (CMT4D) [MIM:601455], also known as hereditarymotor and sensory neuropathy Lom type (HMSNL). CMT4D is arecessive form of Charcot-Marie-Tooth disease, the most commoninherited disorder of the peripheral nervous system. Charcot-Marie-Tooth disease is classified in two main groups on the basisof electrophysiologic properties and histopathology: primaryperipheral demyelinating neuropathy and primary peripheral axonalneuropathy. Demyelinating CMT neuropathies are characterized byseverely reduced nerve conduction velocities (less than 38 m/sec),segmental demyelination and remyelination with onion bulbformations on nerve biopsy, slowly progressive distal muscleatrophy and weakness, absent deep tendon reflexes, and hollowfeet. By convention, autosomal recessive forms of demyelinatingCharcot-Marie-Tooth disease are designated CMT4.

Defects in NDUFA1 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinical disorders,from lethal neonatal disease to adult-onset neurodegenerativedisorders. Phenotypes include macrocephaly with progressiveleukodystrophy, non-specific encephalopathy, cardiomyopathy,myopathy, liver disease, Leigh syndrome, Leber hereditary opticneuropathy, and some forms of Parkinson disease.

Defects in NDUFA11 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinicalmanifestations, from lethal neonatal disease to adult-onsetneurodegenerative disorders. Phenotypes include macrocephaly withprogressive leukodystrophy, non-specific encephalopathy,cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leberhereditary optic neuropathy and some forms of Parkinson disease.

Defects in NDUFAF3 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinical disorders,from lethal neonatal disease to adult-onset neurodegenerativedisorders. Phenotypes include macrocephaly with progressiveleukodystrophy, non-specific encephalopathy, cardiomyopathy,myopathy, liver disease, Leigh syndrome, Leber hereditary opticneuropathy, and some forms of Parkinson disease.

Defects in NDUFAF4 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinical disorders,from lethal neonatal disease to adult-onset neurodegenerativedisorders. Phenotypes include macrocephaly with progressiveleukodystrophy, non-specific encephalopathy, cardiomyopathy,myopathy, liver disease, Leigh syndrome, Leber hereditary opticneuropathy, and some forms of Parkinson disease.

Defects in NDUFS1 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinical disorders,from lethal neonatal disease to adult-onset neurodegenerativedisorders. Phenotypes include macrocephaly with progressiveleukodystrophy, non-specific encephalopathy, cardiomyopathy,myopathy, liver disease, Leigh syndrome, Leber hereditary opticneuropathy, and some forms of Parkinson disease.

Defects in NDUFS2 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinical disorders,from lethal neonatal disease to adult-onset neurodegenerativedisorders. Phenotypes include macrocephaly with progressiveleukodystrophy, non-specific encephalopathy, cardiomyopathy,myopathy, liver disease, Leigh syndrome, Leber hereditary opticneuropathy, and some forms of Parkinson disease.

Defects in NDUFS4 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinical disorders,from lethal neonatal disease to adult-onset neurodegenerativedisorders. Phenotypes include macrocephaly with progressiveleukodystrophy, non-specific encephalopathy, cardiomyopathy,myopathy, liver disease, Leigh syndrome, Leber hereditary opticneuropathy, and some forms of Parkinson disease.

Defects in NDUFS7 are a cause of Leigh syndrome (LS)[MIM:256000]. LS is a severe neurological disorder characterizedby bilaterally symmetrical necrotic lesions in subcortical brainregions.

Defects in NDUFS7 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinical disorders,from lethal neonatal disease to adult-onset neurodegenerativedisorders. Phenotypes include macrocephaly with progressiveleukodystrophy, non-specific encephalopathy, cardiomyopathy,myopathy, liver disease, Leigh syndrome, Leber hereditary opticneuropathy, and some forms of Parkinson disease.

Defects in NDUFS8 are a cause of Leigh syndrome (LS)[MIM:256000]. LS is a severe neurological disorder characterizedby bilaterally symmetrical necrotic lesions in subcortical brainregions.

Defects in NDUFV1 are a cause of Leigh syndrome (LS)[MIM:256000]. LS is a severe neurological disorder characterizedby bilaterally symmetrical necrotic lesions in subcortical brainregions.

Defects in NDUFV1 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinical disorders,from lethal neonatal disease to adult-onset neurodegenerativedisorders. Phenotypes include macrocephaly with progressiveleukodystrophy, non-specific encephalopathy, cardiomyopathy,myopathy, liver disease, Leigh syndrome, Leber hereditary opticneuropathy, and some forms of Parkinson disease.

Defects in NEB are the cause of nemaline myopathy type 2(NEM2) [MIM:256030]. A form of nemaline myopathy. Nemalinemyopathies are muscular disorders characterized by muscle weaknessof varying severity and onset, and abnormal thread-or rod-likestructures in muscle fibers on histologic examination.

Defects in PCSK1 are the cause of proprotein convertase 1deficiency (PC1 deficiency) [MIM:600955]. PC1 deficiency ischaracterized by obesity, hypogonadism, hypoadrenalism, reactivehypoglycemia as well as marked small-intestinal absorptivedysfunction It is due to impaired processing of prohormones.

Defects in NEK1 are the cause of short rib-polydactylysyndrome type 2 (SRPS2) [MIM:263520]. A lethal skeletal dysplasiacharacterized by markedly short ribs, short limbs, polydactyly,and multiple anomalies including a narrow thorax with hypoplasticlungs, extreme polysyndactyly, dysproportionate dwarfism, mediancleft lip and palate, a ventriculoseptal defect and cystickidneys. The radiographic hallmarks include shortened andhorizontal ribs, squared scapulae and elevated clavicles withlateral kinking, normal spine and pelvis configuration, andshortening of the bones of all four extremities, with extremereduction of tibial bone length.

Defects in NELF may be associated with idiopathichypogonadotropic hypogonadism (IHH) [MIM:146110]. IHH is definedas a deficiency of the pituitary secretion of follicle-stimulatinghormone and luteinizing hormone, which results in the impairmentof pubertal maturation and of reproductive function.

Defects in IKBKG are the cause of ectodermal dysplasiaanhidrotic with immunodeficiency X-linked (EDAID) [MIM:300291],also known as hypohidrotic ectodermal dysplasia withimmunodeficiency (HED-ID). Is a form of ectoderma dysplasia, aheterogeneous group of disorders due to abnormal development oftwo or more ectodermal structures. Characterized by absence ofsweat glands, sparse scalp hair, rare conical teeth andimmunological abnormalities resulting in severe infectiousdiseases.

Defects in IKBKG are the cause of ectodermal dysplasiaanhidrotic with immunodeficiency-osteopetrosis-lymphedema(OLEDAID) [MIM:300301].

Defects in IKBKG are a cause of immunodeficiency NEMO-related without anhidrotic ectodermal dysplasia (NEMOID)[MIM:300584], also called immunodeficiency without anhidroticectodermal dysplasia, isolated immunodeficiency or pureimmunodeficiency. Patients manifest immunodeficiency notassociated with other abnormalities, and resulting in increasedinfection susceptibility. Patients suffer from multiple episodesof infectious diseases.

Defects in IKBKG are the cause of susceptibility to X-linked familial atypical micobacteriosis type 1 (AMCBX1)[MIM:300636], also known as X-linked disseminated atypicalmycobacterial infection type 1 or X-linked susceptibility tomycobacterial disease type 1. AMCBX1 is the X-linked recessiveform of mendelian susceptibility to mycobacterial disease (MSMD).MSMD is a congenital syndrome resulting in predisposition toclinical disease caused by weakly virulent mycobacterial species,such as bacillus Calmette-Guerin vaccines and non-tuberculous,environmental mycobacteria. Patients are also susceptible to themore virulent species Mycobacterium tuberculosis.

Defects in IKBKG are the cause of recurrent isolatedinvasive pneumococcal disease type 2 (IPD2) [MIM:300640].Recurrent invasive pneumococcal disease (IPD) is defined as twoepisodes of IPD occurring at least 1 month apart, whether causedby the same or different serotypes or strains. Recurrent IPDoccurs in at least 2% of patients in most series, making IPD themost important known risk factor for subsequent IPD.

Defects in IKBKG are the cause of incontinentia pigmenti(IP) [MIM:308300], formerly designed familial incontinentiapigmenti type II (IP2). IP is a genodermatosis usually prenatallylethal in males. In affected females, it causes abnormalities ofthe skin, hair, eyes, nails, teeth, skeleton, heart, and centralnervous system. The prominent skin signs occur in four classiccutaneous stages: perinatal inflammatory vesicles, verrucouspatches, a distinctive pattern of hyperpigmentation and dermalscarring.

Defects in EMG1 are the cause of Bowen-Conradi syndrome(BWCNS) [MIM:211180]. BWCNS is a combination of malformationscharacterized in newborns by low birth weight, microcephaly, mildjoint restriction, a prominent nose, micrognathia, fifth fingerclinodactyly, and 'rocker-bottom' feet. The syndrome istransmitted as an autosomal recessive trait. The prognosis ispoor, with all infants dying within the first few months of life.

Defects in PRSS12 are the cause of mental retardationautosomal recessive type 1 (MRT1) [MIM:249500]. Mental retardationis a mental disorder characterized by significantly sub-averagegeneral intellectual functioning associated with impairments inadaptative behavior and manifested during the developmentalperiod. Non-syndromic mental retardation patients do not manifestother clinical signs.

Defects in AVP are the cause of autosomal dominantneurohypophyseal diabetes insipidus (ADNDI) [MIM:125700]. ADNDI ischaracterized by persistent thirst, polydipsia and polyuria. Thedisease is transmitted in an autosomal dominant mode and appearsto be largely if not completely penetrant.

Defects in AVP are the cause of autosomal recessiveneurohypophyseal diabetes insipidus (ARNDI) [MIM:125700]. ARNDI ischaracterized by persistent thirst, polydipsia and polyuria. Mostmutations are hypothesized to trigger neurodegeneration viadisruption of preproAVP-NPII processing.

Defects in NEU1 are the cause of sialidosis (SIALIDOSIS)[MIM:256550]. It is a lysosomal storage disease occurring as twotypes with various manifestations. Type 1 sialidosis (cherry redspot-myoclonus syndrome or normosomatic type) is late-onset and itis characterized by the formation of cherry red macular spots inchildhood, progressive debilitating myoclonus, insiduous visualloss and rarely ataxia. The diagnosis can be confirmed by thescreening of the urine for sialyloligosaccharides. Type 2sialidosis (also known as dysmorphic type) occurs as severalvariants of increasing severity with earlier age of onset. It ischaracterized by the presence of abnormal somatic featuresincluding coarse facies and dysostosis multiplex, vertebraldeformities, mental retardation, cherry-red spot/myoclonus,sialuria, cytoplasmic vacuolation of peripheral lymphocytes, bonemarrow cells and conjunctival epithelial cells.

Defects in SERPINI1 are the cause of familialencephalopathy with neuroserpin inclusion bodies (FEN1B)[MIM:604218]. FEN1B is characterized clinically as an autosomaldominantly inherited dementia, histologically by unique neuronalinclusion bodies and biochemically by polymers of neuroserpin.

Defects in NEXN are the cause of cardiomyopathy dilatedtype 1CC (CMD1CC) [MIM:613122]. A disorder characterized byventricular dilation and impaired systolic function, resulting incongestive heart failure and arrhythmia. Patients are at risk ofpremature death.

Defects in NF1 are the cause of neurofibromatosis type 1(NF1) [MIM:162200], also known as von Recklinghausen syndrome. Adisease characterized by patches of skin pigmentation (cafe-au-lait spots), Lisch nodules of the iris, tumors in the peripheralnervous system and fibromatous skin tumors. Individuals with thedisorder have increased susceptibility to the development ofbenign and malignant tumors.

Defects in NF1 are a cause of juvenile myelomonocyticleukemia (JMML) [MIM:607785]. JMML is a pediatric myelodysplasticsyndrome that constitutes approximately 30% of childhood cases ofmyelodysplastic syndrome (MDS) and 2% of leukemia. Germlinemutations of NF1 account for the association of JMML with type 1neurofibromatosis (NF1).

Defects in NF1 are the cause of Watson syndrome (WS)[MIM:193520]. WS is characterized by the presence of pulmonarystenosis, cafe-au-lait spots, and mental retardation. WS isconsidered as an atypical form of NF1.

Defects in NF1 are a cause of familial spinalneurofibromatosis (spinal NF) [MIM:162210]. Familial spinal NF isconsidered to be an alternative form of neurofibromatosis, showingmultiple spinal tumors.

Defects in NF1 are a cause of neurofibromatosis-Noonansyndrome (NFNS) [MIM:601321]. NFNS is characterized bymanifestations of both NF1 and Noonan syndrome (NS). NS is adisorder characterized by dysmorphic facial features, shortstature, hypertelorism, cardiac anomalies, deafness, motor delay,and a bleeding diathesis.

Defects in NF1 may be a cause of colorectal cancer (CRC)[MIM:114500].

Defects in NEFH are a cause of susceptibility toamyotrophic lateral sclerosis (ALS) [MIM:105400]. ALS is aneurodegenerative disorder affecting upper and lower motorneurons, and resulting in fatal paralysis. Sensory abnormalitiesare absent. Death usually occurs within 2 to 5 years. The etiologyis likely to be multifactorial, involving both genetic andenvironmental factors.

Note=A chromosomal aberration involving NFKB2 is found ina case of B-cell non Hodgkin lymphoma (B-NHL). Translocationt(10,14)(q24,q32) with IGHA1. The resulting oncogene is alsocalled Lyt-10C alpha variant.

Note=A chromosomal aberration involving NFKB2 is found ina cutaneous T-cell leukemia (C-TCL) cell line. This rearrangementproduces the p80HT gene which encodes for a truncated 80 kDaprotein (p80HT).

Note=In B-cell leukemia (B-CLL) cell line, LB40 andEB308, can be found after heterogeneous chromosomal aberrations,such as internal deletions.

Defects in NEFL are the cause of Charcot-Marie-Toothdisease type 1F (CMT1F) [MIM:607734]. CMT1F is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of theperipheral nervous system. Charcot-Marie-Tooth disease isclassified in two main groups on the basis of electrophysiologicproperties and histopathology: primary peripheral demyelinatingneuropathy or CMT1, and primary peripheral axonal neuropathy orCMT2. Neuropathies of the CMT1 group are characterized by severelyreduced nerve conduction velocities (less than 38 m/sec),segmental demyelination and remyelination with onion bulbformations on nerve biopsy, slowly progressive distal muscleatrophy and weakness, absent deep tendon reflexes, and hollowfeet. CMT1F is characterized by onset in infancy or childhood(range 1 to 13 years).

Defects in NEFL are the cause of Charcot-Marie-Toothdisease type 2E (CMT2E) [MIM:607684]. CMT2E is an autosomaldominant form of Charcot-Marie-Tooth disease type 2. Neuropathiesof the CMT2 group are characterized by signs of axonalregeneration in the absence of obvious myelin alterations, normalor slightly reduced nerve conduction velocities, and progressivedistal muscle weakness and atrophy.

Defects in NGF are the cause of hereditary sensory andautonomic neuropathy type 5 (HSAN5) [MIM:608654]. The hereditarysensory and autonomic neuropathies are a genetically andclinically heterogeneous group of disorders characterized bydegeneration of dorsal root and autonomic ganglion cells, and bysensory and/or autonomic abnormalities. HSAN5 patients manifestloss of pain perception and impaired temperature sensitivity,ulcers, and in some cases self-mutilation. The autonomicinvolvement is variable.

Defects in NEUROG3 are the cause of diarrhea type 4(DIAR4) [MIM:610370]. DIAR4 is a characterized by severe, life-threatening watery diarrhea associated with generalizedmalabsorption and a paucity of enteroendocrine cells.

Defects in NHEJ1 are the cause of severe combinedimmunodeficiency due to NHEJ1 deficiency (NHEJ1-SCID)[MIM:611291], also known as autosomal recessive T cell-negative, Bcell-negative, NK cell-positive, severe combined immunodeficiencywith microcephaly, growth retardation and sensitivity to ionizingradiation or NHEJ1 syndrome. SCID refers to a genetically andclinically heterogeneous group of rare congenital disorderscharacterized by impairment of both humoral and cell-mediatedimmunity, leukopenia and low or absent antibody levels. Patientswith SCID present in infancy with recurrent, persistent infectionsby opportunistic organisms. The common characteristic of all typesof SCID is absence of T-cell-mediated cellular immunity due to adefect in T-cell development. NHEJ1-SCID is characterized by aprofound T- and B-lymphocytopenia associated with increasedcellular sensitivity to ionizing radiation, microcephaly andgrowth retardation. Some patients may manifest SCID withsensitivity to ionizing radiation without microcephaly and mildgrowth retardation, probably due to hypomorphic NHEJ1 mutations.

Note=A chromosomal aberration involving NHEJ1 is found ina patient with polymicrogyria. Translocation t(2,7)(q35,p22).

Defects in NHLRC1 are a cause of progressive myoclonicepilepsy type 2 (EPM2) [MIM:254780], also known as Lafora disease.EPM2 is an autosomal recessive and severe form of adolescent-onsetprogressive epilepsy. Typically, as seizures increase infrequency, cognitive function declines towards dementia, andaffected individuals die usually within 10 years after onset. EPM2occurs worldwide, but it is particularly common in themediterranean countries of southern Europe and northern Africa, insouthern India and in the Middle East. At the cellular level, itis characterized by accumulation of starch-like polyglucosanscalled Lafora bodies (LBs) that are most abundant in organs withthe highest glucose metabolism: brain, heart, liver and skeletalmuscle. Among other conditions involving polyglucosans, EPM2 isunique in that the inclusions are in neuronal dendrites but notaxons and the forming polyglucosan fibrils are associated with theendoplasmic reticulum.

Defects in SLC9A3R1 are the cause of hypophosphatemicnephrolithiasis/osteoporosis type 2 (NPHLOP2) [MIM:612287].Hypophosphatemia results from idiopathic renal phosphate loss. Itcontributes to the pathogenesis of hypophosphatemic urolithiasis(formation of urinary calculi) as well to that of hypophosphatemicosteoporosis (bone demineralization).

