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  1. NGS Panel – Genetic Testing for Optic Atrophy

Optic Atrophy

August 21, 2017

Disease synonyms

Optic atrophy, OPA, Kjer’s Optic Atrophy, Autosomal Dominant Optic Atrophy, ADOA, Dominant Optic Atrophy and Deafness and DOAplus


Inheritance pattern

Autosomal recessive, autosomal dominant, X-linked


Clinical features

Optic atrophy (OPA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing severe visual loss, typically starting during the first decade of life. The disease affects primarily the retinal ganglion neurons and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the deeper brain visual centers. The prevalence of the disease varies from 1/10,000 in Denmark due to a founder effect, to 1/30,000 in the rest of the world 1, 2. Optic atrophy is also known as dominant optic atrophy or Kjer’s Optic Atrophy, named after the Danish ophthalmologist Dr. Poul Kjer who was the first to describe the disease in the Danish population 1, 4.

Optic atrophy is also a feature of mitochondriopathy, as the genes responsible for OPA encode proteins ubiquitously expressed in mitochondria and associated to its inner membrane. Thus, OPA can be not only an isolated ophthalmological and neurological disease, but it can also be syndromic and include extra-ocular symptoms.

The diagnosis of OPA is based on a combination of clinical findings, electrophysiological studies, family history, and molecular genetic testing, and it is diagnosed in individuals with the following:

  • Bilateral symmetric vision loss
  • Optic nerve paleness (cardinal sign of optic nerve degeneration)
  • Visual field defect
  • Color vision defect, often described as acquired blue-yellow loss (tritanopia)
  • Childhood onset (first decade of life) 3

Electrophysiological recordings showed that visual-evoked responses in affected individuals characteristically demonstrate diminished amplitudes and prolonged latencies 3. Also, the pattern of electroretinogram recordings is abnormal in all patients affected with OPA.

The syndromic form of optic atrophy is accompanied by extra-ophthalmogic findings, including sensorineural hearing loss, ataxia, myopathy, ophtalmophlegia, and others. Mental abnormalities were identified in ~10’% of those affected 4. Syndromic forms of OPA account for up to 20% of all optic atrophies, with extra-ocular signs raging from mild to severe.

Optic atrophy is a clinically and genetically heterogeneous disorder. However, the majority of suspected hereditary optic neuropathy patients (>60%) 5 harbor pathogenic mutations within the OPA1 gene, and ~3% have mutations in the OPA3 gene 8. A broad spectrum of OPA1 pathogenic variants (>370) have been reported to date 5. The OPA1 pathogenic variants are distributed throughout the coding sequence of the gene, but most commonly they are localized in exons 8-16 encoding the GTPase domain of the protein.

Several different pathogenic variants in OPA1 have been reported in individuals with both optic atrophy and hearing loss: p.Arg445His, p.Gly401Asp, p.Leu243Ter, c.983A>G, p.Ile463_Phe464dup, p.Gln437Arg, and p.Ala357LeufsTer4 6.

Furthermore, pathogenic variants causing OPA with cerebellar ataxia, high myopia, spastic paraplegia, or other extra-ocular findings have been reported 7. Autosomal dominant optic atrophy-3 (OPA3), also known as optic atrophy and cataracts, is caused by heterozygous mutations in the OPA3 gene. Optic atrophy type 3 is characterized by classical OPA clinical findings together with the increased urinary excretion of (3-MGC) and 3-methylglutaric acid (3-MGA). Also, methylglutaconic aciduria type III (MGCA3), also known as optic atrophy plus syndrome, is an allelic disorder with similar but more severe features. The mutation c.143-1G>C accounts for 100% of OPA3 pathogenic variants in the Iraqi Jewish population 8. The pathogenic variant c.320_337del, found in an individual of Turkish-Kurdish origin with OPA3-related 3-methylglutaconic aciduria, is the first pathogenic variant found to date in an individual of non-Iraqi Jewish origin 9. The nonsense variant c. 415C>T (p.Gln139Ter), found in the homozygous state in an individual of Indian origin with OPA3-related 3-methylglutaconic aciduria, is the second pathogenic variant found to date in an individual of non-Iraqi Jewish origin 10. Genetic testing for the (most common) OPA3 variants targets the vast majority of OPA3 affected individuals.

