Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs related to the rare diseases.
There are numerous examples wherein mutations in one gene may result in more than one different diseases, usually depending on the mutation involved. In some cases, each of the diseases caused by the altered gene are fundamentally similar (e.g., spherocytosis and elliptocytosis, caused by mutations in the alpha-spectrin gene; Usher syndrome type IIIA and retinitis pigmentosa-61 caused by mutations in the CLRN1 gene). In other case, diseases caused by the same gene may have no obvious relation to one another. For one example, diverse diseases that include Charcot-Marie-Tooth axonal neuropathy, lipodystrophy, Emery-Dreyfus muscular dystrophy, and premature aging syndromes, are all caused by mutation in the LMNA (Lamin A/C) gene. As another example, Stickler syndrome type III (STL3), Fibrochondrogenesis-2 and a form of non-syndromic hearing loss are all caused by mutations in the COL11A2 gene.
What is the significance of these observations? It tells us that it may be impossible to create a gene-based classification of diseases. Think about it: How can you group diseases by causal gene when the diseases caused by the gene are otherwise unrelated? It also tells us that there is a great deal that we do not understand about how genes cause diseases.
In the following list, each disease-causing gene is followed by the different diseases caused by gene alterations.
ABCB6 gene
The Lan(-) blood group phenotype
Microphthalmia, isolated, with coloboma 7
ACTA2 gene
Moyamoya disease-5
Form of thoracic aortic aneurysm
ACYLTRANSFERASE GENE
Fish-eye disease
Norum disease
ALPHA-SPECTRIN GENE
Hereditary spherocytosis-3
Elliptocytosis-2
ALPHA-SYNUCLEIN GENE
Parkinson disease-1
Autosomal dominant Parkinson disease-4
ALX4 gene
Frontonasal dysplasia-2
Parietal foramina-2
ANO5 gene
Gnathodiaphyseal dysplasia; gdd, or osteogenesis imperfecta with unusual skeletal lesions
Limb-girdle muscular dystrophy-2L
Miyoshi muscular dystrophy-3
ARX gene
Proud syndrome
Form of nonspecific X-linked mental retardation
ATN1 gene
Dentatorubral-pallidoluysian atrophy
Haw River syndrome
ATR gene
Seckel syndrome-1
Form of ataxia telangiectasia
BAG3 gene
Autosomal dominant myofibrillar myopathy
Dilated cardiomyopathy-1HH
BAP1 gene
Susceptibility to uveal melanoma
Predisposition to malignant mesothelioma upon asbestos exposure
BCS1L gene
Bjornstad syndrome
GRACILE syndrome
BUB1B gene
Mosaic variegated aneuploidy syndrome-1 (See Glossary item, Aneuploidy)
Form of premature chromatid separation
C20ORF54 gene
Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness
Fazio-Londe disease
CACNA1A gene
Familial hemiplegic migraine
Spinocerebellar ataxia 6
CACNA1F gene
X-linked cone-rod dystrophy-3
Aland Island eye disease
CARD15 gene
Early-onset sarcoidosis
Blau syndrome
CASK gene
FG syndrome-4 ("FG" are the initials of the first proband)
Mental retardation, x-linked, with or without nystagmus
Mental retardation and microcephaly with pontine and cerebellar hypoplasia
CAVEOLIN-3 GENE
Limb-girdle muscular dystrophy type 1C
Tateyama type of distal myopathy
CEP152 gene
Autosomal recessive primary microcephaly-4
Seckel syndrome-5
CEP290 gene
Bardet-Biedl syndrome 14
Joubert syndrome 5
Leber congenital amaurosis 10
Meckel syndrome 4
Senior-Loken syndrome 6
CHAT (Choline acetyltransferase) gene
Presynaptic congenital myasthenia syndrome with episodic ataxia
Familial infantile myasthenia gravis
CHX10 gene
Microphthalmia, isolated-2
Microphthalmia with coloboma-3
Isolated colobomatous microphthalmia-3