Defects in NHS are the cause of Nance-Horan syndrome(NHS) [MIM:302350], also known as cataract-dental syndrome. NHS isa rare X-linked disorder characterized by congenital cataracts,dental anomalies, dysmorphic features, and, in some cases, mentalretardation. Distinctive dental anomalies are seen in affectedmales, including supernumerary incisors and crown shaped permanentteeth. Characteristic facial features are anteverted pinnae, longface, and prominent nasal bridge and nose. Carrier females displaymilder variable symptoms of disease with lens opacities ofteninvolving the posterior Y sutures, and on occasion dentalanomalies and the characteristic facial features described.

Defects in NHS are the cause of cataract congenital X-linked (CXN) [MIM:302200]. A X-linked form of cataract,manifesting as a congenital nuclear opacity with severe visualimpairment in affected males. Heterozygous females have suturecataracts and only slight reduction in vision. Note=Caused by copynumber variations predicted to result in altered transcriptionalregulation of the NHS gene: a 0.8 Mb segmental duplication-triplication encompassing the NHS, SCML1 and RAI2 genes, and an4.8 kb intragenic deletion in NHS intron 1.

Defects in NCSTN are the cause of acne inversa familialtype 1 (ACNIF1) [MIM:142690]. A chronic relapsing inflammatorydisease of the hair follicles characterized by recurrent drainingsinuses, painful skin abscesses, and disfiguring scars.Manifestations typically appear after puberty.

Defects in NIPA1 are the cause of spastic paraplegiaautosomal dominant type 6 (SPG6) [MIM:600363]. Spastic paraplegiais a degenerative spinal cord disorder characterized by a slow,gradual, progressive weakness and spasticity of the lower limbs.

Defects in NIPAL4 are the cause of ichthyosis congenitalautosomal recessive ichthyin-related (ARCII) [MIM:612281]. ARCIIis a disorder of keratinization with abnormal differentiation anddesquamation of the epidermis. The phenotype usually presents asnon-bullous congenital ichthyosiform erythroderma (NCIE) with finewhitish scaling on an erythrodermal background, larger brownishscales are present on the buttocks, neck and legs. Some of thefamilies may show a more lamellar phenotype (lamellar ichthyosis).

Defects in NIPBL are the cause of Cornelia de Langesyndrome type 1 (CDLS1) [MIM:122470]. CDLS is a clinicallyheterogeneous developmental disorder associated with malformationsaffecting multiple systems. CDLS is characterized by facialdysmorphisms, abnormal hands and feet, growth delay, cognitiveretardation and various other malformations includinggastroesophageal dysfunction and cardiac, ophthalmologic andgenitourinary anomalies.

Note=A chromosomal aberration involving NKAIN2 is a causeof lymphoma. Deletion del(6)(q13q21) within NKAIN2 and involvingSUSP1 generates the SUSP1-NKAIN2 product.

Defects in NKX2-1 are the cause of benign hereditarychorea (BHC) [MIM:118700], also known as hereditary chorea withoutdementia. BHC is an autosomal dominant movement disorder. Theearly onset of symptoms (usully before the age of 5) and theobservation that in some BHC families the symptoms tend todecrease in adulthood suggests that the disorder results from adevelopmental disturbance of the brain. BHC is non-progressive andpatients have normal or slightly below normal intelligence. Thereis considerable inter- and intrafamilial variability, includingdysarthria, axial distonia and gait disturbances.

Defects in NKX2-1 are the cause of choreoathetosis,hypothyroidism, and neonatal respiratory distress (CHNRD)[MIM:610978]. This syndrome include neurological, thyroid, andrespiratory problems.

Defects in NKX2-5 are the cause of atrial septal defectwith atrioventricular conduction defects (ASD-AVCD) [MIM:108900].ASD-AVCD is a congenital heart malformation characterized byatrioventricular conduction defects and incomplete closure of thewall between the atria resulting in blood flow from the left tothe right atria.

Defects in NKX2-5 are a cause of tetralogy of Fallot(TOF) [MIM:187500]. TOF is a congenital heart anomaly whichconsists of pulmonary stenosis, ventricular septal defect,dextroposition of the aorta (aorta is on the right side instead ofthe left) and hypertrophy of the right ventricle. This conditionresults in a blue baby at birth due to inadequate oxygenation.Surgical correction is emergent.

Defects in NKX2-5 are the cause of congenitalhypothyroidism non-goitrous type 5 (CHNG5) [MIM:225250]. CHNG5 isa non-autoimmune condition characterized by resistance to thyroid-stimulating hormone (TSH) leading to increased levels of plasmaTSH and low levels of thyroid hormone. CHNG5 presents variableseverity depending on the completeness of the defect. Mostpatients are euthyroid and asymptomatic, with a normal sizedthyroid gland. Only a subset of patients develop hypothyroidismand present a hypoplastic thyroid gland.

Defects in NKX2-6 may be a cause of conotruncal heartmalformations (CTHM) [MIM:217095]. CTHM defines a group ofcongenital heart defects involving the outflow tracts. Examplesinclude truncus arteriosus communis, double-outlet right ventricleand transposition of great arteries. Truncus arteriosus communisis characterized by a single outflow tract instead of a separateaorta and pulmonary artery. In transposition of the greatarteries, the aorta arises from the right ventricle and thepulmonary artery from the left ventricle. In double outlet of theright ventricle, both the pulmonary artery and aorta arise fromthe right ventricle.

Defects in NKX3-2 are the cause of spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) [MIM:613330]. It is askeletal dysplasia characterized by disproportionate short staturewith a short and stiff neck and trunk, relatively long limbs thatmay show flexion contractures of the distal joints, delayed andimpaired ossification of the vertebral bodies, the presence oflarge epiphysea ossification centers and wide growth plates in thelong tubular bones and numerous pseudoepiphyses of the shorttubular bones in hands and feet.

Defects in NLGN3 may be the cause of susceptibility toautism X-linked type 1 (AUTSX1) [MIM:300425]. AUTSX1 is apervasive developmental disorder (PDD), prototypicallycharacterized by impairments in reciprocal social interaction andcommunication, restricted and stereotyped patterns of interestsand activities, and the presence of developmental abnormalities by3 years of age.

Defects in NLGN3 may be the cause of susceptibility to X-linked Asperger syndrome 1 (ASPGX1) [MIM:300494]. ASPGX1 isconsidered to be a form of childhood autism.

Defects in NLGN4X may be the cause of susceptibility toautism X-linked type 2 (AUTSX2) [MIM:300495]. AUTSX2 is apervasive developmental disorder (PDD), prototypicallycharacterized by impairments in reciprocal social interaction andcommunication, restricted and stereotyped patterns of interestsand activities, and the presence of developmental abnormalities by3 years of age.

Defects in NLGN4X may be the cause of susceptibility toX-linked Asperger syndrome 2 (ASPGX2) [MIM:300497]. ASPGX2 isconsidered to be a form of childhood autism.

Defects in NOBOX are the cause of premature ovarianfailure type 5 (POF5) [MIM:611548]. An ovarian disorder defined asthe cessation of ovarian function under the age of 40 years. It ischaracterized by oligomenorrhea or amenorrhea, in the presence ofelevated levels of serum gonadotropins and low estradiol.

Defects in NOD2 are the cause of Blau syndrome (BS)[MIM:186580]. BS is a rare autosomal dominant disordercharacterized by early-onset granulomatous arthritis, uveitis andskin rash.

Defects in NOD2 are a cause of susceptibility toinflammatory bowel disease type 1 (IBD1) [MIM:266600]. IBD1 is achronic, relapsing inflammation of the gastrointestinal tract witha complex etiology. It is subdivided into Crohn disease andulcerative colitis phenotypes. Crohn disease may affect any partof the gastrointestinal tract from the mouth to the anus, but mostfrequently it involves the terminal ileum and colon. Bowelinflammation is transmural and discontinuous, it may containgranulomas or be associated with intestinal or perianal fistulas.In contrast, in ulcerative colitis, the inflammation is continuousand limited to rectal and colonic mucosal layers, fistulas andgranulomas are not observed. Both diseases include extraintestinalinflammation of the skin, eyes, or joints.

Defects in NOD2 are the cause of sarcoidosis early-onset(EOS) [MIM:609464]. EOS is a form of sarcoidosis manifesting inchildren younger than 4 years of age. Sarcoidosis is anidiopathic, systemic, inflammatory disease characterized by theformation of immune granulomas in involved organs. Granulomaspredominantly invade the lungs and the lymphatic system, but alsoskin, liver, spleen, eyes and other organs may be involved. Early-onset sarcoidosis is quite rare and has a distinct triad of skin,joint and eye disorders, without apparent pulmonary involvement.Compared with an asymptomatic and sometimes naturally disappearingcourse of the disease in older children, early-onset sarcoidosisis progressive and in many cases causes severe complications, suchas blindness, joint destruction and visceral involvement.

Defects in NODAL are the cause of visceral heterotaxyautosomal type 5 (HTX5) [MIM:270100]. A form of visceralheterotaxy, a complex disorder due to disruption of the normalleft-right asymmetry of the thoracoabdominal organs. It results inan abnormal arrangement of visceral organs, and a wide variety ofcongenital defects. Clinical features of visceral heterotaxyautosomal type 5 include situs inversus viscerum or situsambiguus, congenital heart defect, transposition of the greatvessels ventricular septal defect, atrial septal defect,truncuscommunis, and dextrocardia.

Defects in NOG are a cause of symphalangism proximalsyndrome (SYM1) [MIM:185800]. SYM1 is characterized by thehereditary absence of the proximal interphalangeal (PIP) joints(Cushing symphalangism). Severity of PIP joint involvementdiminishes towards the radial side. Distal interphalangeal jointsare less frequently involved and metacarpophalangeal joints arerarely affected whereas carpal bone malformation and fusion arecommon. In the lower extremities, tarsal bone coalition is common.Conducive hearing loss is seen and is due to fusion of the stapesto the petrous part of the temporal bone.

Defects in NOG are the cause of multiple synostosessyndrome type 1 (SYNS1) [MIM:186500], also known as synostoses,multiple, with brachydactyly/symphalangism-brachydactyly syndrome.SYNS1 is characterized by tubular-shaped (hemicylindrical) nosewith lack of alar flare, otosclerotic deafness, and multipleprogressive joint fusions commencing in the hand. The jointfusions are progressive, commencing in the fifth proximalinterphalangeal joint in early childhood (or at birth in someindividuals) and progressing in an ulnar-to-radial and proximal-to-distal direction. With increasing age, ankylosis of otherjoints, including the cervical vertebrae, hips, and humeroradialjoints, develop.

Defects in NOG are the cause of tarsal-carpal coalitionsyndrome (TCC) [MIM:186570]. TCC is an autosomal dominant disordercharacterized by fusion of the carpals, tarsals and phalanges,short first metacarpals causing brachydactyly, and humeroradialfusion. TCC is allelic to SYM1, and different mutations in NOG canresult in either TCC or SYM1 in different families.

Defects in NOG are a cause of stapes ankylosis with broadthumb and toes (SABTS) [MIM:184460], also known as Teunissen-Cremers syndrome. SABTS is a congenital autosomal dominantdisorder that includes hyperopia, a hemicylindrical nose, broadthumbs, great toes, and other minor skeletal anomalies but lackedcarpal and tarsal fusion and symphalangism.

Defects in NOG are the cause of brachydactyly type B2(BDB2) [MIM:611377]. BDB2 is a subtype of brachydactylycharacterized by hypoplasia/aplasia of distal phalanges incombination with distal symphalangism, fusion of carpal/tarsalbones, and partial cutaneous syndactyly.

Note=A chromosomal aberration involving NONO may be acause of papillary renal cell carcinoma (PRCC). Translocationt(X,X)(p11.2,q13.1) with TFE3.

Defects in NOP10 are a cause of dyskeratosis congenitaautosomal recessive (ARDKC) [MIM:224230]. ARDKC is a rare,progressive bone marrow failure syndrome characterized by thetriad of reticulated skin hyperpigmentation, nail dystrophy, andmucosal leukoplakia. Early mortality is often associated with bonemarrow failure, infections, fatal pulmonary complications, ormalignancy.

Defects in NOTCH1 are a cause of bicuspid aortic valve(BAV) [MIM:109730]. A common defect in the aortic valve in whichtwo rather than three leaflets are present. It is often associatedwith aortic valve calcification and insufficiency. In extremecases, the blood flow may be so restricted that the left ventriclefails to grow, resulting in hypoplastic left heart syndrome.

Defects in NOTCH2 are the cause of Alagille syndrome type2 (ALGS2) [MIM:610205]. Alagille syndrome is an autosomal dominantmultisystem disorder defined clinically by hepatic bile ductpaucity and cholestasis in association with cardiac, skeletal, andophthalmologic manifestations. There are characteristic facialfeatures and less frequent clinical involvement of the renal andvascular systems.

Defects in NOTCH2 are the cause of Hajdu-Cheney syndrome(HAJCS) [MIM:102500]. A rare skeletal disorder characterized bythe association of facial anomalies, acro-osteolysis, generalosteoporosis, insufficient ossification of the skull, andperiodontal disease (premature loss of permanent teeth). Otherfeatures include cleft palate, congenital heart defects,polycystic kidneys, orthopedic problems and anomalies of thegenitalia, intestines and eyes. Note=NOTCH2 mutations associatedwith Hajdu-Cheney syndrome cluster to the last coding exon of thegene. This suggests that the mutant mRNA products may escapenonsense-mediated decay and the resulting truncated NOTCH2proteins act in a gain-of-function manner.

Defects in NOTCH3 are the cause of cerebral autosomaldominant arteriopathy with subcortical infarcts andleukoencephalopathy (CADASIL) [MIM:125310]. CADASIL causes a typeof stroke and dementia of which key features include recurrentsubcortical ischemic events and vascular dementia. The disorderaffects relatively young adults of both sexes. Mutations affecthighly conserved cysteine residues within epidermal growth factor(EGF)-like repeat domains in the extracellular part of thereceptor.

Note=A chromosomal aberration involving NPAS3 is found ina family with schizophrenia. Translocation t(9,14)(q34,q13).

Defects in NPC1 are the cause of Niemann-Pick diseasetype C1 (NPDC1) [MIM:257220]. A lysosomal storage disorder thataffects the viscera and the central nervous system. It is due todefective intracellular processing and transport of low-densitylipoprotein derived cholesterol. It causes accumulation ofcholesterol in lysosomes, with delayed induction of cholesterolhomeostatic reactions. Niemann-Pick disease type C1 has a highlyvariable clinical phenotype. Clinical features include variablehepatosplenomegaly and severe progressive neurological dysfunctionsuch as ataxia, dystonia and dementia. The age of onset can varyfrom infancy to late adulthood. An allelic variant of Niemann-Pickdisease type C1 is found in people with Nova Scotia ancestry.Patients with the Nova Scotian clinical variant are less severelyaffected.

Defects in NPC2 are the cause of Niemann-Pick diseasetype C2 (NPDC2) [MIM:607625]. A lysosomal storage disorder thataffects the viscera and the central nervous system. It is due todefective intracellular processing and transport of low-densitylipoprotein derived cholesterol. It causes accumulation ofcholesterol in lysosomes, with delayed induction of cholesterolhomeostatic reactions. Niemann-Pick disease type C2 has a highlyvariable clinical phenotype. Clinical features include variablehepatosplenomegaly and severe progressive neurological dysfunctionsuch as ataxia, dystonia and dementia. The age of onset can varyfrom infancy to late adulthood.

Defects in NPHS1 are the cause of nephrotic syndrome type1 (NPHS1) [MIM:256300], also known as Finnish congenital nephrosis(CNF). A renal disease characterized clinically by proteinuria,hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies shownon-specific histologic changes such as focal segmentalglomerulosclerosis and diffuse mesangial proliferation. Someaffected individuals have an inherited steroid-resistant form andprogress to end-stage renal failure.

Defects in NPHP1 are the cause of nephronophthisis type 1(NPHP1) [MIM:256100], also known as familial juvenilenephronophthisis 1. NPHP1 is an autosomal recessive inheriteddisease characterized by anemia, polyuria, polydipsia,isosthenuria and death in uremia. Symmetrical destruction of thekidneys involving both tubules and glomeruli occurs. Theunderlying pathology is a chronic tubulo-interstitial nephropathywith characteristic tubular basement membrane thickening andmedullary cyst formation. Associations with extrarenal symptoms,especially ocular lesions, are frequent. The age at death rangesfrom about 4 to 15 years.

Defects in NPHP1 are the cause of Senior-Loken syndrometype 1 (SLSN1) [MIM:266900], also known as juvenilenephronophthisis with Leber amaurosis. SLSN is a renal-retinaldisorder characterized by progressive wasting of the filteringunit of the kidney, with or without medullary cystic renaldisease, and progressive eye disease. Typically this disorderbecomes apparent during the first year of life.

Defects in NPHP1 are the cause of Joubert syndrome type 4(JBTS4) [MIM:609583]. JBTS is an autosomal recessive disorderpresenting with cerebellar ataxia, oculomotor apraxia, hypotonia,neonatal breathing abnormalities and psychomotor delay.Neuroradiologically, it is characterized by cerebellar vermianhypoplasia/aplasia, thickened and reoriented superior cerebellarpeduncles, and an abnormally large interpeduncular fossa, givingthe appearance of a molar tooth on transaxial slices (molar toothsign). Additional variable features include retinal dystrophy andrenal disease. JBTS4 is a phenotypically mild form.

Defects in NPHP3 are the cause of nephronophthisis type 3(NPHP3) [MIM:604387], also known as adolescent nephronophthisis.NPHP3 is a autosomal recessive disorder resulting in end-stagerenal disease. It is characterized by polyuria, polydipsia,anemia. Onset of terminal renal failure occurr significantly later(median age, 19 years) than in juvenile nephronophthisis. Renalpathology is characterized by alterations of tubular basementmembranes, tubular atrophy and dilation, sclerosingtubulointerstitial nephropathy, and renal cyst developmentpredominantly at the corticomedullary junction.