Optic nerve degeneration and optic atrophy are present in many disorders in which mitochondrial impairment is the underlying cause for the degeneration of retinal cells. In addition to OPA-genes, mutations in WFS1 and MFN2 cause optic atrophy inherited in an autosomal dominant manner, mutations in AUH, C12orf65, NDUFS1, POLG, SPG7 and TMEM126A are inherited in an autosomal recessive manner, and mutations in TIMM8A are inherited in an X-linked manner. An overview of genes associated with optic atrophy is listed in the table.


Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ABCA4 601691 Macular degeneration, age-related, 2; Stargardt disease type 1; Retinitis pigmentosa 19; Cone-rod dystrophy 3 AD, AR 58
ABCB6 605452 Dyschromatosis universalis hereditaria 3 AD 4
ABHD12 613599 Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract AR 0
ACO2 100850 Infantile cerebellar-retinal degeneration AR 2
ACVR1 102576 Fibrodysplasia ossificans progressiva AD 4
ADAM9 602713 Cone-rod dystrophy 9 AR 8
ADGRV1 602851 Febrile seizures, familial, 4; Usher syndrome type 2C AD, AR, DiD 26
AFG3L2 604581 spinocerebellar ataxia 28; spastic ataxia 5 AD, AR 23
AGK 610345 Sengers syndrome; autosomal recessive cataract type 38 AR 8
AHI1 608894 Joubert syndrome 3 AR 16
AIPL1 604392 Leber congenital amaurosis 4 AD, AR 8
ALDH18A1 138250 Cutis laxa, autosomal recessive, type IIIA; Spastic paraplegia 9A, autosomal dominant; spastic paraplegia 9B; Cutis laxa, autosomal dominant 3 AD, AR 11
ALDH1A3 600463 isolated microphthalmia 8 AR 10
AP3B1 603401 Hermansky-Pudlak syndrome type 2 AR 18
APTX 606350 Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia AR 30
ARL13B 608922 Joubert syndrome 8 AR 2
ARL6 608845 Bardet-Biedl syndrome type 1; Bardet-Biedl syndrome 3; Retinitis pigmentosa 55 AR, DiR 6
ASB10 615054 Glaucoma 1, open angle, F 0
ATF6 605537 Achromatopsia 7 AR 0
AUH 600529 3-methylglutaconic aciduria, type I AR 8
B9D1 614144 Meckel Syndrome, Type 9 AR 11
B9D2 611951 Meckel syndrome 10 AR 4
BBS1 209901 Bardet-Biedl syndrome type 1 AR, DiR 14
BBS10 610148 Bardet-Biedl syndrome type 10 AR 11
BBS12 610683 Bardet-Biedl syndrome type 12 AR 8
BBS2 606151 Bardet-Biedl syndrome type 2; retinitis pigmentosa type 74 AR 16
BBS4 600374 Bardet-Biedl syndrome 4 AR 11
BBS5 603650 Bardet-Biedl syndrome 5 AR 27
BBS7 607590 Bardet-Biedl syndrome type 7 AR 17
BBS9 607968 Bardet-Biedl syndrome type 9 AR 24
BCOR 300485 Microphthalmia, syndromic 2 XLD 13
BEST1 607854 vitelliform macular dystrophy-2; vitreoretinochoroidopathy; Bestrophinopathy, autosomal recessive; Retinitis pigmentosa 50 AD 29
BFSP1 603307 Cataract 33, multiple types AD, AR 1
BFSP2 603212 AD 0
BLOC1S3 609762 Hermansky-Pudlak syndrome 8 AR 3
BLOC1S6 604310 Hermansky-pudlak syndrome 9 AR 0
BMP4 112262 orofacial cleft type 11; Microphthalmia, syndromic 6 AD 8
C12orf65 613541 Combined oxidative phosphorylation deficiency 7 AR 2