CLCN5 gene
X-linked recessive hypophosphatemic rickets
X-linked recessive nephrolithiasis with renal failure
Dent disease-1
CLN8 gene
Neuronal ceroid lipofuscinosis-8
Progressive epilepsy with mental retardation
CLRN1 gene
Usher syndrome type IIIA
Retinitis pigmentosa-61
COL11A2 gene
Stickler syndrome type III
Fibrochondrogenesis-2
Form of nonsyndromic hearing loss
COL2A1 gene
Stickler syndrome type I, sometimes called membranous vitreous type
Osteoarthritis with mild chondrodysplasia
Achondrogenesis type II
Czech dysplasia
COL7A1 gene
Classic dystrophic epidermolysis bullosa pruriginosa
Nonsyndromic congenital nail disorder-8
COL9A1 gene
Form of autosomal recessive form of Stickler syndrome
Multiple epiphyseal dysplasia-6
COL9A2 gene
Multiple epiphyseal dysplasia-2
Stickler syndrome type V
COLLAGEN GENE
Autosomal dominant epidermolysis bullosa dystrophica
Pretibial dystrophic epidermolysis bullosa
Stickler syndrome
Strudwick type of spondyloepimetaphyseal dysplasia
Spondyloperipheral dysplasia
Ehlers-Danlos syndrome type IV
CONNEXIN-26 GENE
Keratitis-ichthyosis-deafness syndrome
Deafness, autosomal dominant-3A
CRYAB gene
Posterior polar cataract-2
Fatal infantile hypertonic myofibrillar myopathy
CYLD gene
Familial cylindromatosis
Multiple familial trichoepithelioma-1
Brooke-Spiegler syndrome
DOCK8 gene
Hyper-IgE recurrent infection syndrome, also known as Job syndrome
Autosomal dominant mental retardation-2
DYM gene
Dyggve-Melchior-Clausen disease
Smith-McCort dysplasia
DYNC1H1 gene
Autosomal dominant axonal Charcot-Marie-Tooth disease type 2O
Autosomal dominant mental retardation-13
ENPP1 gene
Generalized arterial calcification of infancy-1
Autosomal recessive hypophosphatemic rickets-2
ESCO2 gene
SC phocomelia syndrome, also known as SC pseudothalidomide syndrome
Roberts syndrome
FBLN5 gene
Autosomal recessive cutis laxa type IA
Macular degeneration, age-related-3
FBN1 gene
Acromicric dysplasia
Stiff skin syndrome
Autosomal dominant form of isolated ectopia lentis
Weill-Marchesani syndrome-1
Weill-Marchesani syndrome-2
Geleophysic dysplasia-2
FGFR1 gene
Trigonocephaly-1
8p11 myeloproliferative disorder
FGFR2 gene
Beare-Stevenson cutis gyrata syndrome
Form of craniosynostosis
Classic Crouzon syndrome
FGFR3 gene
Muenke craniosynostosis syndrome
Hypochondroplasia
CATSHL syndrome
Crouzon syndrome with acanthosis nigricans
FIG4 gene
Charcot-Marie-Tooth type 4J
Form of autosomal dominant ALS
Amyotrophic lateral sclerosis 11
FLNA gene
Terminal osseous dysplasia
FG syndrome-2
X-linked cardiac valvular dysplasia
FLNC gene
Filamin C-related myofibrillar myopathy
Distal myopathy-4 (MPD4), also known as Williams distal myopathy
FMR1 gene
Fragile X tremor/ataxia syndrome
Fragile X mental retardation syndrome
FOXL2 gene
Blepharophimosis, ptosis, and epicanthus inversus syndrome, with premature ovarian failure (BPES type I)
Blepharophimosis, ptosis, and epicanthus inversus syndrome, without premature ovarian failure without premature ovarian failure (BPES type II)
FREM1 gene
Bifid nose with or without anorectal and renal anomalies
Trigonocephaly-2
GATA2 gene
Primary lymphedema with myelodysplasia
Dendritic cell, monocyte, B lymphocyte, and natural killer lymphocyte deficiency
GDAP1 gene
Autosomal recessive axonal CMT with vocal cord paresis
Autosomal recessive demyelinating CMT4A
Autosomal recessive axonal Charcot-Marie-Tooth disease type 2K
GDF3 gene
Klippel-Feil syndrome-3
Isolated microphthalmia with coloboma-6
Isolated microphthalmia-7
GDF6 gene
Klippel-Feil syndrome-1
Isolated microphthalmia-4
GJA1 gene
Syndactyly type III