Defects in NPHP3 are a cause of renal-hepatic-pancreaticdysplasia (RHPD) [MIM:208540]. RHPD is an autosomal recessivedisorder with variable expression, and patients surviving theneonatal period progress to renal and hepatic failure which can betreated successfully with combined liver-kidney transplantation.

Defects in NPHP3 are the cause of Meckel syndrome type 7(MKS7) [MIM:267010]. It is a form of Meckel syndrome, an autosomalrecessive disorder. It is characterized by a combination of renalcysts and variably associated features including developmentalanomalies of the central nervous system (typically encephalocele),hepatic ductal dysplasia and cysts, and polydactyly.

Defects in NPHP4 are the cause of nephronophthisis type 4(NPHP4) [MIM:606966], also known as familial juvenilenephronophthisis 4. NPHP4 is an autosomal recessive inheriteddisease resulting in end-stage renal disease at age rangingbetween 6 and 35 years. It is a progressive tubulo-interstitialkidney disorder characterized by polydipsia, polyuria, anemia andgrowth retardation. The most prominent histological features aremodifications of the tubules with thickening of the basementmembrane, interstitial fibrosis and, in the advanced stages,medullary cysts.

Defects in NPHP4 are the cause of Senior-Loken syndrometype 4 (SLSN4) [MIM:606996]. SLSN is a renal-retinal disordercharacterized by progressive wasting of the filtering unit of thekidney, with or without medullary cystic renal disease, andprogressive eye disease. Typically this disorder becomes apparentduring the first year of life.

Note=A chromosomal aberration involving NPM1 is found ina form of non-Hodgkin lymphoma. Translocation t(2,5)(p23,q35) withALK. The resulting chimeric NPM1-ALK protein homodimerize and thekinase becomes constitutively activated.

Note=A chromosomal aberration involving NPM1 is found ina form of acute promyelocytic leukemia. Translocationt(5,17)(q32,q11) with RARA.

Note=A chromosomal aberration involving NPM1 is a causeof myelodysplastic syndrome (MDS). Translocation t(3,5)(q25.1,q34)with MLF1.

Note=Defects in NPM1 are associated with acutemyelogenous leukemia (AML). Mutations in exon 12 affecting the C-terminus of the protein are associated with an aberrantcytoplasmic location.

Defects in NPSR1 are a cause of asthma-related traitstype 2 (ASRT2) [MIM:608584]. Asthma-related traits includeclinical symptoms of asthma, such as coughing, wheezing, dyspnea,bronchial hyperresponsiveness as assessed by methacholinechallenge test, serum IgE levels, atopy and atopic dermatitis.

Defects in SLC34A1 are the cause of hypophosphatemicnephrolithiasis/osteoporosis type 1 (NPHLOP1) [MIM:612286].Hypophosphatemia results from idiopathic renal phosphate loss. Itcontributes to the pathogenesis of hypophosphatemic urolithiasis(formation of urinary calculi) as well to that of hypophosphatemicosteoporosis (bone demineralization).

Defects in SLC34A1 are the cause of Fanconi renotubularsyndrome type 2 (FRTS2) [MIM:613388]. It is a disease resultingfrom a generalized dysfunction of the proximal kidney tubuleleading to decreased solute and water reabsorption. Patients havepolydipsia and polyuria with phosphaturia, glycosuria andaminoaciduria. They may develop hypophosphatemic rickets orosteomalacia, acidosis and a tendency toward dehydration. Someeventually develop renal insufficiency.

Defects in SLC34A2 are a cause of pulmonary alveolarmicrolithiasis (PALM) [MIM:265100]. Pulmonary alveolarmicrolithiasis is a rare disease characterized by the depositionof calcium phosphate microliths throughout the lungs. Mostpatients are asymptomatic for several years or even for decadesand generally, the diagnosis is incidental to clinicalinvestigations unrelated to the disease. Cases with early onset orrapid progression are rare. A 'sandstorm-appearing' chestroentgenogram is a typical diagnostic finding. The onset of thispotentially lethal disease varies from the neonatal period to oldage and the disease follows a long-term, progressive course,resulting in a slow deterioration of lung functions. Pulmonaryalveolar microlithiasis is a recessive monogenic disease with fullpenetrance.

Defects in SLC34A3 are the cause of hereditaryhypophosphatemic rickets with hypercalciuria (HHRH) [MIM:241530].HHRH is an autosomal recessive form of hypophosphatemiacharacterized by reduced renal phosphate reabsorption and rickets.Increased serum levels of 1,25-dihydroxyvitamin D lead to increasein urinary calcium excretion.

Defects in NR0B1 are the cause of X-linked adrenalhypoplasia congenital (XL-AHC) [MIM:300200], also known as X-linked Addison disease (AHX). XL-AHC is a developmental disorderof the adrenal gland that results in profound hormonaldeficiencies and is lethal if untreated. It is characterized bythe absence of the permanent zone of the adrenal cortex and by astructural disorganization of the glands. Hypogonadotropichypogonadism (HHG) is frequently associated with this disorder.HHG is a condition resulting from or characterized by abnormallydecreased gonadal function, with retardation of growth and sexualdevelopment.

Defects in NR0B1 are a cause of dosage-sensitive sexreversal (DSSR) [MIM:300018]. It is a condition characterized bymale-to-female sex reversal in the presence of a normal 46,XYkaryotype. Note=XY individuals with a duplication of part of theshort arm of the X chromosome and an intact SRY gene develop asfemales. The single X chromosome in these individuals does notundergo X-chromosome inactivation, therefore, these individualspresumably carry 2 active copies of genes, including the NR0B1gene, in the duplicated region. Individuals with deletion of thisregion develop as males. Genes within the dosage-sensitive sexreversal region are, therefore, not essential for testisdevelopment, but, when present in a double dose, interfere withtestis formation.

Defects in NR0B2 may be associated with obesity (OBESITY)[MIM:601665]. It is a condition characterized by an increase ofbody weight beyond the limitation of skeletal and physicalrequirements, as the result of excessive accumulation of body fat.

Defects in NR2E3 are a cause of enhanced S cone syndrome(ESCS) [MIM:268100]. ESCS is an autosomal recessive retinopathy inwhich patients have increased sensitivity to blue light,perception of blue light is mediated by what is normally the leastpopulous cone photoreceptor subtype, the S (short wavelength,blue) cones. ESCS is also associated with visual loss, with nightblindness occurring from early in life, varying degrees of L(long, red)- and M (middle, green)-cone vision, and retinaldegeneration.

Defects in NR2E3 are the cause of retinitis pigmentosatype 37 (RP37) [MIM:611131]. RP leads to degeneration of retinalphotoreceptor cells. Patients typically have night visionblindness and loss of midperipheral visual field. As theircondition progresses, they lose their far peripheral visual fieldand eventually central vision as well. RP37 inheritance isautosomal dominant.

Defects in NR4A3 are a cause of Ewing sarcoma (ES)[MIM:612219]. A highly malignant, metastatic, primitive smallround cell tumor of bone and soft tissue that affects children andadolescents. It belongs to the Ewing sarcoma family of tumors, agroup of morphologically heterogeneous neoplasms that share thesame cytogenetic features. They are considered neural tumorsderived from cells of the neural crest. Ewing sarcoma representsthe less differentiated form of the tumors. Note=A chromosomalaberration involving NR4A3 is found in patients with Erwingsarcoma. Translocation t(9,22)(q22-31,q11-12) with EWSR1.

Note=A chromosomal aberration involving NR4A3 is a causeof a form of extraskeletal myxoid chondrosarcomas (EMC).Translocation t(9,17)(q22,q11) with TAF2N.

Defects in SLC11A2 are a cause of hypochromic microcyticanemia (HCMA) [MIM:206100]. The disease is characterized by anabnormal hemoglobin content in the erythrocytes which are reducedin size. It may be hereditary or acquired. Mutations in SLC11A2are associated with progressive liver iron overload and normal tomoderately elevated serum ferritin levels.

Note=A chromosomal aberration involving NRG1 producesgamma-heregulin. Translocation t(8,11) with ODZ4. Thetranslocation fuses the 5'-end of ODZ4 to NRG1 (isoform 8). Theproduct of this translocation was first thought to be analternatively spliced isoform. Gamma-heregulin is a solubleactivating ligand for the ERBB2-ERBB3 receptor complex and acts asan autocrine growth factor in a specific breast cancer cell line(MDA-MB-175). Not detected in breast carcinoma samples, includingductal, lobular, medullary, and mucinous histological types,neither in other breast cancer cell lines.

Defects in NRL are the cause of retinitis pigmentosa type27 (RP27) [MIM:613750]. RP leads to degeneration of retinalphotoreceptor cells. Patients typically have night visionblindness and loss of midperipheral visual field. As theircondition progresses, they lose their far peripheral visual fieldand eventually central vision as well. RP27 inheritance isautosomal dominant.

Defects in NRL are a cause of retinal degenerationautosomal recessive clumped pigment type (RDCP) [MIM:162080]. Aretinopathy characterized by night blindness since earlychildhood, consistent with a severe reduction in rod function.Color vision is normal although there is a relatively enhancedfunction of short-wavelength-sensitive cones in the macula. Signsof retinal degeneration and clusters of clumped pigment depositsin the peripheral fundus at the level of the retinal pigmentepithelium are present (clumped pigmentary retinal degeneration).

Note=Genetic variations in NRTN may contribute toHirschsprung disease, in association with mutations of RET gene,and possibly mutations in other loci. Hirschsprung disease is adisorder of neural crest development is characterized by theabsence of intramural ganglion cells in the hindgut, oftenresulting in intestinal obstruction.

Defects in NSD1 are the cause of Sotos syndrome (SOTOSS)[MIM:117550], also known as cerebral gigantism. It is a disordercharacterized by excessively rapid growth, acromegalic features,and a nonprogressive cerebral disorder with mental retardation.High-arched palate and prominent jaw are noted in severalpatients. Most cases of Sotos syndrome are sporadic and mayrepresent new dominant mutation.

Defects in NSD1 are the cause of Weaver syndrome (WES)[MIM:277590]. WES is a syndrome of accelerated growth and osseousmaturation, unusual craniofacial appearance, hoarse and low-pitched cry, and hypertonia with camptodactyly.

Defects in NSD1 are a cause of Beckwith-Wiedemannsyndrome (BWS) [MIM:130650]. BWS is a genetically heterogeneousdisorder characterized by anterior abdominal wall defectsincluding exomphalos (omphalocele), pre- and postnatal overgrowth,and macroglossia. Additional less frequent complications includespecific developmental defects and a predisposition to embryonaltumors.

Note=A chromosomal aberration involving NSD1 is found inchildhood acute myeloid leukemia. Translocation t(5,11)(q35,p15.5)with NUP98.

Note=A chromosomal aberration involving NSD1 is found inan adult form of myelodysplastic syndrome (MDS). Insertion ofNUP98 into NSD1 generates a NUP98-NSD1 fusion product.

Note=A chromosomal aberration involving WHSC1 is a causeof multiple myeloma tumors. Translocation t(4,14)(p16.3,q32.3)with IgH.

Note=WHSC1 is located in the Wolf-Hirschhorn syndrome(WHS) critical region. WHS results from by sub-telomeric deletionsin the short arm of chromosome 4. WHSC1 is deleted in every case,however deletion of linked genes contributes to both the severityof the core characteristics and the presence of the additionalsyndromic problems.

Note=Defects in WHSC1L1 may be involved in non small celllung carcinomas (NSCLC). Amplified or overexpressed in NSCLC.

Note=A chromosomal aberration involving WHSC1L1 is foundin childhood acute myeloid leukemia. Translocationt(8,11)(p11.2,p15) with NUP98.

Defects in NSDHL are the cause of congenitalhemidysplasia with ichthyosiform erythroderma and limb defects(CHILD) [MIM:308050]. CHILD is an X-linked dominant disorder oflipid metabolism with disturbed cholesterol biosynthesis, whichtypically results in male lethality. Clinically, it ischaracterized by congenital, unilateral, ichthyosisformerythroderma with striking lateralization, sharp midlinedemarcation, and ipsilateral limb defects and hypoplasia of thebody. Limbs defects range from hypoplasia of digits or ribs tocomplete amelia, often including scoliosis.

Note=NSUN5P1 is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.

Note=NSUN5C is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.

Note=NSUN5 is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.

Note=LAT2 is located in the Williams-Beuren syndrome(WBS) critical region. WBS results from a hemizygous deletion ofseveral genes on chromosome 7q11.23, thought to arise as aconsequence of unequal crossing over between highly homologouslow-copy repeat sequences flanking the deleted region.Haploinsufficiency of LAT2 may be the cause of certaincardiovascular and musculo-skeletal abnormalities observed in thedisease.

Defects in SLC10A2 are a cause of primary bile acidmalabsorption (PBAM) [MIM:613291]. PBAM is an idiopathicintestinal disorder associated with congenital diarrhea,steatorrhea, interruption of the enterohepatic circulation of bileacids, and reduced plasma cholesterol levels.

Defects in NTF4 may be associated with susceptibility toprimary open angle glaucoma type 1O (GLC1O) [MIM:613100]. A formof primary open angle glaucoma (POAG). POAG is characterized by aspecific pattern of optic nerve and visual field defects. Theangle of the anterior chamber of the eye is open, and usually theintraocular pressure is increased. The disease is asymptomaticuntil the late stages, by which time significant and irreversibleoptic nerve damage has already taken place.

Defects in NTRK1 are a cause of congenital insensitivityto pain with anhidrosis (CIPA) [MIM:256800]. CIPA is characterizedby a congenital insensitivity to pain, anhidrosis (absence ofsweating), absence of reaction to noxious stimuli, self-mutilatingbehavior, and mental retardation. This rare autosomal recessivedisorder is also known as congenital sensory neuropathy withanhidrosis or hereditary sensory and autonomic neuropathy type IVor familial dysautonomia type II.

Defects in NTRK1 are a cause of thyroid papillarycarcinoma (TPC) [MIM:188550]. TPC is a common tumor of the thyroidthat typically arises as an irregular, solid or cystic mass fromotherwise normal thyroid tissue. Papillary carcinomas aremalignant neoplasm characterized by the formation of numerous,irregular, finger-like projections of fibrous stroma that iscovered with a surface layer of neoplastic epithelial cells.Note=Chromosomal aberrations involving NTRK1 are found in thyroidpapillary carcinomas. Translocation t(1,3)(q21,q11) with TFGgenerates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3'-end of NTRK1, a rearrangement with TPM3 generates the TRKtranscript by fusing TPM3 to the 3'-end of NTRK1.

Chromosomal aberrations involving NTRK1 are a cause ofthyroid papillary carcinoma (PACT) [MIM:188550]. Intrachromosomalrearrangement that links the protein kinase domain of NTRK1 to the5'-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 isa 55 kDa protein reacting with antibodies against the C-terminusof the NTRK1 protein.

Defects in MT-ND1 are a cause of Leber hereditary opticneuropathy (LHON) [MIM:535000]. LHON is a maternally inheriteddisease resulting in acute or subacute loss of central vision, dueto optic nerve dysfunction. Cardiac conduction defects andneurological defects have also been described in some patients.LHON results from primary mitochondrial DNA mutations affectingthe respiratory chain complexes.

Defects in MT-ND1 are a cause of mitochondrialencephalomyopathy with lactic acidosis and stroke-like episodessyndrome (MELAS) [MIM:540000]. MELAS is a geneticallyheterogenious disorder, characterized by episodic vomiting,seizures, and recurrent cerebral insults resembling strokes andcausing hemiparesis, hemianopsia, or cortical blindness.

Defects in MT-ND1 may be associated with susceptibilityto Alzheimer disease mitochondrial (AD-MT) [MIM:502500]. Alzheimerdisease is a neurodegenerative disorder characterized byprogressive dementia, loss of cognitive abilities, and depositionof fibrillar amyloid proteins as intraneuronal neurofibrillarytangles, extracellular amyloid plaques and vascular amyloiddeposits. The major constituent of these plaques is the neurotoxicamyloid-beta-APP 40-42 peptide (s), derived proteolytically fromthe transmembrane precursor protein APP by sequential secretaseprocessing. The cytotoxic C-terminal fragments (CTFs) and thecaspase-cleaved products such as C31 derived from APP, are alsoimplicated in neuronal death.

Defects in MT-ND1 may be associated with non-insulin-dependent diabetes mellitus (NIDDM).

Note=A chromosomal aberration involving NUP214 is foundin a subset of acute myeloid leukemia (AML), also known as acutenon-lymphocytic leukemia. Translocation t(6,9)(p23,q34) with DEK.It results in the formation of a DEK-CAN fusion gene.

Note=A chromosomal aberration involving NUP214 is foundin some cases of acute undifferentiated leukemia (AUL).Translocation t(6,9)(q21,q34.1) with SET.

Defects in MT-ND2 are a cause of Leber hereditary opticneuropathy (LHON) [MIM:535000]. LHON is a maternally inheriteddisease resulting in acute or subacute loss of central vision, dueto optic nerve dysfunction. Cardiac conduction defects andneurological defects have also been described in some patients.LHON results from primary mitochondrial DNA mutations affectingthe respiratory chain complexes.

Defects in MT-ND2 may be associated with susceptibilityto Alzheimer disease mitochondrial (AD-MT) [MIM:502500]. Alzheimerdisease is a neurodegenerative disorder characterized byprogressive dementia, loss of cognitive abilities, and depositionof fibrillar amyloid proteins as intraneuronal neurofibrillarytangles, extracellular amyloid plaques and vascular amyloiddeposits. The major constituent of these plaques is the neurotoxicamyloid-beta-APP 40-42 peptide (s), derived proteolytically fromthe transmembrane precursor protein APP by sequential secretaseprocessing. The cytotoxic C-terminal fragments (CTFs) and thecaspase-cleaved products such as C31 derived from APP, are alsoimplicated in neuronal death.