C1QTNF5 608752 Retinal degeneration, late-onset, autosomal dominant AD 7
C8orf37 614477 Cone-rod dystrophy 16; Bardet-Biedl syndrome type 21 AR 3
CA4 114760 Retinitis pigmentosa 17 AD 3
CABP4 608965 Night blindness, congenital stationary (incomplete), 2B, autosomal recessive AR 6
CACNA1F 300110 Night blindness, congenital stationary (incomplete), 2A, X-linked; Cone-rod dystropy, X-linked, 3; Aland Island eye disease XL, XLR 14
CACNA2D4 608171 Retinal cone dystrophy 4 AR 16
CANT1 613165 Desbuquois dysplasia type 1 AR 2
CC2D2A 612013 COACH syndrome; Meckel syndrome 6; Joubert syndrome 9 AR 24
CCDC28B 610162 Bardet-Biedl syndrome type 1 AR, DiR 1
CDH23 605516 Usher syndrome type 1D; deafness type 12; susceptibility to pituitary adenomas AD, AR, DiR 41
CDH3 114021 Hypotrichosis, congenital, with juvenile macular dystrophy AR 8
CDHR1 609502 Retinitis pigmentosa 65 AR 16
CEP164 614848 nephronophthisis 15 AR 14
CEP290 610142 Joubert syndrome type 5; Senior-Loken syndrome type 6; Meckel syndrome type 4; Leber congenital amaurosis type 10; Bardet-Biedl syndrome type 14 AR 51
CEP41 610523 Joubert syndrome 15 AR 3
CERKL 608381 Retinitis pigmentosa type 26 14
CHD7 608892 CHARGE syndrome; hypogonadotropic hypogonadism-5 with or without anosmia AD 103
CHM 300390 Choroideremia XLD 2
CHMP4B 610897 AD 0
CIB2 605564 deafness type 48; Usher syndrome type 1J AR 5
CISD2 611507 Wolfram syndrome 2 AR 14
CLCN7 602727 Osteopetrosis, autosomal dominant 2; Osteopetrosis, autosomal recessive 4 AD, AR 25
CLN3 607042 neuronal ceroid lipofuscinosis type 3 AR 16
CLN5 608102 neuronal ceroid lipofuscinosis type 5 AR 13
CLN6 606725 adulte onset neuronal ceroid lipofuscinosis, Kufs type; neuronal ceroid lipofuscinosis type 6 AR 38
CLN8 607837 neuronal ceroid lipofuscinosis type 8; neuronal ceroid lipofuscinosistype 8, Northern epilepsy variant AR 6
CLPB 616254 3-methylglutaconic aciduria type VII with cataracts, neurologic involvement and neutropenia AR 2
CLRN1 606397 Usher Syndrome type 3A; retinitis pigmentosa type 61 AR 1
CNGA1 123825 Retinitis pigmentosa 49 11
CNGA3 600053 Achromatopsia type 2 AR 2
CNGB1 600724 Retinitis pigmentosa 45 AR 25
CNGB3 605080 Achromatopsia type 3 AR 12
CNNM4 607805 Jalili syndrome AR 0
COL11A1 120280 Marshall syndrome; Fibrochondrogenesis 1; Stickler syndrome 2 AD, AR 48
COL11A2 120290 Stickler syndrome, type III; Otospondylomegaepiphyseal dysplasia; Deafness, autosomal dominant 13; Deafness, autosomal recessive 53; Fibrochondrogenesis 2 AD, AR 38
COL2A1 120140 Epiphyseal dysplasia, multiple, with myopia and deafness; Legg-Calve-Perthes disease; Platyspondylic skeletal dysplasia, Torrance type; Kniest dysplasia; congenital spondyloepiphyseal dysplasia; SMED Strudwick type; Achondrogenesis, type II or hypochondrogenesis; Spondyloperipheral dysplasia; Osteoarthritis with mild chondrodysplasia; Avascular necrosis of the femoral head; Czech dysplasia; Stickler syndrome type 1; Stanescu type spondyloepiphyseal dysplasia AD 38