Oculodentodigital dysplasia
Atrioventricular septal defect 3
GJB2 gene
Autosomal recessive deafness-1A
Hystrix-like ichthyosis-deafnesss syndrome
GJC2 gene (encodes gap junction protein, gamma 2)
Autosomal recessive spastic paraplegia-44
Hereditary lymphedema type IC
Form of Pelizaeus-Merzbacher disease
GLUCOKINASE GENE
Familial hyperinsulinemic hypoglycemia-3
Maturity onset diabetes of the young-2
GNAS gene
Progressive osseous heteroplasia
Pseudopseudohypoparathyroidism
Pseudohypoparathyroidism type Ia
GPR143 gene
Ocular albinism type I
X-linked congenital nystagmus-6
Nystagmus 6, congenital, X-linked
HCN4 gene
Brugada syndrome-8
Autosomal dominant form of sick sinus syndrome
HEDGEHOG GENE
Holoprosencephaly-3
Isolated microphthalmia with coloboma-5
HPRT gene
Lesch-Nyhan syndrome
Kelley-Seegmiller syndrome
HRG gene
Histidine-rich glycoprotein deficiency
Thrombocythemia-11
HSPB8 gene
HMN2A
Axonal Charcot-Marie-Tooth disease type 2L
HMN2A
IGHMBP2 gene
Distal hereditary motor neuronopathy type VI (dHMN6 or HMN6)
Spinal muscular atrophy, with respiratory distress-1
INF2 gene
FSGS5
Focal segmental glomerulosclerosis-5
Charcot-Marie-Tooth disease E with focal segmental glomerulonephritis
JAK2 gene
Thrombocythemia-3
Polycythemia vera, the most common form of primary polycythemia
KCNE2 gene
ATFB4
Form of atrial fibrillation
Long QT syndrome-6
KCNH2 gene
Long QT syndrome-2
Short QT syndrome-1
KCNJ11 gene
Hyperinsulinemic hypoglycemia-2 (HHF2)
TNDM3
KCNJ5 gene
Familial hyperaldosteronism type III
Long QT syndrome-13
KCNQ1 gene
Form of Jervell and Lange-Nielsen syndrome (JLNS1)
Form of autosomal dominant atrial fibrillation
ATFB3 (607554)
Short QT syndrome-2
KIF1A gene
Hereditary sensory neuropathy type IIC
Form of mental retardation
KLF1 gene
Congenital dyserythropoietic anemia type IV (See Glossary item, Dyserythropoiesis)
Form of hereditary persistence of fetal hemoglobin
KRT74 gene
Hypotrichosis simplex of the scalp-2
Autosomal dominant form of woolly hair
Hypotrichosis simplex of the scalp-2
LDB3 gene
Left ventricular noncompaction-3
Form of dilated cardiomyopathy with or without left ventricular noncompaction
LMNA gene
Form of autosomal recessive axonal CMT
Slovenian type heart-hand syndrome
LRP4 gene
Cenani-Lenz syndactyly syndrome
Sclerosteosis-2
LRP5 gene
Familial exudative vitreoretinopathy-4
Autosomal dominant osteopetrosis type I
MATRILIN-3 GENE
Form of multiple epiphyseal dysplasia
Form of autosomal recessive spondyloepimetaphyseal dysplasia
MECP2 gene
Form of neonatal severe encephalopathy
Classic Rett syndrome
MED12 gene
Lujan-Fryns syndrome
Opitz-Kaveggia syndrome, also known as FG syndrome-1
MFRP gene
Posterior microphthalmia, retinitis pigmentosa, foveoschisis, and optic disc drusen
MCOP5
MLL2 gene
Kabuki syndrome-1
Otitis media in infancy
MSX1 gene
Form of selective tooth agenesis
Orofacial cleft 5
Witkop syndrome
MYH6 gene
Familial hypertrophic cardiomyopathy-14
Form of dilated cardiomyopathy
MYH7 gene
Form of scapuloperoneal myopathy
Hypertrophic cardiomyopathy-1
Cardiomyopathy, dilated, 1S
MYH9 gene
Fechtner syndrome
May-Hegglin anomaly
Sebastian syndrome
NEMO gene
Anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, and lymphedema
Atypical mycobacteriosis, familial
Familial incontinentia pigmenti
Invasive pneumococcal disease, recurrent isolated, type 2
NF1 gene
Neurofibromatosis-1
Watson syndrome
Neurofibromatosis-Noonan syndrome variant of neurofibromatosis-1
NHS gene
Nance-Horan syndrome
X-linked congenital cataract
NKX2-5 gene
Atrial septal defect of the secundum type, with or without atrioventricular conduction defects