Defects in MT-ND4L are a cause of Leber hereditary opticneuropathy (LHON) [MIM:535000]. LHON is a maternally inheriteddisease resulting in acute or subacute loss of central vision, dueto optic nerve dysfunction. Cardiac conduction defects andneurological defects have also been described in some patients.LHON results from primary mitochondrial DNA mutations affectingthe respiratory chain complexes.

Defects in MT-ND5 are a cause of Leber hereditary opticneuropathy (LHON) [MIM:535000]. LHON is a maternally inheriteddisease resulting in acute or subacute loss of central vision, dueto optic nerve dysfunction. Cardiac conduction defects andneurological defects have also been described in some patients.LHON results from primary mitochondrial DNA mutations affectingthe respiratory chain complexes.

Defects in MT-ND5 are a cause of Leigh syndrome (LS)[MIM:256000]. LS is a severe neurological disorder characterizedby bilaterally symmetrical necrotic lesions in subcortical brainregions.

Defects in MT-ND5 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinical disorders,from lethal neonatal disease to adult-onset neurodegenerativedisorders. Phenotypes include macrocephaly with progressiveleukodystrophy, non-specific encephalopathy, cardiomyopathy,myopathy, liver disease, Leigh syndrome, Leber hereditary opticneuropathy, and some forms of Parkinson disease.

Defects in MT-ND5 are a cause of mitochondrialencephalomyopathy with lactic acidosis and stroke-like episodessyndrome (MELAS) [MIM:540000]. MELAS is a geneticallyheterogenious disorder, characterized by episodic vomiting,seizures, and recurrent cerebral insults resembling strokes andcausing hemiparesis, hemianopsia, or cortical blindness.

Defects in MT-ND6 are a cause of Leber hereditary opticneuropathy (LHON) [MIM:535000]. LHON is a maternally inheriteddisease resulting in acute or subacute loss of central vision, dueto optic nerve dysfunction. Cardiac conduction defects andneurological defects have also been described in some patients.LHON results from primary mitochondrial DNA mutations affectingthe respiratory chain complexes.

Defects in MT-ND6 are a cause of Leber hereditary opticneuropathy with dystonia (LDYT) [MIM:500001], also called familialdystonia with visual failure and striatal lucencies. LDYT is partof a spectrum of Leber hereditary optic neuropathy. It ischaracterized by the association of optic atrophy and centralvision loss with dystonia.

Defects in MT-ND6 are a cause of mitochondrialencephalomyopathy with lactic acidosis and stroke-like episodessyndrome (MELAS) [MIM:540000]. MELAS is a geneticallyheterogenious disorder, characterized by episodic vomiting,seizures, and recurrent cerebral insults resembling strokes andcausing hemiparesis, hemianopsia, or cortical blindness.

Defects in MT-ND6 are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinicalmanifestations from lethal neonatal disease to adult-onsetneurodegenerative disorders. Phenotypes include macrocephaly withprogressive leukodystrophy, non-specific encephalopathy,cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leberhereditary optic neuropathy, and some forms of Parkinson disease.

Defects in NUBPL are a cause of mitochondrial complex Ideficiency (MT-C1D) [MIM:252010]. A disorder of the mitochondrialrespiratory chain that causes a wide range of clinicalmanifestations from lethal neonatal disease to adult-onsetneurodegenerative disorders. Phenotypes include macrocephaly withprogressive leukodystrophy, non-specific encephalopathy,cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leberhereditary optic neuropathy, and some forms of Parkinson disease.

Defects in NUP62 are the cause of infantile striatonigraldegeneration (SNDI) [MIM:271930], also known as infantilebilateral striatal necrosis (IBSN) or familial striataldegeneration. SNDI is a neurological disorder characterized bysymmetrical degeneration of the caudate nucleus, putamen andoccasionally the globus pallidus, with little involvement of therest of the brain. The clinical features include developmentalregression, choreoathetosis, dystonia, spasticity, dysphagia,failure to thrive, nystagmus, optic atrophy and mentalretardation.

Note=A chromosomal aberration involving NUP98 is found ina form of acute myeloid leukemia. Translocation t(7,11)(p15,p15)with HOXA9. Translocation t(11,17)(p15,p13) with PHF23.

Note=A chromosomal aberration involving NUP98 is found inchildhood acute myeloid leukemia. Translocation t(5,11)(q35,p15.5)with NSD1. Translocation t(8,11)(p11.2,p15) with WHSC1L1.

Note=A chromosomal aberration involving NUP98 is found ina form of therapy-related myelodysplastic syndrome. Translocationt(11,20)(p15,q11) with TOP1.

Note=A chromosomal aberration involving NUP98 is found ina form of T-cell acute lymphoblastic leukemia (T-ALL).Translocation t(3,11)(q12.2,p15.4) with LNP1.

Note=A chromosomal aberration involving NUP98 isassociated with pediatric acute myeloid leukemia (AML) withintermediate characteristics between M2-M3 French-American-British(FAB) subtypes. Translocation t(9,11)(p22,p15) with PSIP1/LEDGF.The chimeric transcript is an in-frame fusion of NUP98 exon 8 toPSIP1/LEDGF exon 4.

Note=A chromosomal aberration involving NUT is found in arare, aggressive, and lethal carcinoma arising in midline organsof young people. Translocation t(15,19)(q14,p13) with BRD4 whichproduces a BRD4-NUT fusion protein.

Note=A chromosomal aberration involving NUT is found in arare, aggressive, and lethal carcinoma arising in midline organsof young people. Translocation t(15,9)(q14,q34) with BRD3 whichproduces a BRD3-NUT fusion protein.

Note=A chromosomal aberration involving NXF5 has beenobserved in one patient with a syndromic form of mentalretardation and short stature. Pericentric inversioninv(X)(p21.1,q22) that interrupts NXF5.

Defects in NYX are the cause of congenital stationarynight blindness type 1A (CSNB1A) [MIM:310500], also called X-linked congenital stationary night blindness (XLCSNB). Congenitalstationary night blindness is a non-progressive retinal disordercharacterized by impaired night vision. CSNB1A is characterized byimpaired scotopic vision, myopia, hyperopia, nystagmus and reducedvisual acuity.

Defects in OAT are the cause of hyperornithinemia withgyrate atrophy of choroid and retina (HOGA) [MIM:258870]. HOGA isa slowly progressive blinding autosomal recessive disorder.

Note=A chromosomal aberration involving POU2AF1/OBF1 maybe a cause of a form of B-cell leukemia. Translocationt(3,11)(q27,q23) with BCL6.

Defects in OBSL1 are the cause of 3M syndrome type 2(3M2) [MIM:612921]. An autosomal recessive disorder characterizedby severe pre- and postnatal growth retardation, facialdysmorphism, large head circumference, and normal intelligence andendocrine function. Skeletal changes include long slender tubularbones and tall vertebral bodies.

Defects in OCLN are the cause of band-like calcificationwith simplified gyration and polymicrogyria (BLCPMG) [MIM:251290],also known as pseudo-TORCH syndrome. BLCPMG is a neurologicdisorder with characteristic clinical and neuroradiologic featuresthat mimic intrauterine TORCH infection in the absence of evidenceof infection. Affected individuals have congenital microcephaly,intracranial calcifications, and severe developmental delay.

Defects in OCRL are the cause of Lowe oculocerebrorenalsyndrome (OCRL) [MIM:309000]. It is an X-linked multisystemdisorder affecting eyes, nervous system, and kidney. It ischaracterized by hydrophthalmia, cataract, mental retardation,vitamin D-resistant rickets, aminoaciduria, and reduced ammoniaproduction by the kidney. Ocular abnormalities include cataract,glaucoma, microphthalmos, and decreased visual acuity.Developmental delay, hypotonia, behavior abnormalities, andareflexia are also present. Renal tubular involvement ischaracterized by impaired reabsorption of bicarbonate, aminoacids, and phosphate. Musculoskeletal abnormalities such as jointhypermobility, dislocated hips, and fractures may develop asconsequences of renal tubular acidosis and hypophosphatemia.Cataract is the only significant manifestation in carriers and isdetected by slit-lamp examination.

Defects in OCRL are the cause of Dent disease type 2(DD2) [MIM:300555]. DD2 is a renal disease belonging to the 'Dentdisease complex', a group of disorders characterized by proximalrenal tubular defect, hypercalciuria, nephrocalcinosis, and renalinsufficiency. The spectrum of phenotypic features is remarkablysimilar in the various disorders, except for differences in theseverity of bone deformities and renal impairment. Characteristicabnormalities include low-molecular-weight proteinuria and otherfeatures of Fanconi syndrome, such as glycosuria, aminoaciduria,and phosphaturia, but typically do not include proximal renaltubular acidosis. Progressive renal failure is common, as arenephrocalcinosis and kidney stones.

Defects in DBT are the cause of maple syrup urine diseasetype 2 (MSUD2) [MIM:248600]. MSUD is an autosomal recessivedisorder characterized by mental and physical retardation, feedingproblems, and a maple syrup odor to the urine.

Defects in BCKDHA are a cause of maple syrup urinedisease type IA (MSUD1A) [MIM:248600]. MSUD is an autosomalrecessive disorder characterized by mental and physicalretardation, feeding problems, and a maple syrup odor to theurine.

Defects in BCKDHB are the cause of maple syrup urinedisease type IB (MSUD1B) [MIM:248600]. MSUD is an autosomalrecessive disorder characterized by mental and physicalretardation, feeding problems, and a maple syrup odor to theurine.

Note=Primary biliary cirrhosis is a chronic, progressivecholestatic liver disease characterized by the presence ofantimitochondrial autoantibodies in patients' serum. It manifestswith inflammatory obliteration of intra-hepatic bile duct, leadingto liver cell damage and cirrhosis. Patients with primary biliarycirrhosis show autoantibodies against the E2 component of pyruvatedehydrogenase complex.

Defects in DLAT are the cause of pyruvate dehydrogenaseE2 deficiency (PDHE2 deficiency) [MIM:245348], also known aslactic acidemia due to defect of E2 lipoyl transacetylase of thepyruvate dehydrogenase complex. Pyruvate dehydrogenase (PDH)deficiency is a major cause of primary lactic acidosis andneurological dysfunction in infancy and early childhood. In thisform of PDH deficiency episodic dystonia is the major neurologicalmanifestation, with other more common features of pyruvatedehydrogenase deficiency, such as hypotonia and ataxia, being lessprominent.

Defects in PDHA1 are a cause of pyruvate decarboxylase E1component deficiency (PDHE1 deficiency) [MIM:312170]. PDHE1deficiency is the most common enzyme defect in patients withprimary lactic acidosis. It is associated with variable clinicalphenotypes ranging from neonatal death to prolonged survivalcomplicated by developmental delay, seizures, ataxia, apnea, andin some cases to an X-linked form of Leigh syndrome (X-LS).

Defects in PDHA1 are the cause of X-linked Leigh syndrome(X-LS) [MIM:308930]. X-LS is an early-onset progressiveneurodegenerative disorder with a characteristic neuropathologyconsisting of focal, bilateral lesions in one or more areas of thecentral nervous system, including the brainstem, thalamus, basalganglia, cerebellum, and spinal cord. The lesions are areas ofdemyelination, gliosis, necrosis, spongiosis, or capillaryproliferation. Clinical symptoms depend on which areas of thecentral nervous system are involved. The most common underlyingcause is a defect in oxidative phosphorylation. LS may be afeature of a deficiency of any of the mitochondrial respiratorychain complexes.

Defects in PDHB are a cause of pyruvate dehydrogenase E1component deficiency (PDHE1 deficiency) [MIM:312170]. PDHE1deficiency is the most common enzyme defect in patients withprimary lactic acidosis. It is associated with variable clinicalphenotypes ranging from neonatal death to prolonged survivalcomplicated by developmental delay, seizures, ataxia, apnea, andin some cases to an X-linked form of Leigh syndrome (LS) (Leighencephalomyelopathy).

Defects in PDHX are the cause of pyruvate dehydrogenaseE3-binding protein deficiency (PDHE3BPD) [MIM:245349].

Note=A chromosomal aberration involving OFCC1 is found inpatients with orofacial cleft.

Defects in OFD1 are the cause of oral-facial-digitalsyndrome type 1 (OFD1) [MIM:311200]. OFD1 is a X-linked dominantcondition with lethality in males. The syndrome is characterizedby clefts of the jaw and tongue in the area of the lateralincisors and canines. Other features are malformations of the faceand skull, malformation of the hands (specifically syndactyly,clinodactyly, brachydactyly and occasionally postaxialpolydactyly) and mental retardation. OFD1 also causes polycystickidney disease.

Defects in OFD1 are associated with Simpson-Golabi-Behmelsyndrome type 2 (SGBS2) [MIM:300209]. SGBS2 is a severe variant ofSimpson-Golabi-Behmel syndrome, a condition characterized by pre-and postnatal overgrowth (gigantism), facial dysmorphism and avariety of inconstant visceral and skeletal malformations.

Defects in OFD1 are the cause of Joubert syndrome type 10(JBTS10) [MIM:300804]. A disorder presenting with cerebellarataxia, oculomotor apraxia, hypotonia, neonatal breathingabnormalities and psychomotor delay. Neuroradiologically, it ischaracterized by cerebellar vermian hypoplasia/aplasia, thickenedand reoriented superior cerebellar peduncles, and an abnormallylarge interpeduncular fossa, giving the appearance of a molartooth on transaxial slices (molar tooth sign). Additional variablefeatures include retinal dystrophy and renal disease.

Defects in OGG1 may be a cause of renal cell carcinoma(RCC) [MIM:144700]. It is a heterogeneous group of sporadic orhereditary carcinoma derived from cells of the proximal renaltubular epithelium. It is subclassified into clear cell renalcarcinoma (non-papillary carcinoma), papillary renal cellcarcinoma, chromophobe renal cell carcinoma, collecting ductcarcinoma with medullary carcinoma of the kidney, and unclassifiedrenal cell carcinoma.

Note=A chromosomal aberration involving OLIG2 may be acause of a form of T-cell acute lymphoblastic leukemia (T-ALL).Translocation t(14,21)(q11.2,q22) with TCRA.

Note=Independent association genetic studies haveimplicated OLR1 gene variants in myocardial infarctionsusceptibility.

Note=OLR1 may be involved in Alzheimer disease (AD).Involvement in AD is however unclear: according to some authors(PubMed:12354387, PubMed:12810610 and PubMed:15976314), variationsin OLR1 modify the risk of AD, while according to other(PubMed:15000751 and PubMed:15060104) they do not.

Defects in OPA1 are a cause of optic atrophy type 1(OPA1) [MIM:165500]. OPA1 is a dominantly inherited opticneuropathy occurring in 1 in 50,000 individuals that featuresprogressive loss in visual acuity leading, in many cases, to legalblindness.

Defects in OPA1 are the cause of optic atrophy 1 withdeafness (OPA1D) [MIM:125250]. Some individuals with mutations inOPA1 manifest also ophthalmoplegia and myopathy.

Defects in OPA3 are the cause of 3-methylglutaconicaciduria type 3 (MGA3) [MIM:258501], also known as optic atrophyplus syndrome or Costeff optic atrophy syndrome. MGA3 is anautosomal recessive neuro-ophthalmologic syndrome consisting ofearly-onset bilateral optic atrophy, spasticity, extrapyramidaldysfunction, and cognitive deficit. Urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid is increased. MGA3can be distinguished from MGA1 by the absence of increase of 3-hydroxyisovaleric acid levels.

Defects in OPA3 are the cause of optic atrophy type 3(OPA3) [MIM:165300], also known as autosomal dominant opticatrophy and cataract (ADOAC) or cataract, optic atrophy andneurologic disorder. Hereditary optic atrophy form a heterogeneousgroup of disorders. The autosomal dominant forms are characterizedby an insidious onset of visual impairment in early childhood withmoderate to severe loss of visual acuity, temporal optic diskpallor, color vision deficits and centrocecal scotoma of variabledensity.

Defects in OPCML are a cause of susceptibility to ovariancancer (OC) [MIM:167000]. Ovarian cancer common malignancyoriginating from ovarian tissue. Although many histologic types ofovarian neoplasms have been described, epithelial ovariancarcinoma is the most common form. Ovarian cancers are oftenasymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients arediagnosed with advanced disease.

Defects in OPHN1 are the cause of mental retardation X-linked OPHN1-related (MRXSO) [MIM:300486], formerly designatedMRX60. MRXSO is a syndromic mental retardation. Patients presentmental retardation associated with cerebellar hypoplasia anddistinctive facial dysmorphism.

Defects in OPN1SW are the cause of tritan color blindness(tritanopia) [MIM:190900].

Defects in RHO are the cause of retinitis pigmentosa type4 (RP4) [MIM:613731]. RP leads to degeneration of retinalphotoreceptor cells. Patients typically have night visionblindness and loss of midperipheral visual field. As theircondition progresses, they lose their far peripheral visual fieldand eventually central vision as well.

Defects in RHO are the cause of congenital stationarynight blindness autosomal dominant type 1 (CSNBAD1) [MIM:610445],also known as rhodopsin-related congenital stationary nightblindness. Congenital stationary night blindness is a non-progressive retinal disorder characterized by impaired nightvision.

Defects in OPN1MW are the cause of partial colorblindnessdeutan series (CBD) [MIM:303800], also known as deuteranopia.

Defects in OPN1MW are a cause of blue cone monochromacy(BCM) [MIM:303700]. A rare X-linked congenital stationary conedysfunction syndrome characterized by the absence of functionallong wavelength-sensitive and medium wavelength-sensitive cones inthe retina. Color discrimination is severely impaired from birth,and vision is derived from the remaining preserved blue (S) conesand rod photoreceptors. BCM typically presents with reduced visualacuity, pendular nystagmus, and photophobia. Patients often havemyopia.