COL4A1 120130 porencephaly 1; Brain small vessel disease with or without ocular anomalies; Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps; Hemorrhage, intracerebral, susceptibility to AD 71
COL9A1 120210 Stickler syndrome, type IV; Epiphyseal dysplasia, multiple, 6 AD 17
COL9A2 120260 Stickler syndrome, type V AD, AR 12
COL9A3 120270 multiple epiphyseal dysplasia type 3 AD 6
COX7B 300885 Linear skin defects with multiple congenital anomalies 2 XLD 0
CPLANE1 614571 oral-facial-digital syndrome 6; Joubert syndrome 17 AR 31
CRB1 604210 pigmented paravenous chorioretinal atrophy; retinitis pigmentosa type 12; Leber congenital amaurosis type 8 AD, AR 15
CRX 602225 Cone-rod retinal dystrophy-2; Leber congenital amaurosis 7 AD 6
CRYAA 123580 Cataract 9, multiple types AD, AR 1
CRYAB 123590 Myopathy, myofibrillar, 2; Cataract 16, multiple types; Myopathy, Myofibrillar, Fatal Infantile Hypertonic, Alpha-B Crystallin-Related; dilated cardiomyopathy-1II AD, AR 1
CRYBA1 123610 AD 0
CRYBA4 123631 Cataract 23 0
CRYBB1 600929 Cataract 17, multiple types AD, AR 4
CRYBB2 123620 AD 0
CRYBB3 123630 Cataract 22, autosomal recessive AD, AR 1
CRYGB 123670 AD 0
CRYGC 123680 Cataract 2, multiple types AD 1
CRYGD 123690 Cataract 4, multiple types AD 1
CRYGS 123730 AD 0
CSPP1 611654 Joubert syndrome 21 AR 11
CTC1 613129 Cerebroretinal microangiopathy with calcifications and cysts AR 3
CTDP1 604927 Congenital cataracts, facial dysmorphism, and neuropathy AR 26
CTNNB1 116806 colorectal cancer; Hepatocellular Carcinoma; Medulloblastoma; Ovarian Cancer; neurodevelopmental disorder with spastic diplegia and visual defects AD 13
CTSD 116840 neuronal ceroid lipofuscinosis type 10 AR 8
CYP1B1 601771 primary congenital glaucoma type 3A; anterior segment dysgenesis type 6, multiple subtypes AR 1
CYP27A1 606530 cerebrotendinous xanthomatosis AR 6
DGUOK 601465 mitochondrial DNA depletion syndrome 3 AR 8
DHDDS 608172 retinitis pigmentosa type 59; Developmental delay and seizures with or without movement abnormalities AD, AR 2
DKC1 300126 X-linked dyskeratosis congenita XLR 3
DNA2 601810 Progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal dominant, 6 AD, AR 9
DNAJC19 608977 3-methylglutaconic aciduria, type 5 AR 4
DNM1L 603850 Encephalopahty, lethal, due to defective mitochondrial peroxisomal fission AD, AR 8
DTNBP1 607145 Hermansky-Pudlak syndrome 7 AR 6
EDN3 131242 congenital central hypoventilation syndrome; Waardenburg syndrome type 4B; Hirschsprung disease 4 AD, AR 8
EDNRB 131244 Waardenburg syndrome type 4A; Hirschsprung disease, susceptibility to, 2; ABCD syndrome AD, AR 6
EFEMP1 601548 Doyne honeycomb degeneration of retina AD 4
ELOVL4 605512 Spinocerebellar ataxia 34; Stargardt disease 3; Ichthyosis, spastic quadriplegia, and mental retardation AD, AR 4
ENPP1 173335 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Arterial calcification, generalized, of infancy, 1; OBESITY; Hypophosphatemic rickets, autosomal recessive, 2; Cole disease AD, AR 8