Congenital nongoitrous hypothyroidism-5
Hypoplastic left heart syndrome-2
NOTCH2 gene
Hajdu-Cheney syndrome
Alagille syndrome-2
NPHP1 gene
Senior-Loken syndrome-1
Form of Joubert syndrome plus nephronophthisis
NPHP3 gene
Meckel syndrome, type 7
Nephronophthisis-3
NPHP4 gene
Form of Senior-Loken syndrome that maps to 1p36
Type 4 nephronophthisis
NPHP6 gene
Form of Senior-Loken syndrome that maps to 12q21-32
Joubert syndrome-5
NR0B1 gene
X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism
46,XY sex reversal-2
NR5A1 gene
Premature Ovarian Failure-7
Form of 46,XY sex reversal
NRAS gene
Form of Noonan syndrome (NS6)
Form of autoimmune lymphoproliferative syndrome, designated type IV (ALPS4)
NSD1 gene
Familial Sotos syndrome
Sotos syndrome
Weaver syndrome-1
Classic Sotos syndrome
OPTN gene
Amyotrophic lateral sclerosis-12
Form of adult-onset primary open angle glaucoma (POAG), designated GLC1E
P63 GENE
Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome-3
Split-hand/split-foot malformation
PAX3 gene
Craniofacial-deafness-hand syndrome
Waardenburg syndrome type-3
Waardenburg syndrome type-1
PDE6B gene
Autosomal dominant congenital stationary night blindness-2
Form of retinitis pigmentosa
PDE8B gene
Autosomal dominant striatal degeneration
Primary pigmented nodular adrenocortical disease-3
PDX1 gene
Congenital pancreatic agenesis
Maturity onset diabetes of the young-4
PIGA gene
Paroxysmal nocturnal hemoglobinuria
Multiple congenital anomalies-hypotonia-seizures syndrome-2
PLA2G6 gene
Neurodegeneration with brain iron accumulation-2A
Neurodegeneration with brain iron accumulation-2B
Adult-onset dystonia-parkinsonism, also known as Parkinson disease-14
PLEC1 gene
Epidermolysis bullosa simplex with pyloric atresiawhich
Epidermolysis bullosa simplex
Autosomal recessive limb-girdle muscular dystrophy type 2Q
POLG gene
Alpers syndrome
Neurogastrointestinal encephalopathy
POLYMERASE-GAMMA GENE
Autosomal recessive progressive external ophthalmoplegia (PEOB)
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
POMGNT1 gene
Walker-Warburg syndrome (WWS) or muscle-eye-brain disease
Muscular dystrophy-dystroglycanopathy-B3
Muscular dystrophy-dystroglycanopathy-C3
PRKAR1A gene
Acrodysostosis with hormone resistance
Carney complex, type 1
PROM1 gene
Macular dystrophy, retinal, type 2
Stargardt disease-4
PROMININ-1 GENE
Stargardt disease-4
Retinal macular dystrophy-2
Cone-rod dystrophy-12
PRPS1 gene
Arts syndrome
X-linked deafness-1
PRRT2 gene
Familial infantile convulsions with paroxysmal choreoathetosis
Benign familial infantile seizures-2
Paroxysmal kinesigenic dyskinesia
PSEN1 gene
Dilated cardiomyopathy-1U
Familial acne inversa-3
Form of early onset Alzheimer's disease
PTPN11 gene
Noonan syndrome-1
Metachondromatosis
PYCR1 gene
Autosomal recessive cutis laxa type IIIB
Autosomal recessive cutis laxa type IIB
RAB27A gene
Melanosis with immunologic abnormalities with or without neurologic impairment
Griscelli syndrome type 2
RAF1 gene
Form of Noonan syndrome
LEOPARD syndrome-2
RDS gene
Retinitis pigmentosa-7
Adult-onset vitelliform macular dystrophy (AVMD)
RET gene
Susceptibility to Hirschsprung disease-1
Multiple endocrine neoplasia-2B
Familial medullary thyroid carcinoma MTC
ROR2 gene
Brachydactyly type B1
Autosomal recessive Robinow syndrome
RPE65 gene
Leber congenital amaurosis-2
Form of autosomal recessive retinitis pigmentosa
RPGR gene
Retinitis pigmentosa-3
X-linked cone-rod dystrophy
X-linked retinitis pigmentosa with recurrent respiratory infections
RPGRIP1 gene
Autosomal recessive cone-rod dystrophy-13