Defects in OPN1MW are a cause of cone dystrophy type 5(COD5) [MIM:303700]. A X-linked cone dystrophy. Cone dystrophiesare retinal dystrophies characterized by progressive degenerationof the cone photoreceptors with preservation of rod function, asindicated by electroretinogram. However, some rod involvement maybe present in some cone dystrophies, particularly at late stage.Affected individuals suffer from photophobia, loss of visualacuity, color vision and central visual field. Another sign is theabsence of macular lesions for many years. Cone dystrophies aredistinguished from the cone-rod dystrophies in which some loss ofperipheral vision also occurs.

Defects in OPN1LW are the cause of partial colorblindnessprotan series (CBP) [MIM:303900], also known as protanopia.

Defects in OPN1LW are a cause of blue cone monochromacy(BCM) [MIM:303700]. A rare X-linked congenital stationary conedysfunction syndrome characterized by the absence of functionallong wavelength-sensitive and medium wavelength-sensitive cones inthe retina. Color discrimination is severely impaired from birth,and vision is derived from the remaining preserved blue (S) conesand rod photoreceptors. BCM typically presents with reduced visualacuity, pendular nystagmus, and photophobia. Patients often havemyopia.

Defects in OPTN are the cause of primary open angleglaucoma type 1E (GLC1E) [MIM:137760]. Primary open angle glaucoma(POAG) is characterized by a specific pattern of optic nerve andvisual field defects. The angle of the anterior chamber of the eyeis open, and usually the intraocular pressure is increased. Thedisease is asymptomatic until the late stages, by which timesignificant and irreversible optic nerve damage has already takenplace.

Defects in OPTN are a cause of susceptibility to normalpressure glaucoma (NPG) [MIM:606657].

Defects in OPTN are the cause of amyotrophic lateralsclerosis type 12 (ALS12) [MIM:613435]. It is a neurodegenerativedisorder affecting upper motor neurons in the brain and lowermotor neurons in the brain stem and spinal cord, resulting infatal paralysis. Sensory abnormalities are absent. Death usuallyoccurs within 2 to 5 years. The etiology of amyotrophic lateralsclerosis is likely to be multifactorial, involving both geneticand environmental factors. The disease is inherited in 5-10% ofthe cases.

Defects in HCRT are the cause of narcolepsy type 1(NRCLP1) [MIM:161400]. Narcolepsy is a neurological disablingsleep disorder, characterized by excessive daytime sleepiness,sleep fragmentation, symptoms of abnormal rapid-eye-movement (REM)sleep, such as cataplexy, hypnagogic hallucinations, and sleepparalysis. Cataplexy is a sudden loss of muscle tone triggered byemotions, which is the most valuable clinical feature used todiagnose narcolepsy. Human narcolepsy is primarily a sporadicallyoccurring disorder but familial clustering has been observed.Note=Human narcolepsy is associated with a deficient orexinsystem. Orexins are absent and/or greatly diminished in the brainand cerebrospinal fluid (CSF) of most narcoleptic patients.

Genetic variations in ORMDL3 are associated withsusceptibility to asthma (ASTHMA) [MIM:600807]. The most commonchronic disease affecting children and young adults. It is acomplex genetic disorder with a heterogeneous phenotype, largelyattributed to the interactions among many genes and between thesegenes and the environment. It is characterized by recurrentattacks of paroxysmal dyspnea, with weezing due to spasmodiccontraction of the bronchi.

Defects in SLC25A15 are the cause of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH syndrome)[MIM:238970]. It is an autosomal recessive disorder resulting invarious neurologic symptoms, including mental retardation, spasticparaparesis with pyramidal signs, cerebellar ataxia, and episodicdisturbance of consciousness or coma caused by hyperammonemia. Itcauses a functional impairment of the urea cycle.

Defects in OSMR are the cause of amyloidosis type 9(AMYL9) [MIM:105250], also known as primary cutaneous amyloidosis(PCA), primary localized cutaneous amyloidosis (PLCA), familiallichen amyloidosis or familial cutaneous lichen amyloidosis. AMYL9is a hereditary primary amyloidosis characterized by localizedcutaneous amyloid deposition. This condition usually presents withitching (especially on the lower legs) and visible changes of skinhyperpigmentation and thickening (lichenification) that may beexacerbated by chronic scratching and rubbing. The amyloiddeposits probably reflect a combination of degenerate keratinfilaments, serum amyloid P component, and deposition ofimmunoglobulins.

Defects in OSTM1 are the cause of osteopetrosis autosomalrecessive type 5 (OPTB5) [MIM:259720], also called infantilemalignant osteopetrosis 3. Osteopetrosis is a rare genetic diseasecharacterized by abnormally dense bone, due to defectiveresorption of immature bone. The disorder occurs in two forms: asevere autosomal recessive form occurring in utero, infancy, orchildhood, and a benign autosomal dominant form occurring inadolescence or adulthood. OPTB5 patients manifest primary centralnervous system involvement in addition to the classical stigmataof severe bone sclerosis, growth failure, anemia, thrombocytopeniaand visual impairment with optic atrophy.

Defects in OTC are the cause of ornithinecarbamoyltransferase deficiency (OTCD) [MIM:311250]. OTCD is an X-linked disorder of the urea cycle which causes a form ofhyperammonemia. Mutations with no residual enzyme activity arealways expressed in hemizygote males by a very severe neonatalhyperammonemic coma that generally proves to be fatal.Heterozygous females are either asymptomatic or express oroticaciduria spontaneously or after protein intake. The disorder istreatable with supplemental dietary arginine and low protein diet.The arbitrary classification of patients into the 'neonatal' group(clinical hyperammonemia in the first few days of life) and 'late'onset (clinical presentation after the neonatal period) has beenused to differentiate severe from mild forms.

Defects in OTOA are the cause of deafness autosomalrecessive type 22 (DFNB22) [MIM:607039]. DFNB22 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in OTOF are the cause of deafness autosomalrecessive type 9 (DFNB9) [MIM:601071]. DFNB9 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in OTOF are a cause of non-syndromic auditoryneuropathy autosomal recessive (NSRAN) [MIM:601071]. NSRAN is aform of sensorineural hearing impairment with absent or severelyabnormal auditory brainstem response but normal otoacousticemissions. Auditory neuropathies result from a lesion in the areaincluding the inner hair cells, connections between the inner haircells and the cochlear branch of the auditory nerve, the auditorynerve itself and auditory pathways of the brainstem. In some casesNSRAN phenotype can be temperature sensitive.

Defects in OTX2 are the cause of microphthalmia syndromictype 5 (MCOPS5) [MIM:610125]. Microphthalmia is a clinicallyheterogeneous disorder of eye formation, ranging from small sizeof a single eye to complete bilateral absence of ocular tissues.Up to 80% of cases of microphthalia occur in association withsyndromes that include non-ocular abnormalities. MCOPS5 patientsmanifest unilateral or bilateral microphthalmia/clinicalanophthalmia and variable additional features including coloboma,microcornea, cataract, retinal dystrophy, hypoplasia or agenesisof the optic nerve, agenesis of the corpus callosum, developmentaldelay, joint laxity, hypotonia, and seizures.

Defects in P2RY12 are the cause of P2RY12 deficiency(P2RY12D) [MIM:609821]. It is a condition characterized by severeimpairment of platelet response to ADP and abnormal bleedingmarked by excessive posttraumatic and postsurgical blood loss.

Defects in LEPRE1 are the cause of osteogenesisimperfecta type 8 (OI8) [MIM:610915]. A connective tissue disordercharacterized by disproportionate short stature, severeosteoporosis, shortening of the long bones, white sclerae, a roundface and a short barrel-shaped chest.

Note=TP53 is found in increased amounts in a wide varietyof transformed cells. TP53 is frequently mutated or inactivated inabout 60% of cancers. TP53 defects are found in Barrett metaplasiaa condition in which the normally stratified squamous epitheliumof the lower esophagus is replaced by a metaplastic columnarepithelium. The condition develops as a complication inapproximately 10% of patients with chronic gastroesophageal refluxdisease and predisposes to the development of esophagealadenocarcinoma.

Defects in TP53 are a cause of esophageal cancer (ESCR)[MIM:133239].

Defects in TP53 are a cause of Li-Fraumeni syndrome (LFS)[MIM:151623]. LFS is an autosomal dominant familial cancersyndrome that in its classic form is defined by the existence of aproband affected by a sarcoma before 45 years with a first degreerelative affected by any tumor before 45 years and another firstdegree relative with any tumor before 45 years or a sarcoma at anyage. Other clinical definitions for LFS have been proposed(PubMed:8118819 and PubMed:8718514) and called Li-Fraumeni likesyndrome (LFL). In these families affected relatives develop adiverse set of malignancies at unusually early ages. Four types ofcancers account for 80% of tumors occurring in TP53 germlinemutation carriers: breast cancers, soft tissue and bone sarcomas,brain tumors (astrocytomas) and adrenocortical carcinomas. Lessfrequent tumors include choroid plexus carcinoma or papillomabefore the age of 15, rhabdomyosarcoma before the age of 5,leukemia, Wilms tumor, malignant phyllodes tumor, colorectal andgastric cancers.

Defects in TP53 are involved in head and neck squamouscell carcinomas (HNSCC) [MIM:275355], also known as squamous cellcarcinoma of the head and neck.

Defects in TP53 are a cause of lung cancer (LNCR)[MIM:211980].

Defects in TP53 are a cause of choroid plexus papilloma(CPLPA) [MIM:260500]. Choroid plexus papilloma is a slow-growingbenign tumor of the choroid plexus that often invades theleptomeninges. In children it is usually in a lateral ventriclebut in adults it is more often in the fourth ventricle.Hydrocephalus is common, either from obstruction or from tumorsecretion of cerebrospinal fluid. If it undergoes malignanttransformation it is called a choroid plexus carcinoma. Primarychoroid plexus tumors are rare and usually occur in earlychildhood.

Defects in TP53 are a cause of adrenocortical carcinoma(ADCC) [MIM:202300]. ADCC is a rare childhood tumor of the adrenalcortex. It occurs with increased frequency in patients with theBeckwith-Wiedemann syndrome and is a component tumor in Li-Fraumeni syndrome.

Defects in PYCR1 are the cause of cutis laxa autosomalrecessive type 2B (ARCL2B) [MIM:612940]. A multisystem disordercharacterized by the appearance of premature aging, wrinkled andlax skin with reduced elasticity, joint laxity, craniofacialdysmorphic features, intrauterine growth retardation with somedegree of postnatal growth deficiency, and developmental delay.

Defects in ALDH18A1 are the cause of mental retardation-joint hypermobility-skin laxity with or without metabolicabnormalities (MRJHSL) [MIM:612652]. Clinical manifestationsinclude microcephaly, progressive neurologic dysfunction, mentalretardation, progeroid appearance, joint hypermobility, skinlaxity and hyperelasticity, cataracts. Some patients manifestmetabolic disturbances such as hyperammonemia, hypoornithinemia,hypocitrullinemia, hypoargininemia and hypoprolinemia.

Defects in TP63 are the cause of acro-dermato-ungual-lacrimal-tooth syndrome (ADULT syndrome) [MIM:103285], a form ofectodermal dysplasia. Ectodermal dysplasias (EDs) constitute aheterogeneous group of developmental disorders affecting tissuesof ectodermal origin. EDs are characterized by abnormaldevelopment of two or more ectodermal structures such as hair,teeth, nails and sweat glands, with or without any additionalclinical sign. Each combination of clinical features represents adifferent type of ectodermal dysplasia. ADULT syndrome involvesectrodactyly, syndactyly, finger- and toenail dysplasia,hypoplastic breasts and nipples, intensive freckling, lacrimalduct atresia, frontal alopecia, primary hypodontia, and loss ofpermanent teeth. ADULT differs significantly from EEC3 syndrome bythe absence of facial clefting.

Defects in TP63 are the cause of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) [MIM:106260]. AEC is anautosomal dominant condition characterized by congenitalectodermal dysplasia with coarse, wiry, sparse hair, dystrophicnails, slight hypohidrosis, scalp infections, ankyloblepharonfiliform adnatum, maxillary hypoplasia, hypodontia and cleftlip/palate.

Defects in TP63 are the cause of ectrodactyly-ectodermaldysplasia-cleft lip/palate syndrome type 3 (EEC3) [MIM:604292].EEC3 is an autosomal dominant syndrome characterized byectrodactyly of hands and feet, ectodermal dysplasia and facialclefting.

Defects in TP63 are the cause of split-hand/footmalformation type 4 (SHFM4) [MIM:605289]. Split-hand/split-footmalformation is a limb malformation involving the central rays ofthe autopod and presenting with syndactyly, median clefts of thehands and feet, and aplasia and/or hypoplasia of the phalanges,metacarpals, and metatarsals. There is restricted overlap betweenthe mutational spectra of EEC3 and SHFM4.

Defects in TP63 are the cause of limb-mammary syndrome(LMS) [MIM:603543]. LMS is characterized by ectrodactyly, cleftpalate and mammary-gland abnormalities.

Note=Defects in TP63 are a cause of cervical, colon, headand neck, lung and ovarian cancers.

Defects in TP63 are a cause of ectodermal dysplasia Rapp-Hodgkin type (EDRH) [MIM:129400], also called Rapp-Hodgkinsyndrome or anhidrotic ectodermal dysplasia with cleft lip/palate.Ectodermal dysplasia defines a heterogeneous group of disordersdue to abnormal development of two or more ectodermal structures.EDRH is characterized by the combination of anhidrotic ectodermaldysplasia, cleft lip, and cleft palate. The clinical syndrome iscomprised of a characteristic facies (narrow nose and smallmouth), wiry, slow-growing, and uncombable hair, sparse eyelashesand eyebrows, obstructed lacrimal puncta/epiphora, bilateralstenosis of external auditory canals, microsomia, hypodontia,cone-shaped incisors, enamel hypoplasia, dystrophic nails, andcleft lip/cleft palate.

Defects in TP63 are the cause of non-syndromic orofacialcleft type 8 (OFC8) [MIM:129400]. Non-syndromic orofacial cleft isa common birth defect consisting of cleft lips with or withoutcleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides andrange in severity from a simple notch in the upper lip to acomplete opening in the lip extending into the floor of thenostril and involving the upper gum.

Defects in PLA2G6 are the cause of neurodegeneration withbrain iron accumulation type 2B (NBIA2B) [MIM:610217]. Aneurodegenerative disorder associated with iron accumulation inthe brain, primarily in the basal ganglia. It is characterized byprogressive extrapyramidal dysfunction leading to rigidity,dystonia, dysarthria and sensorimotor impairment.

Defects in PLA2G6 are the cause of neurodegeneration withbrain iron accumulation type 2A (NBIA2A) [MIM:256600], also knownas Seitelberger disease. NBIA2A is a neurodegenerative diseasecharacterized by pathologic axonal swelling and spheroid bodies inthe central nervous system. Onset is within the first 2 years oflife with death by age 10 years.

Defects in PLA2G6 are the cause of dystonia-parkinsonismPaisan-Ruiz type (DYTPR) [MIM:612953]. An adult-onset progressiveneurodegenerative disorder characterized by parkinsonism,dystonia, severe cognitive decline, cerebral and cerebellaratrophy and absent iron in the basal ganglia on magnetic resonanceimaging.

Defects in PABPN1 are the cause of oculopharyngealmuscular dystrophy (OPMD) [MIM:164300]. OPMD is a form of late-onset slowly progressive myopathy characterized by eyelid ptosis,dysphagia and, sometimes by other cranial and limb-muscleinvolvement.

Genetic variations in PADI4 are a cause of susceptibilityto rheumatoid arthritis (RA) [MIM:180300]. It is a systemicinflammatory disease with autoimmune features and a complexgenetic component. It primarily affects the joints and ischaracterized by inflammatory changes in the synovial membranesand articular structures, widespread fibrinoid degeneration of thecollagen fibers in mesenchymal tissues, and by atrophy andrarefaction of bony structures. Note=Could have an important rolein the pathogenesis of rheumatoid arthritis by increasingcitrullination of proteins in rheumatoid arthritis synovialtissues, leading, in a cytokine-rich milieu, to a break intolerance to citrullinated peptides processed and presented in theappropriate HLA context.

Defects in PLA2G7 are the cause of platelet-activatingfactor acetylhydrolase deficiency (PLA2G7 deficiency)[MIM:601690]. It is a trait which is present in 27% of Japanese.It could have a significant physiologic effect in the presence ofinflammatory bodily responses.

Defects in PHYH are a cause of Refsum disease (RD)[MIM:266500]. RD is an autosomal recessive disorder characterizedclinically by a tetrad of abnormalities: retinitis pigmentosa,peripheral neuropathy, cerebellar ataxia, and elevated proteinlevels in the cerebrospinal fluid (CSF). Patients exhibitaccumulation of the branched-chain fatty acid, phytanic acid, inblood and tissues. Less constant features are nerve deafness,anosmia, skeletal abnormalities, ichthyosis, cataracts and cardiacimpairment. Manifestations of the disease appear in the second orthird decade of life.

Defects in SERPINE1 are the cause of plasminogenactivator inhibitor-1 deficiency (PAI-1D) [MIM:613329]. It is ahematologic disorder characterized by increased bleeding aftertrauma, injury, or surgery. Affected females have menorrhagia. Thebleeding defect is due to increased fibrinolysis of fibrin bloodclots due to deficiency of plasminogen activator inhibitor-1,which inhibits tissue and urinary activators of plasminogen.

Note=High concentrations of SERPINE1 seem to contributeto the development of venous but not arterial occlusions.

Defects in PAK3 are the cause of mental retardation X-linked type 30 (MRX30) [MIM:300558], also called X-linked mentalretardation type 47 (MRX47). Mental retardation is a mentaldisorder characterized by significantly sub-average generalintellectual functioning associated with impairments in adaptativebehavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest otherclinical signs.

Note=Genetic variations in PALB2 are associated withbreast cancer susceptibility.

Defects in PALB2 are the cause of Fanconi anemiacomplementation group N (FANCN) [MIM:610832]. It is a disorderaffecting all bone marrow elements and resulting in anemia,leukopenia and thrombopenia. It is associated with cardiac, renaland limb malformations, dermal pigmentary changes, and apredisposition to the development of malignancies. At the cellularlevel it is associated with hypersensitivity to DNA-damagingagents, chromosomal instability (increased chromosome breakage)and defective DNA repair.

Defects in PALB2 are the cause of pancreatic cancer type3 (PNCA3) [MIM:613348]. It is a malignant neoplasm of thepancreas. Tumors can arise from both the exocrine and endocrineportions of the pancreas, but 95% of them develop from theexocrine portion, including the ductal epithelium, acinar cells,connective tissue, and lymphatic tissue.

Genetic variations in PALLD are associated withsusceptibility to pancreatic cancer type 1 (PNCA1) [MIM:606856].Expression is increased early in the development of pancreaticcancer: in normal-appearing whole tissue immediately adjacent tocancer, in the pre-cancer, and in both the familial and sporadicforms of the cancer.

Note=Genetic variations in PALLD may be associated withmyocardial infarction.

Defects in PANK2 are the cause of neurodegeneration withbrain iron accumulation type 1 (NBIA1) [MIM:234200], also known aspantothenate kinase-associated neurodegeneration (PKAN) orHallervorden-Spatz syndrome (HSS). It is an autosomal recessiveneurodegenerative disorder associated with iron accumulation inthe brain, primarily in the basal ganglia. Clinical manifestationsinclude progressive muscle spasticity, hyperreflexia, musclerigidity, dystonia, dysarthria, and intellectual deteriorationwhich progresses to severe dementia over several years. It isclinically classified into classic, atypical, and intermediatephenotypes. Classic forms present with onset in the first decade,rapid progression, loss of independent ambulation within 15 years.Atypical forms have onset in the second decade, slow progression,maintenance of independent ambulation up to 40 years later.Intermediate forms manifest onset in the first decade with slowprogression or onset in the second decade with rapid progression.Patients with early onset tend to also develop pigmentaryretinopathy, whereas those with later onset tend to also havespeech disorders and psychiatric features. All patients have the'eye of the tiger' sign on brain MRI.

Defects in PANK2 are the cause ofhypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa,and pallidal degeneration (HARP) [MIM:607236]. HARP is a raresyndrome with many clinical similarities to NBIA1.

Defects in MTPAP are the cause of spastic ataxiaautosomal recessive type 4 (SPAX4) [MIM:613672]. A slowlyprogressive neurodegenerative disease characterized by cerebellarataxia, spastic paraparesis, dysarthria, and optic atrophy.Note=Affected individuals exhibit a drastic decrease in poly(A)tail length of representative mitochondrial mRNA transcripts,including COX1 and RNA14 (PubMed:20970105).

Defects in PAPSS2 are the cause of spondyloepimetaphysealdysplasia Pakistani type (SEMD-PA) [MIM:612847]. A bone diseasecharacterized by epiphyseal dysplasia with mild metaphysealabnormalities. Clinical features include short stature evidencedat birth, short and bowed lower limbs, mild brachydactyly,kyphoscoliosis, abnormal gait, enlarged knee joints. Some patientsmay manifest premature pubarche and hyperandrogenism associatedwith skeletal dysplasia and short stature.

Defects in PARK7 are the cause of Parkinson disease type7 (PARK7) [MIM:606324]. A neurodegenerative disorder characterizedby resting tremor, postural tremor, bradykinesia, muscularrigidity, anxiety and psychotic episodes. PARK7 has onset before40 years, slow progression and initial good response to levodopa.Some patients may show traits reminiscent of amyotrophic lateralsclerosis-parkinsonism/dementia complex (Guam disease).

Note=Overexpressed at significantly higher levels infatal high-risk diffuse large B-cell lymphomas (DLB-CL) comparedto cured low-risk tumors. Overexpression in B-cell lymphomatransfectants may promote malignant B-cell migration. Maytherefore be involved in promoting B-cell migration anddissemination of high-risk DLB-CL tumors.

Note=A chromosomal aberration involving PATZ1 isassociated with small round cell sarcoma. Translocationt(1,22)(p36.1,q12) with EWSR1.

Defects in PAX2 are the cause of renal-coloboma syndrome(RCS) [MIM:120330], also known as papillorenal syndrome or opticnerve coloboma with renal disease. RCS is an autosomal dominantdisease characterized by the association of renal hypoplasia,vesicoureteral reflux and dysplasia of the retina and optic disk.

Note=Defects in PAX2 may be responsible for isolatedrenal hypoplasia as observed in oligomeganephronia, a rarecongenital and usually sporadic anomaly characterized by bilateralrenal hypoplasia, with a reduced number of enlarged nephrons andwithout urinary tract abnormalities.

Defects in PAX3 are the cause of Waardenburg syndrometype 1 (WS1) [MIM:193500]. WS1 is an autosomal dominant disordercharacterized by wide bridge of nose owing to lateral displacementof the inner canthus of each eye (dystopia canthorum), pigmentarydisturbances such as frontal white blaze of hair, heterochromia ofirides, white eyelashes, leukoderma and sensorineural deafness.The syndrome shows variable clinical expression and some affectedindividuals do not manifest hearing impairment.

Defects in PAX3 are the cause of Waardenburg syndrometype 3 (WS3) [MIM:148820], also known as Klein-Waardenburgsyndrome or Waardenburg syndrome with upper limb anomalies orwhite forelock with malformations. WS3 is a very rare autosomaldominant disorder, which shares many of the characteristics ofWS1. Patients additionally present with musculoskeletalabnormalities.

Defects in PAX3 are the cause of craniofacial-deafness-hand syndrome (CDHS) [MIM:122880]. CDHS is thought to be anautosomal dominant disease which comprises absence or hypoplasiaof the nasal bones, hypoplastic maxilla, small and short nose withthin nares, limited movement of the wrist, short palpebralfissures, ulnar deviation of the fingers, hypertelorism andprofound sensory-neural deafness.

Defects in PAX3 are a cause of rhabdomyosarcoma type 2(RMS2) [MIM:268220]. It is a form of rhabdomyosarcoma, a highlymalignant tumor of striated muscle derived from primitivemesenchimal cells and exhibiting differentiation alongrhabdomyoblastic lines. Rhabdomyosarcoma is one of the mostfrequently occurring soft tissue sarcomas and the most common inchildren. It occurs in four forms: alveolar, pleomorphic,embryonal and botryoidal rhabdomyosarcomas. Note=A chromosomalaberration involving PAX3 is found in rhabdomyosarcoma.Translocation (2,13)(q35,q14) with FOXO1. The resulting protein isa transcriptional activator.

Note=A chromosomal aberration involving PAX3 is a causeof rhabdomyosarcoma. Translocation t(2,2)(q35,p23) with NCOA1generates the NCOA1-PAX3 oncogene consisting of the N-terminuspart of PAX3 and the C-terminus part of NCOA1. The fusion proteinacts as a transcriptional activator. Rhabdomyosarcoma is the mostcommon soft tissue carcinoma in childhood, representing 5-8% ofall malignancies in children.

Defects in PAX4 are a cause of noninsulin-dependentdiabetes mellitus (NIDDM) [MIM:125853], also known as diabetesmellitus type 2 or maturity-onset diabetes. NIDDM is characterizedby an autosomal dominant mode of inheritance, onset duringadulthood and insulin resistance.

Genetic variations in PAX4 are associated withsusceptibility to insulin-dependent diabetes mellitus (IDDM)[MIM:222100]. IDDM normally starts in childhood or adolescence andis caused by the body's own immune system which destroys theinsulin-producing beta cells in the pancreas. Classical featuresare polydipsia, polyphagia and polyuria, due to hyperglycemia-induced osmotic diuresis.

Defects in PAX4 are a cause of susceptibility to diabetesmellitus ketosis-prone (KPD) [MIM:612227]. KPD is an atypical formof diabetes mellitus characterized by an acute initialpresentation with severe hyperglycemia and ketosis, as seen inclassic type 1 diabetes, but after initiation of insulin therapy,prolonged remission is often possible with cessation of insulintherapy and maintenance of appropriate metabolic control.Metabolic studies show a markedly blunted insulin secretoryresponse to glucose, partially reversible with the improvement ofblood glucose control. Variable levels of insulin resistance areobserved, especially in obese patients. Pancreatic beta-cellautoimmunity is a rare finding.

Defects in PAX4 are the cause of maturity-onset diabetesof the young type 9 (MODY9) [MIM:612225]. MODY is a form ofdiabetes that is characterized by an autosomal dominant mode ofinheritance, onset in childhood or early adulthood (usually before25 years of age), a primary defect in insulin secretion andfrequent insulin-independence at the beginning of the disease.

Note=A chromosomal aberration involving PAX5 is a causeof acute lymphoblastic leukemia. Translocation t(9,18)(p13,q11.2)with ZNF521. Translocation t(9,3)(p13,p14.1) with FOXP1.Translocation t(9,12)(p13,p13) with ETV6.

Defects in PAX6 are the cause of aniridia (AN)[MIM:106210]. A congenital, bilateral, panocular disordercharacterized by complete absence of the iris or extreme irishypoplasia. Aniridia is not just an isolated defect in irisdevelopment but it is associated with macular and optic nervehypoplasia, cataract, corneal changes, nystagmus. Visual acuity isgenerally low but is unrelated to the degree of iris hypoplasia.Glaucoma is a secondary problem causing additional visual lossover time.

Defects in PAX6 are a cause of Peters anomaly (PAN)[MIM:604229]. Peters anomaly consists of a central cornealleukoma, absence of the posterior corneal stroma and Descemetmembrane, and a variable degree of iris and lenticular attachmentsto the central aspect of the posterior cornea.

Defects in PAX6 are a cause of foveal hypoplasia (FOVHYP)[MIM:136520]. Foveal hypoplasia can be isolated or associated withpresenile cataract. Inheritance is autosomal dominant.

Defects in PAX6 are a cause of keratitis hereditary(KERH) [MIM:148190]. An ocular disorder characterized by cornealopacification, recurrent stromal keratitis and vascularization.

Defects in PAX6 are a cause of coloboma ocular (COLO)[MIM:120200], also known as uveoretinal coloboma or coloboma ofiris, choroid and retina. Ocular colobomas are a set ofmalformations resulting from abnormal morphogenesis of the opticcup and stalk, and the fusion of the fetal fissure (opticfissure). Severe colobomatous malformations may cause as much as10% of the childhood blindness. The clinical presentation ofocular coloboma is variable. Some individuals may present withminimal defects in the anterior iris leaf without other oculardefects. More complex malformations create a combination of iris,uveoretinal and/or optic nerve defects without or withmicrophthalmia or even anophthalmia.

Defects in PAX6 are a cause of coloboma of optic nerve(COLON) [MIM:120430].

Defects in PAX6 are a cause of bilateral optic nervehypoplasia (BONH) [MIM:165550], also known as bilateral opticnerve aplasia. A congenital anomaly in which the optic discappears abnormally small. It may be an isolated finding or part ofa spectrum of anatomic and functional abnormalities that includespartial or complete agenesis of the septum pellucidum, othermidline brain defects, cerebral anomalies, pituitary dysfunction,and structural abnormalities of the pituitary.

Defects in PAX6 are a cause of aniridia cerebellar ataxiaand mental deficiency (ACAMD) [MIM:206700], also known asGillespie syndrome. A rare condition consisting of partialrudimentary iris, cerebellar impairment of the ability to performcoordinated voluntary movements, and mental retardation.

Defects in PAX7 are a cause of rhabdomyosarcoma type 2(RMS2) [MIM:268220]. It is a form of rhabdomyosarcoma, a highlymalignant tumor of striated muscle derived from primitivemesenchimal cells and exhibiting differentiation alongrhabdomyoblastic lines. Rhabdomyosarcoma is one of the mostfrequently occurring soft tissue sarcomas and the most common inchildren. It occurs in four forms: alveolar, pleomorphic,embryonal and botryoidal rhabdomyosarcomas. Note=A chromosomalaberration involving PAX7 is found in rhabdomyosarcoma.Translocation t(1,13)(p36,q14) with FOXO1. The resulting proteinis a transcriptional activator.

Defects in PAX8 are the cause of congenitalhypothyroidism non-goitrous type 2 (CHNG2) [MIM:218700]. CHNG2 isa disease characterized by thyroid dysgenesis, the most frequentcause of congenital hypothyroidism, accounting for 85% of case.The thyroid gland can be completely absent (athyreosis),ectopically located and/or severely hypoplastic. Ectopic thyroidgland is the most frequent malformation, with thyroid tissue beingfound most often at the base of the tongue.

Defects in PAX9 are the cause of tooth agenesis selectivetype 3 (STHAG3) [MIM:604625]. A form of selective tooth agenesis,a common anomaly characterized by the congenital absence of one ormore teeth. Selective tooth agenesis without associated systemicdisorders has sometimes been divided into 2 types: oligodontia,defined as agenesis of 6 or more permanent teeth, and hypodontia,defined as agenesis of less than 6 teeth. The number in both casesdoes not include absence of third molars (wisdom teeth).

Defects in PBRM1 are a cause of renal cell carcinoma(RCC) [MIM:144700]. It is a heterogeneous group of sporadic orhereditary carcinoma derived from cells of the proximal renaltubular epithelium. It is subclassified into clear cell renalcarcinoma (non-papillary carcinoma), papillary renal cellcarcinoma, chromophobe renal cell carcinoma, collecting ductcarcinoma with medullary carcinoma of the kidney, and unclassifiedrenal cell carcinoma.

Note=A chromosomal aberration involving PBX1 is a causeof pre-B-cell acute lymphoblastic leukemia (B-ALL). Translocationt(1,19)(q23,p13.3) with TCF3. E2A-PBX1 transforms cells byconstitutively activating transcription of genes regulated by PBX1or by other members of the PBX protein family.

Note=A chromosomal aberration involving PCDH11Y is acause of multiple congenital abnormalities, including severebilateral vesicoureteral reflux (VUR) with ureterovesical junctiondefects. Translocation t(Y,3)(p11,p12) with ROBO2.

Defects in PCCA are the cause of propionic acidemia typeI (PA-1) [MIM:606054]. PA-1 is a life-threatening diseasecharacterized by episodic vomiting, lethargy and ketosis,neutropenia, periodic thrombocytopenia, hypogammaglobulinemia,developmental retardation, and intolerance to protein.

Defects in PCCB are the cause of propionic acidemia typeII (PA-2) [MIM:606054]. PA-2 is a life-threatening diseasecharacterized by episodic vomiting, lethargy and ketosis,neutropenia, periodic thrombocytopenia, hypogammaglobulinemia,developmental retardation, and intolerance to protein.

Defects in PCDH15 are the cause of Usher syndrome type 1F(USH1F) [MIM:602083]. USH is a genetically heterogeneous conditioncharacterized by the association of retinitis pigmentosa andsensorineural deafness. Age at onset and differences in auditoryand vestibular function distinguish Usher syndrome type 1 (USH1),Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3).USH1 is characterized by profound congenital sensorineuraldeafness, absent vestibular function and prepubertal onset ofprogressive retinitis pigmentosa leading to blindness.

Defects in PCDH15 are a cause of Usher syndrome type 1D/F(USH1DF) [MIM:601067]. USH1DF patients are heterozygous formutations in CDH23 and PCDH15, indicating a digenic inheritancepattern.

Defects in PCDH15 are the cause of deafness autosomalrecessive type 23 (DFNB23) [MIM:609533]. DFNB23 is a form ofsensorineural hearing loss. Sensorineural deafness results fromdamage to the neural receptors of the inner ear, the nervepathways to the brain, or the area of the brain that receivessound information.

Defects in PCDH19 are the cause of epilepticencephalopathy early infantile type 9 (EIEE9) [MIM:300088], alsoknown as epilepsy female-restricted with mental retardation. Acondition characterized by seizure with onset in infancy or earlychildhood, cognitive impairment, and delayed development ofvariable severity in some patients. Additional features includeautistic signs and psychosis. The disorder is sex-limited, withthe phenotype being restricted to females.

Defects in SLC46A1 are the cause of hereditary folatemalabsorption (HFM) [MIM:229050]. HFM is a rare autosomalrecessive disorder characterized by impaired intestinal folateabsorption with folate deficiency resulting in anemia,hypoimmunoglobulinemia with recurrent infections, and recurrent orchronic diarrhea. In many patients, neurological abnormalitiessuch as seizures or mental retardation become apparent duringearly childhood, attributed to impaired transport of folates intothe central nervous system. When diagnosed early, the disorder canbe treated by administration of folate. If untreated, it can befatal and, if treatment is delayed, the neurological defects canbecome permanent.

Defects in PCK1 are the cause of cytosolicphosphoenolpyruvate carboxykinase deficiency (cytosolic PEPCKdeficiency) [MIM:261680]. PEPCK deficiency is a metabolic disorderresulting from impaired gluconeogenesis. It is a rare disease withless than 10 cases reported in the literature. Clinicalcharacteristics include hypotonia, hepatomegaly, failure tothrive, lactic acidosis and hypoglycemia. Autoposy reveals fattyinfiltration of both the liver and kidneys. The disorder istransmitted as an autosomal recessive trait.

Defects in PCK2 are the cause of mitochondrialphosphoenolpyruvate carboxykinase deficiency (mitochondrial PEPCKdeficiency) [MIM:261650]. PEPCK deficiency is a metabolic disorderresulting from impaired gluconeogenesis. It is a rare disease withless than 10 cases reported in the literature. Clinicalcharacteristics include hypotonia, hepatomegaly, failure tothrive, lactic acidosis and hypoglycemia. Autoposy reveals fattyinfiltration of both the liver and kidneys. The disorder istransmitted as an autosomal recessive trait.

Defects in PCM1 are a cause of thyroid papillarycarcinoma (TPC) [MIM:188550]. TPC is a common tumor of the thyroidthat typically arises as an irregular, solid or cystic mass fromotherwise normal thyroid tissue. Papillary carcinomas aremalignant neoplasm characterized by the formation of numerous,irregular, finger-like projections of fibrous stroma that iscovered with a surface layer of neoplastic epithelial cells.Note=A chromosomal aberration involving PCM1 is found in thyroidpapillary carcinomas. Translocation t(8,10)(p21.3,q11.2) with RETlinks the protein kinase domain of RET to the major portion ofPCM1.