Leber congenital amaurosis-6
SAMHD1 gene
Aicardi-Goutieres syndrome-5
Chilblain lupus-2
SCN1A gene
Febrile seizures, familial, type 3A
Familial hemiplegic migraine-3
SCN1B gene
Generalized epilepsy with febrile seizures plus, type 1
Brugada syndrome-5
SCN2A gene
Benign familial neonatal-infantile seizures-3
Early infantile epileptic encephalopathy-11
SCN4A gene
Hypokalemic periodic paralysis type 2
Form of congenital myasthenic syndrome
SCN5A gene
Brugada syndrome-1
Long QT syndrome-3
Sick sinus syndrome (some cases)
Atrial fibrillation, (some cases)
Dilated cardiomyopathy (some cases)
SEMA4A gene
Form of RP
Cone-rod dystrophy-10
SH3TC2 gene
Charcot-Marie-Tooth disease type 4C
Mild mononeuropathy of the median nerve
SHH gene
Holoprosencephaly-3
Microphthalmia with coloboma 5
SLC16A1 gene
Erythrocyte lactate transporter defect
Form of hyperinsulinemic hypoglycemia
SLC25A19 gene
Amish lethal microcephaly
Thiamine metabolism dysfunction syndrome-3
Bilateral striatal degeneration and progressive polyneuropathy
SLC26A4 gene
Enlarged vestibular aqueduct
Pendred syndrome
SLC2A1 gene
Dystonia 18 (DYT18)
Autosomal recessive primary hypertrophic osteoarthropathy-2
SLC33A1 gene
Spastic paraplegia-42
Congenital cataracts, hearing loss, and neurodegeneration
SLC34A1 gene
Autosomal recessive form of Fanconi renotubular syndrome
Hypophosphatemic nephrolithiasis/osteoporosis-1
Fanconi renotubular syndrome-2
SLC4A1 gene
Band 3 Coimbra
Waldner blood group expression
Autosomal recessive distal renal tubular acidosis with hemolytic anemia
SLC4A11 gene
Corneal endothelial dystrophy-2
Fuchs endothelial corneal dystrophy-4
SMAD4 gene
Myhre syndrome
Juvenile polyposis syndrome
SOS1 gene
Gingival fibromatosis-1
Form of Noonan syndrome
SOST gene
Craniodiaphyseal dysplasia, autosomal dominant
SclerosteosiS
Van Buchem disease
STAT1 gene
Mycobacterial and viral infections, susceptibility to, autosomal recessive
Familial chronic mucocutaneous candidiasis-7
SYCP3 gene
Spermatogenic failure 4
Recurrent pregnancy loss 4
TGFBR2 gene
Loeys-Dietz syndrome type 2B
Hereditary nonpolyposis colorectal cancer-6
TITIN GENE
Autosomal dominant dilated cardiomyopathy-1G
Limb-girdle muscular dystrophy type 2J
Tardive tibial muscular dystrophy
TMEM216 gene
Meckel syndrome type 2
Joubert syndrome-2
TNFRSF13B gene
Immunoglobulin A (IgA) deficiency-2
Common variable immunodeficiency-2
TREX1 gene
Aicardi-Goutieres syndrome-1 (can also be caused by mutations in the SAMHD1, TREX1, or Ribonuclease H2 genes)
Chilblain lupus-1
TRPV4 gene
Brachyolmia type 3
Metatropic dysplasia
Parastremmatic dwarfism
Form of scapuloperoneal spinal muscular atrophy
Maroteaux type of spondyloepiphyseal dysplasia
Kozlowski type of spondylometaphyseal dysplasia
Congenital distal spinal muscular atrophy
Hereditary motor and sensory neuropathy type IIC
TTR gene
Form of hereditary amyloidosis
Euthyroidal hyperthyroxinemia
TULP1 gene
Retinitis pigmentosa-14
Leber congenital amaurosis-15
VHL gene
Von Hippel-Lindau syndrome
Familial erythrocytosis-2
VSX1 gene
Posterior polymorphous corneal dystrophy-1
Craniofacial anomalies and anterior segment dysgenesis syndrome
WAS gene
Wiskott-Aldrich syndrome
X-linked thrombocytopenia
X-linked neutropenia
WDR35 gene
Cranioectodermal dysplasia-2
Short rib-polydactyly syndrome type V
WNK1 gene
Hereditary sensory and autonomic neuropathy type IIA
Form of pseudohypoaldosteronism type II
- Jules Berman
key words: rare diseases, allelic heterogeneity, allelic to, polymorphism, gene variation, genetic heterogeneity, genetics, genetics of disease, jules j berman