Note=A chromosomal aberration involving PCM1 is found ina variety of hematological malignancies including atypical chronicmyeloid leukemia (atypical CML) and T-cell lymphoma. Translocationt(8,9)(p22,p24) with JAK2 links the protein kinase domain of JAK2to the major portion of PCM1.

Defects in PCNT are the cause of microcephalicosteodysplastic primordial dwarfism type 2 (MOPD2) [MIM:210720],also known as osteodysplastic primordial dwarfism type 2. Adultswith this rare inherited condition have an average height of 100centimeters and a brain size comparable to that of a 3-month-oldbaby, but are of near-normal intelligence.

Defects in PCSK9 are the cause of familialhypercholesterolemia 3 (FH3) [MIM:603776]. FH3 inheritance isautosomal dominant.

Genetic variations in PTGDR are associated withsusceptibility to asthma-related traits type 1 (ASRT1)[MIM:607277]. Asthma-related traits include clinical symptoms ofasthma, such as coughing, wheezing and dyspnea.

Defects in PDCD10 are the cause of cerebral cavernousmalformations type 3 (CCM3) [MIM:603285]. Cerebral cavernousmalformations (CCMs) are congenital vascular anomalies of thecentral nervous system that can result in hemorrhagic stroke,seizures, recurrent headaches, and focal neurologic deficits. CCMshave an incidence of 0.1%-0.5% in the general population andusually present clinically during the 3rd to 5th decade of life.The lesions are characterized by grossly enlarged blood vesselsconsisting of a single layer of endothelium and without anyintervening neural tissue, ranging in diameter from a fewmillimeters to several centimeters.

Genetic variation in PDCD1 is associated withsusceptibility to systemic lupus erythematosus type 2 (SLEB2)[MIM:605218]. Systemic lupus erythematosus is a chronic,inflammatory and often febrile multisystemic disorder ofconnective tissue. It affects principally the skin, joints,kidneys and serosal membranes. It is thought to represent afailure of the regulatory mechanisms of the autoimmune system.

Defects in PDE11A are the cause of primary pigmentednodular adrenocortical disease type 2 (PPNAD2) [MIM:610475].Primary pigmented nodular adrenocortical disease is a rarebilateral adrenal defect causing ACTH-independent Cushingsyndrome. PPNAD2 is characterized by adrenal glands with overallnormal size and weight, and multiple small yellow-to-dark brownnodules surrounded by a cortex with a uniform appearance.Microscopically, there are moderate diffuse cortical hyperplasiawith mostly nonpigmented nodules, multiple capsular deficits andmassive circumscribed and infiltrating extra-adrenal corticalexcrescences with micronodules. PPNAD2 leads to Cushing syndrome.

Note=Genetic variations in PDE4D might be associated withsusceptibility to stroke. PubMed:17006457 states that associationwith stroke has to be considered with caution.

Defects in PDE6A are a cause of retinitis pigmentosaautosomal recessive (ARRP) [MIM:268000]. RP leads to degenerationof retinal photoreceptor cells. Patients typically have nightvision blindness and loss of midperipheral visual field. As theircondition progresses, they lose their far peripheral visual fieldand eventually central vision as well.

Defects in PDE6B are a cause of retinitis pigmentosa (RP)[MIM:268000]. RP leads to degeneration of retinal photoreceptorcells. Patients typically have night vision blindness and loss ofmidperipheral visual field. As their condition progresses, theylose their far peripheral visual field and eventually centralvision as well.

Defects in PDE6B are a cause of congenital stationarynight blindness autosomal dominant type 2 (CSNBAD2) [MIM:163500],also known as congenital stationary night blindness Rambusch type.Congenital stationary night blindness is a non-progressive retinaldisorder characterized by impaired night vision.

Defects in PDE6C are the cause of cone dystrophy type 4(COD4) [MIM:613093]. An early-onset cone dystrophy. Conedystrophies are retinal dystrophies characterized by progressivedegeneration of the cone photoreceptors with preservation of rodfunction, as indicated by electroretinogram. However, some rodinvolvement may be present in some cone dystrophies, particularlyat late stage. Affected individuals suffer from photophobia, lossof visual acuity, color vision and central visual field. Anothersign is the absence of macular lesions for many years. Conedystrophies are distinguished from the cone-rod dystrophies inwhich some loss of peripheral vision also occurs.

Defects in PDE8B are the cause of striatal degenerationautosomal dominant (ADSD) [MIM:609161]. It is a movement disorderaffecting the striatal part of the basal ganglia and characterizedby bradykinesia, dysarthria and muscle rigidity. These symptomsresemble idiopathic Parkinson disease, but tremor is not present.

Note=A chromosomal aberration involving PDGFB is found indermatofibrosarcoma protuberans. Translocation t(17,22)(q22,q13)with PDGF.

Defects in PDP1 are the cause of pyruvate dehydrogenasephosphatase deficiency (PDP deficiency) [MIM:608782]. PDPdeficiency results in lactic acidosis leading to neurologicaldysfunction.

Defects in PDX1 are a cause of pancreatic agenesis (PAC)[MIM:260370]. This autosomal recessive disorder is characterizedby absence or hypoplasia of pancreas, leading to early-onsetinsulin-dependent diabetes mellitus. This was found in aframeshift mutation that produces a truncated protein and resultsin a second initiation that produces a second protein that act asa dominant negative mutant.

Defects in PDX1 are a cause of non-insulin-dependentdiabetes mellitus (NIDDM) [MIM:125853], also known as diabetesmellitus type 2. NIDDM is characterized by an autosomal dominantmode of inheritance, onset during adulthood and insulinresistance.

Defects in PDX1 are the cause of maturity-onset diabetesof the young type 4 (MODY4) [MIM:606392], also symbolized MODY-4.MODY is a form of diabetes that is characterized by an autosomaldominant mode of inheritance, onset in childhood or earlyadulthood (usually before 25 years of age), a primary defect ininsulin secretion and frequent insulin-independence at thebeginning of the disease.

Defects in PDYN are the cause of spinocerebellar ataxiatype 23 (SCA23) [MIM:610245]. Spinocerebellar ataxia is aclinically and genetically heterogeneous group of cerebellardisorders. Patients show progressive incoordination of gait andoften poor coordination of hands, speech and eye movements, due todegeneration of the cerebellum with variable involvement of thebrainstem and spinal cord. SCA23 is an adult-onset autosomaldominant form characterized by slowly progressive gait and limbataxia, with variable additional features, including peripheralneuropathy and dysarthria.

Note=A chromosomal aberration disrupting PDZD7 has beenfound in patients with non-syndromic sensorineural deafness.Translocation t(10,11),t(10,11).

Note=PDZD7 mutations have been found in combination withmutations in USH2A and GPR98/USH2C in patients affected by Ushersyndrome, suggesting a role as contributor to digenic Ushersyndrome or a modifier of retinal disease expression. Ushersyndrome is characterized by the association of retinitispigmentosa and sensorineural deafness.

Note=A chromosomal aberration involving CBFB isassociated with acute myeloid leukemia of M4EO subtype.Pericentric inversion inv(16)(p13,q22). The inversion produces afusion protein that consists of the 165 N-terminal residues ofCBF-beta (PEPB2) with the tail region of MYH11.

Defects in PSENEN are the cause of acne inversa familialtype 2 (ACNIF2) [MIM:613736]. A chronic relapsing inflammatorydisease of the hair follicles characterized by recurrent drainingsinuses, painful skin abscesses, and disfiguring scars.Manifestations typically appear after puberty.

Defects in PEO1 are the cause of progressive externalophthalmoplegia with mitochondrial DNA deletions autosomaldominant type 3 (PEOA3) [MIM:609286]. Progressive externalophthalmoplegia is characterized by progressive weakness of ocularmuscles and levator muscle of the upper eyelid. In a minority ofcases, it is associated with skeletal myopathy, whichpredominantly involves axial or proximal muscles and which causesabnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A largeproportion of chronic ophthalmoplegias are associated with othersymptoms, leading to a multisystemic pattern of this disease.Additional symptoms are variable, and may include cataracts,hearing loss, sensory axonal neuropathy, ataxia, depression,hypogonadism, and parkinsonism.

Defects in PEO1 are a cause of sensory ataxic neuropathydysarthria and ophthalmoparesis (SANDO) [MIM:607459]. SANDO is aclinically heterogeneous systemic disorder with variable featuresresulting from mitochondrial dysfunction. It shares phenotypiccharacteristics with autosomal recessive progressive externalophthalmoplegia and mitochondrial neurogastrointestinalencephalopathy syndrome. The clinical triad of symptoms consistsof sensory ataxic, neuropathy, dysarthria, and ophthalmoparesis.

Defects in PEO1 are the cause of mitochondrial DNAdepletion syndrome type 7 (MTDPS7) [MIM:271245], also known asspinocerebellar ataxia infantile-onset (IOSCA). A severe diseaseassociated with mitochondrial dysfunction. Some patients areaffected by progressive atrophy of the cerebellum, brain stem, thespinal cord, and sensory axonal neuropath. Clinical featuresinclude hypotonia, athetosis, ataxia, ophthalmoplegia,sensorineural hearing deficit, sensory axonal neuropathy,epileptic encephalopathy and female hypogonadism. Some individualsmanifest a hepatocerebral phenotype characterized by liverinsufficiency, increased serum and CSF lactate, hypotonia,psychomotor retardation and peripheral neuropathy.

Defects in PEPD are a cause of prolidase deficiency (PD)[MIM:170100]. Prolidase deficiency is an autosomal recessivedisorder associated with iminodipeptiduria. The clinical phenotypeincludes skin ulcers, mental retardation, recurrent infections,and a characteristic facies. These features, however areincompletely penetrant and highly variable in both age of onsetand severity. There is a tight linkage between the polymorphismsof prolidase and the myotonic dystrophy trait.

Defects in PER2 are a cause of familial advanced sleep-phase syndrome (FASPS) [MIM:604348]. FASPS is characterized byvery early sleep onset and offset. Individuals are 'morning larks'with a 4 hours advance of the sleep, temperature and melatoninrhythms.

Defects in EPX are the cause of eosinophil peroxidasedeficiency (EPD) [MIM:261500]. EPD is an autosomal recessivedefect where anomalous eosinophils are characterized by nuclearhypersegmentation, hypogranulation, and negative peroxidase andphospholipid staining.

Defects in PRF1 are the cause of hemophagocyticlymphohistiocytosis familial type 2 (FHL2) [MIM:603553], alsoknown as HPLH2. Familial hemophagocytic lymphohistiocytosis (FHL)is a genetically heterogeneous, rare autosomal recessive disorder.It is characterized by immune dysregulation with hypercytokinemiaand defective natural killer cell function. The clinical featuresof the disease include fever, hepatosplenomegaly, cytopenia,hypertriglyceridemia, hypofibrinogenemia, and neurologicalabnormalities ranging from irritability and hypotonia to seizures,cranial nerve deficits, and ataxia. Hemophagocytosis is aprominent feature of the disease, and a non-malignant infiltrationof macrophages and activated T lymphocytes in lymph nodes, spleen,and other organs is also found.

Defects in MPO are the cause of myeloperoxidasedeficiency (MPD) [MIM:254600]. MPD is an autosomal recessivedefect that results in disseminated candidiasis.

Defects in GIGYF2 are may be the cause of Parkinsondisease type 11 (PARK11) [MIM:607688]. A complex neurodegenerativedisorder characterized by bradykinesia, resting tremor, muscularrigidity and postural instability, as well as by a clinicallysignificant response to treatment with levodopa. The pathologyinvolves the loss of dopaminergic neurons in the substantia nigraand the presence of Lewy bodies (intraneuronal accumulations ofaggregated proteins), in surviving neurons in various areas of thebrain.

Note=An alternative splicing in the thyroperoxidase mRNAcan cause Graves' disease.

Defects in TPO are the cause of congenital hypothyroidismdue to dyshormonogenesis type 2A (CHDH2A) [MIM:274500], alsocalled genetic defect in thyroid hormonogenesis 2A or thyroidhormone organification defect II. CHDH2A is due to defectiveconversion of accumulated iodide to organically bound iodine. Theiodide organification defect can be partial or complete.

Defects in PEX10 are the cause of peroxisome biogenesisdisorder complementation group 7 (PBD-CG7) [MIM:602859], alsoknown as PBD-CGB. PBD refers to a group of peroxisomal disordersarising from a failure of protein import into the peroxisomalmembrane or matrix. The PBD group is comprised of four disorders:Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD),infantile Refsum disease (IRD), and classical rhizomelicchondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinctfrom RCDP and constitute a clinical continuum of overlappingphenotypes known as the Zellweger spectrum. The PBD group isgenetically heterogeneous with at least 14 distinct genetic groupsas concluded from complementation studies.

Defects in PEX10 are a cause of Zellweger syndrome (ZWS)[MIM:214100]. ZWS is a fatal peroxisome biogenesis disordercharacterized by dysmorphic facial features, hepatomegaly, ocularabnormalities, renal cysts, hearing impairment, profoundpsychomotor retardation, severe hypotonia and neonatal seizures.Death occurs within the first year of life.

Defects in PEX10 are a cause of adrenoleukodystrophyneonatal (NALD) [MIM:202370]. NALD is a peroxisome biogenesisdisorder (PBD) characterized by the accumulation of very long-chain fatty acids, adrenal insufficiency and mental retardation.

Defects in PEX12 are the cause of peroxisome biogenesisdisorder complementation group 3 (PBD-CG3) [MIM:601758]. PBDrefers to a group of peroxisomal disorders arising from a failureof protein import into the peroxisomal membrane or matrix. The PBDgroup is comprised of four disorders: Zellweger syndrome (ZWS),neonatal adrenoleukodystrophy (NALD), infantile Refsum disease(IRD), and classical rhizomelic chondrodysplasia punctata (RCDP).ZWS, NALD and IRD are distinct from RCDP and constitute a clinicalcontinuum of overlapping phenotypes known as the Zellwegerspectrum. The PBD group is genetically heterogeneous with at least14 distinct genetic groups as concluded from complementationstudies.

Defects in PEX12 are a cause of Zellweger syndrome (ZWS)[MIM:214100]. ZWS is a fatal peroxisome biogenesis disordercharacterized by dysmorphic facial features, hepatomegaly, ocularabnormalities, renal cysts, hearing impairment, profoundpsychomotor retardation, severe hypotonia and neonatal seizures.Death occurs within the first year of life.

Defects in PEX13 are the cause of peroxisome biogenesisdisorder complementation group 13 (PBD-CG13) [MIM:601789], alsoknown as PBD-CGH. PBD-CG13 is a peroxisomal disorder arising froma failure of protein import into the peroxisomal membrane ormatrix. The peroxisome biogenesis disorders (PBD group) aregenetically heterogeneous with at least 14 distinct genetic groupsas concluded from complementation studies. Include disorders are:Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD),infantile Refsum disease (IRD), and classical rhizomelicchondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinctfrom RCDP and constitute a clinical continuum of overlappingphenotypes known as the Zellweger spectrum (PBD-ZSS).

Defects in PEX13 are a cause of adrenoleukodystrophyneonatal (NALD) [MIM:202370]. NALD is a peroxisome biogenesisdisorder (PBD) characterized by the accumulation of very long-chain fatty acids, adrenal insufficiency and mental retardation.

Defects in PEX14 are the cause of peroxisome biogenesisdisorder complementation group K (PBD-CGK) [MIM:601791]. PBD-CGKis a peroxisomal disorder arising from a failure of protein importinto the peroxisomal membrane or matrix. The peroxisome biogenesisdisorders (PBD group) are genetically heterogeneous with at least14 distinct genetic groups as concluded from complementationstudies. Include disorders are: Zellweger syndrome (ZWS), neonataladrenoleukodystrophy (NALD), infantile Refsum disease (IRD), andclassical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALDand IRD are distinct from RCDP and constitute a clinical continuumof overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).

Defects in PEX14 are a cause of Zellweger syndrome (ZWS)[MIM:214100]. ZWS is a fatal peroxisome biogenesis disordercharacterized by dysmorphic facial features, hepatomegaly, ocularabnormalities, renal cysts, hearing impairment, profoundpsychomotor retardation, severe hypotonia and neonatal seizures.Death occurs within the first year of life.

Defects in PEX16 are the cause of peroxisome biogenesisdisorder complementation group 9 (PBD-CG9) [MIM:603360], alsoknown as PBD-CGD. PBD refers to a group of peroxisomal disordersarising from a failure of protein import into the peroxisomalmembrane or matrix. The PBD group is comprised of four disorders:Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD),infantile Refsum disease (IRD), and classical rhizomelicchondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinctfrom RCDP and constitute a clinical continuum of overlappingphenotypes known as the Zellweger spectrum. The PBD group isgenetically heterogeneous with at least 14 distinct genetic groupsas concluded from complementation studies.

Defects in PEX16 are a cause of Zellweger syndrome (ZWS)[MIM:214100]. ZWS is a fatal peroxisome biogenesis disordercharacterized by dysmorphic facial features, hepatomegaly, ocularabnormalities, renal cysts, hearing impairment, profoundpsychomotor retardation, severe hypotonia and neonatal seizures.Death occurs within the first year of life.

Defects in PEX19 are the cause of peroxisome biogenesisdisorder complementation group 14 (PBD-CG14) [MIM:600279], alsoknown as PBD-CGJ. PBD refers to a group of peroxisomal disordersarising from a failure of protein import into the peroxisomalmembrane or matrix. The PBD group is comprised of four disorders:Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD),infantile Refsum disease (IRD), and classical rhizomelicchondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinctfrom RCDP and constitute a clinical continuum of overlappingphenotypes known as the Zellweger spectrum. The PBD group isgenetically heterogeneous with at least 14 distinct genetic groupsas concluded from complementation studies.

Defects in PEX19 are a cause of Zellweger syndrome (ZWS)[MIM:214100]. ZWS is a fatal peroxisome biogenesis disordercharacterized by dysmorphic facial features, hepatomegaly, ocularabnormalities, renal cysts, hearing impairment, profoundpsychomotor retardation, severe hypotonia and neonatal seizures.Death occurs within the first year of life.

Defects in PEX1 are the cause of peroxisome biogenesisdisorder complementation group 1 (PBD-CG1) [MIM:602136], alsoknown as PBD-CGE. PBD refers to a group of peroxisomal disordersarising from a failure of protein import into the peroxisomalmembrane or matrix. The PBD group is comprised of four disorders:Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD),infantile Refsum disease (IRD), and classical rhizomelicchondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinctfrom RCDP and constitute a clinical continuum of overlappingphenotypes known as the Zellweger spectrum. The PBD group isgenetically heterogeneous with at least 14 distinct genetic groupsas concluded from complementation studies.

Defects in PEX1 are a cause of adrenoleukodystrophyneonatal (NALD) [MIM:202370]. NALD is a peroxisome biogenesisdisorder (PBD) characterized by the accumulation of very long-chain fatty acids, adrenal insufficiency and mental retardation.

Defects in PEX1 are a cause of infantile Refsum disease(IRD) [MIM:266510]. IRD is a mild peroxisome biogenesis disorder(PBD). Clinical features include early onset, mental retardation,minor facial dysmorphism, retinopathy, sensorineural hearingdeficit, hepatomegaly, osteoporosis, failure to thrive, andhypocholesterolemia. The biochemical abnormalities includeaccumulation of phytanic acid, very long chain fatty acids(VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid.

Defects in PEX26 are the cause of peroxisome biogenesisdisorder complementation group 8 (PBD-CG8) [MIM:608666], alsoknown as PBD-CGA. PBD refers to a group of peroxisomal disordersarising from a failure of protein import into the peroxisomalmembrane or matrix. The PBD group is comprised of four disorders:Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD),infantile Refsum disease (IRD), and classical rhizomelicchondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinctfrom RCDP and constitute a clinical continuum of overlappingphenotypes known as the Zellweger spectrum. The PBD group isgenetically heterogeneous with at least 13 distinct genetic groupsas concluded from complementation studies.

Defects in PEX26 are a cause of Zellweger syndrome (ZWS)[MIM:214100]. ZWS is a fatal peroxisome biogenesis disordercharacterized by dysmorphic facial features, hepatomegaly, ocularabnormalities, renal cysts, hearing impairment, profoundpsychomotor retardation, severe hypotonia and neonatal seizures.Death occurs within the first year of life.

Defects in PEX26 are a cause of adrenoleukodystrophyneonatal (NALD) [MIM:202370]. NALD is a peroxisome biogenesisdisorder characterized by the accumulation of very long-chainfatty acids, adrenal insufficiency and mental retardation.

Defects in PEX26 are a cause of infantile Refsum disease(IRD) [MIM:266510]. IRD is a mild peroxisome biogenesis disorder.Clinical features include early onset, mental retardation, minorfacial dysmorphism, retinopathy, sensorineural hearing deficit,hepatomegaly, osteoporosis, failure to thrive, andhypocholesterolemia. The biochemical abnormalities includeaccumulation of phytanic acid, very long chain fatty acids(VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid.

Defects in PEX2 are the cause of peroxisome biogenesisdisorder complementation group 5 (PBD-CG5) [MIM:170993], alsoknown as PBD-CGF. PBD refers to a group of peroxisomal disordersarising from a failure of protein import into the peroxisomalmembrane or matrix. The PBD group is comprised of four disorders:Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD),infantile Refsum disease (IRD), and classical rhizomelicchondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinctfrom RCDP and constitute a clinical continuum of overlappingphenotypes known as the Zellweger spectrum. The PBD group isgenetically heterogeneous with at least 14 distinct genetic groupsas concluded from complementation studies.

Defects in PEX2 are a cause of Zellweger syndrome (ZWS)[MIM:214100]. ZWS is a fatal peroxisome biogenesis disordercharacterized by dysmorphic facial features, hepatomegaly, ocularabnormalities, renal cysts, hearing impairment, profoundpsychomotor retardation, severe hypotonia and neonatal seizures.Death occurs within the first year of life.

Defects in PEX2 are a cause of infantile Refsum disease(IRD) [MIM:266510]. IRD is a mild peroxisome biogenesis disorder(PBD). Clinical features include early onset, mental retardation,minor facial dysmorphism, retinopathy, sensorineural hearingdeficit, hepatomegaly, osteoporosis, failure to thrive, andhypocholesterolemia. The biochemical abnormalities includeaccumulation of phytanic acid, very long chain fatty acids(VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid.

Defects in PEX3 are the cause of peroxisome biogenesisdisorder complementation group 12 (PBD-CG12) [MIM:603164], alsoknown as PBD-CGG. PBD refers to a group of peroxisomal disordersarising from a failure of protein import into the peroxisomalmembrane or matrix. The PBD group is comprised of four disorders:Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD),infantile Refsum disease (IRD), and classical rhizomelicchondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinctfrom RCDP and constitute a clinical continuum of overlappingphenotypes known as the Zellweger spectrum. The PBD group isgenetically heterogeneous with at least 14 distinct genetic groupsas concluded from complementation studies.

Defects in PEX3 are a cause of Zellweger syndrome (ZwS)[MIM:214100]. ZWS is a fatal peroxisome biogenesis disordercharacterized by dysmorphic facial features, hepatomegaly, ocularabnormalities, renal cysts, hearing impairment, profoundpsychomotor retardation, severe hypotonia and neonatal seizures.Death occurs within the first year of life.

Defects in PEX5 are a cause of adrenoleukodystrophyneonatal (NALD) [MIM:202370]. NALD is a peroxisome biogenesisdisorder (PBD) characterized by the accumulation of very long-chain fatty acids, adrenal insufficiency and mental retardation.Inheritance is autosomal recessive.

Defects in PEX5 are a cause of Zellweger syndrome (ZWS)[MIM:214100]. ZWS is a fatal peroxisome biogenesis disordercharacterized by dysmorphic facial features, hepatomegaly, ocularabnormalities, renal cysts, hearing impairment, profoundpsychomotor retardation, severe hypotonia and neonatal seizures.Death occurs within the first year of life.

Defects in PEX5 may be a cause of infantile Refsumdisease (IRD) [MIM:266510]. IRD is a mild peroxisome biogenesisdisorder (PBD). Clinical features include early onset, mentalretardation, minor facial dysmorphism, retinopathy, sensorineuralhearing deficit, hepatomegaly, osteoporosis, failure to thrive,and hypocholesterolemia. The biochemical abnormalities includeaccumulation of phytanic acid, very long chain fatty acids(VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid.

Defects in PEX6 are the cause of peroxisome biogenesisdisorder complementation group 4 (PBD-CG4) [MIM:601498], alsoknown as PBD-CGC. PBD refers to a group of peroxisomal disordersarising from a failure of protein import into the peroxisomalmembrane or matrix. The PBD group is comprised of four disorders:Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD),infantile Refsum disease (IRD), and classical rhizomelicchondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinctfrom RCDP and constitute a clinical continuum of overlappingphenotypes known as the Zellweger spectrum. The PBD group isgenetically heterogeneous with at least 14 distinct genetic groupsas concluded from complementation studies.

Defects in PEX6 are a cause of Zellweger syndrome (ZWS)[MIM:214100]. ZWS is a fatal peroxisome biogenesis disordercharacterized by dysmorphic facial features, hepatomegaly, ocularabnormalities, renal cysts, hearing impairment, profoundpsychomotor retardation, severe hypotonia and neonatal seizures.Death occurs within the first year of life.

Defects in PEX7 are the cause of peroxisome biogenesisdisorder complementation group 11 (PBD-CG11) [MIM:601757]. PBDrefers to a group of peroxisomal disorders arising from a failureof protein import into the peroxisomal membrane or matrix. The PBDgroup is comprised of four disorders: Zellweger syndrome (ZWS),neonatal adrenoleukodystrophy (NALD), infantile Refsum disease(IRD), and classical rhizomelic chondrodysplasia punctata (RCDP).ZWS, NALD and IRD are distinct from RCDP and constitute a clinicalcontinuum of overlapping phenotypes known as the Zellwegerspectrum. The PBD group is genetically heterogeneous with at least13 distinct genetic groups as concluded from complementationstudies.

Defects in PEX7 are the cause of rhizomelicchondrodysplasia punctata type 1 (RCDP1) [MIM:215100]. RCDP1 ischaracterized by rhizomelic shortening of femur and humerus,vertebral disorders, cataract, cutaneous lesions and severe mentalretardation.

Defects in PEX7 are a cause of Refsum disease (RD)[MIM:266500], also known as phytanic acid oxidase deficiency. RDis clinically characterized by a tetrad of abnormalities:retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia,and elevated protein levels in the cerebrospinal fluid (CSF).Patients exhibit accumulation of the branched-chain fatty acid,phytanic acid, in blood and tissues. Less constant features arenerve deafness, anosmia, skeletal abnormalities, ichthyosis,cataracts and cardiac impairment. Manifestations of the diseaseappear in the second or third decade of life.

Defects in PGAM2 are the cause of glycogen storagedisease type 10 (GSD10) [MIM:261670]. A metabolic disordercharacterized by myoglobinuria, increased serum creatine kinaselevels, decreased phosphoglycerate mutase activity, myalgia,muscle pain, muscle cramps and excercise intolerance.

Defects in HSPG2 are the cause of Schwartz-Jampelsyndrome (SJS1) [MIM:255800], a rare autosomal recessive disordercharacterized by permanent myotonia (prolonged failure of musclerelaxation) and skeletal dysplasia, resulting in reduced stature,kyphoscoliosis, bowing of the diaphyses and irregular epiphyses.

Defects in HSPG2 are the cause of dyssegmental dysplasiaSilverman-Handmaker type (DDSH) [MIM:224410]. The dyssegmentaldysplasias are rare, autosomal recessive skeletal dysplasias withanisospondyly and micromelia. There are two recognized types: thesevere, lethal DDSH and the milder Rolland-Desbuquois form.Individuals with DDSH also have a flat face, micrognathia, cleftpalate and reduced joint mobility, and frequently have anencephalocoele. The endochondral growth plate is short, thecalcospherites (which are spherical calcium-phosphorus crystalsproduced by hypertrophic chondrocytes) are unfused, and there ismucoid degeneration of the resting cartilage.

Defects in ACAN are the cause of spondyloepiphysealdysplasia type Kimberley (SEDK) [MIM:608361]. Spondyloepiphysealdysplasias are a heterogeneous group of congenitalchondrodysplasias that specifically affect epiphyses andvertebrae. The autosomal dominant SEDK is associated withpremature degenerative arthropathy.

Defects in ACAN are the cause of spondyloepimetaphysealdysplasia aggrecan type (SEMD-ACAN) [MIM:612813]. A bone diseasecharacterized by severe short stature, macrocephaly, severemidface hypoplasia, short neck, barrel chest and brachydactyly.The radiological findings comprise long bones with generalizedirregular epiphyses with widened metaphyses, especially at theknees, platyspondyly, and multiple cervical-vertebral clefts.

Defects in ACAN are the cause of osteochondritisdissecans short stature and early-onset osteoarthritis (OD)[MIM:165800]. It is a type of osteochondritis defined as aseparation of cartilage and subchondral bone from the surroundingtissue, primarily affecting the knee, ankle and elbow joints. Itis clinically characterized by multiple osteochondritic lesions inknees and/or hips and/or elbows, disproportionate short statureand early-onset osteoarthritis.

Defects in HPGD are the cause of primary hypertrophicosteoathropathy autosomal recessive (PHOAR) [MIM:259100], alsoknown as pachydermoperiostosis autosomal recessive. Primaryhypertrophic osteoarthropathy is characterized by digitalclubbing, osterarthropathy, variable features of pachydermia,delayed closure of the fontanels, and congenital heart disease.

Defects in HPGD are the cause of cranioosteoarthropathy(COA) [MIM:259100]. Clinical features include infantile onset ofswelling of the joints, digital clubbing, hyperhidrosis, delayedclosure of the fontanels, periostosis, and variable patent ductusarteriosus. Pachydermia is not a prominent feature.

Defects in HPGD are a cause of isolated congenital nailclubbing (ICNC) [MIM:119900], also called clubbing of digits orhereditary acropachy. ICNC is a rare genodermatosis characterizedby enlargement of the nail plate and terminal segments of thefingers and toes, resulting from proliferation of the connectivetissues between the nail matrix and the distal phalanx. It isusually symmetrical and bilateral (in some cases unilateral). Innail clubbing usually the distal end of the nail matrix isrelatively high compared to the proximal end, while the nail plateis complete but its dimensions and diameter more or less vary incomparison to normal. There may be different fingers and toesinvolved to varying degrees. Some fingers or toes are spared, butthe thumbs are almost always involved.

Note=A chromosomal aberration involving PDGFRA is foundin some cases of hypereosinophilic syndrome. Interstitialchromosomal deletion del(4)(q12q12) causes the fusion of FIP1L1and PDGFRA (FIP1L1-PDGFRA).

Note=A chromosomal aberration involving PDGFRB is foundin a form of chronic myelomonocytic leukemia (CMML). Translocationt(5,12)(q33,p13) with EVT6/TEL. It is characterized by abnormalclonal myeloid proliferation and by progression to acutemyelogenous leukemia (AML).

Note=A chromosomal aberration involving PDGFRB may be acause of acute myelogenous leukemia. Translocationt(5,14)(q33,q32) with TRIP11. The fusion protein may be involvedin clonal evolution of leukemia and eosinophilia.

Note=A chromosomal aberration involving PDGFRB may be acause of juvenile myelomonocytic leukemia. Translocationt(5,17)(q33,p11.2) with SPECC1.

Defects in PDGFRB are a cause of myeloproliferativedisorder chronic with eosinophilia (MPE) [MIM:131440]. Ahematologic disorder characterized by malignant eosinophilsproliferation. Note=A chromosomal aberration involving PDGFRB isfound in many instances of myeloproliferative disorder chronicwith eosinophilia. Translocation t(5,12) with ETV6 on chromosome12 creating an PDGFRB-ETV6 fusion protein.

Note=A chromosomal aberration involving PDGFRB may be thecause of a myeloproliferative disorder (MBD) associated witheosinophilia. Translocation t(1,5)(q23,q33) that forms a PDE4DIP-PDGFRB fusion protein.

Defects in PDGFRL are associated with colorectal cancer(CRC) [MIM:114500].

Defects in PGK1 are the cause of phosphoglycerate kinase1 deficiency (PGK1D) [MIM:300653]. It is a condition with a highlyvariable clinical phenotype that includes hemolytic anemia,rhabdomyolysis, myopathy and neurologic involvement. Patients canexpress one or more of these manifestations.

Defects in PGM1 are the cause of glycogen storage diseasetype 14 (GSD14) [MIM:612934]. A metabolic disorder resulting in amyopathy characterized by exercise-induced intolerance withepisodes of rhabdomyolysis, normal elevation of lactate, andhyperammonemia on a forearm-exercise test.

Defects in DCN are the cause of congenital stromalcorneal dystrophy (CSCD) [MIM:610048]. Corneal dystrophies areinherited, bilateral, primary alterations of the cornea that arenot associated with prior inflammation or secondary to systemicdisease. Most show autosomal dominant inheritance.

Defects in PAH are the cause of phenylketonuria (PKU)[MIM:261600]. PKU is an autosomal recessive inborn error ofphenylalanine metabolism, due to severe phenylalanine hydroxylasedeficiency. It is characterized by blood concentrations ofphenylalanine persistently above 1200 mumol (normal concentration100 mumol) which usually causes mental retardation (unless lowphenylalanine diet is introduced early in life). They tend to havelight pigmentation, rashes similar to eczema, epilepsy, extremehyperactivity, psychotic states and an unpleasant 'mousy' odor.

Defects in PAH are the cause of non-phenylketonuriahyperphenylalaninemia (Non-PKU HPA) [MIM:261600]. Non-PKU HPA is amild form of phenylalanine hydroxylase deficiency characterized byphenylalanine levels persistently below 600 mumol, which allowsnormal intellectual and behavioral development without treatment.Non-PKU HPA is usually caused by the combined effect of a mildhyperphenylalaninemia mutation and a severe one.

Defects in PAH are the cause of hyperphenylalaninemia(HPA) [MIM:261600]. HPA is the mildest form of phenylalaninehydroxylase deficiency.

Defects in PHEX are a cause of X-linked hypophosphatemicrickets (HYP) [MIM:307800]. HYP is an X-linked dominant disordercharacterized by impaired phosphate uptake in the kidney, which islikely to be caused by abnormal regulation of sodium phosphatecotransport in the proximal tubules. Clinical manifestationsinclude skeletal deformities, growth failure, craniosynostosis,paravertebral calcifications, pseudofractures in lowerextremities, and muscular hypotonia with onset in early childhood.X-linked hypophosphatemic rickets is the most common form ofhypophosphatemia with an incidence of 1 in 20000.

Note=A chromosomal aberration involving PHF23 is found ina patient with acute myeloid leukemia (AML). Translocationt(11,17)(p15,p13) with NUP98.

Defects in PHF6 are the cause of Boerjeson-Forssman-Lehmann syndrome (BFLS) [MIM:301900], also known as Boerjeson-Forssman syndrome (BORJ). BFLS is a X-linked recessive disordercharacterized by moderate to severe mental retardation, epilepsy,hypogonadism, hypometabolism, obesity with marked gynecomastia,swelling of subcutaneous tissue of the face, narrow palpebralfissure and large but not deformed ears.

Defects in PHF8 are the cause of mental retardationsyndromic X-linked Siderius type (MRXSSD) [MIM:300263]. A disordercharacterized by mild to borderline mental retardation with orwithout cleft lip/cleft palate.

Defects in PHKG2 are a cause of glycogen storage diseasetype 9C (GSD9C) [MIM:613027], also known as autosomal liverglycogenosis. GSD9C is a metabolic disorder manifesting in infancywith hepatomegaly, growth retardation, and elevated plasmaaminotransferases and lipids.