EPHA2 176946 multiple types cataract type 6 AD 2
ERCC1 126380 Cerebrooculofacioskeletal syndrome 4 AR 0
ERCC2 126340 xeroderma pigmentosum complementation group D; photosensitive trichothiodystrophy type 1; cerebrooculofacioskeletal syndrome type 2 AR 8
ERCC5 133530 xeroderma pigmentosum complementation group G; cerebrooculofacioskeletal syndrome type 3 AR 4
ERCC6 609413 Cockayne syndrome, type B; Lung Cancer; Cerebrooculofacioskeletal syndrome 1 AD, AR 12
EYA1 601653 Branchiootorenal Syndrome 1; Otofaciocervical Syndrome 1; Branchiootic syndrome 1 AD 2
EYS 612424 retinitis pigmentosa type 25 AR 42
FAM126A 610531 hypomyelinating leukodystrophy-5 AR 11
FAM161A 613596 retinitis pigmentosa type 28 5
FLVCR1 609144 Ataxia, posterior column, with retinitis pigmentosa AR 23
FOXC1 601090 Iridogoniodysgenesis, type 1; Axenfeld-Rieger syndrome, type 3 AD 8
FOXE3 601094 Anterior segment dysgenesis 2, multiple subtypes; Cataract 34, multiple types AD, AR 0
FOXL2 605597 Blepharophimosis, epicanthus inversus, and ptosis AD, AR 12
FRAS1 607830 Fraser syndrome AR 10
FREM1 608944 Manitoba oculotrichoanal syndrome; Bifid nose with or without anorectal and renal anomalies; Trigonocephaly 2 AD, AR 6
FREM2 608945 Fraser syndrome type 2 AR 6
FSCN2 607643 Retinitis pigmentosa 30 3
FTL 134790 Hyperferritinemia With Or Without Cataract; neurodegeneration with brain iron accumulation 3 AD, AR 6
FYCO1 607182 Cataract 18, autosomal recessive AR 11
FZD4 604579 Exudative vitreoretinopathy AD 1
GALE 606953 Galactose epimerase deficiency AR 5
GALK1 604313 galactokinase deficiency AR 6
GALT 606999 galactosemia AR 12
GBA 606463 Lewy body dementia; Susceptibility to late-onset Parkinson disease; Gaucher disease type 1; Gaucher disease type 2 (acute); Gaucher disease type 3 (subacute/ chronic); Gaucher disease, cardiovascular form; Gaucher disease, perinatal-lethal form AD, AR 176
GCNT2 600429 Cataract 13 with adult i phenotype AD, AR 8
GDF3 606522 Klippel-Feil syndrome 3, autosomal dominant; Microphthalmia with coloboma 6; isolated microphthalmia 7 AD 1
GDF6 601147 Klippel-feil syndrome 1, autosomal dominant; isolated microphthalmia 4; Microphthalmia with coloboma 6; Leber congenital amaurosis 17 AD, AR 2
GJA1 121014 Oculodentodigital dysplasia AD, AR 3
GJA3 121015 Cataract 14, multiple types AD 0
GJA8 600897 Cataract 1, multiple types AD 3
GNAT2 139340 Acromatopsia 0
GNPTG 607838 mucolipidosis III gamma AR 9
GPR143 300808 Albinism, Ocular, Type I; Nystagmus 6, congenital, X-linked XL, XLR 7
GRIP1 604597 AR 2
GRN 138945 frontotemporal lobar degeneration with ubiquitin-positive inclusions; neuronal ceroid lipofuscinosis type 11 AD, AR 16
GUCA1A 600364 Cone-rod dystrophy 14 AD 0
GUCA1B 602275 Retinitis pigmentosa 48 3
GUCY2D 600179 Leber congenital amaurosis type 1; cone-rod dystrophy type 6 AD, AR 18
HCCS 300056 Microphthalmia, syndromic 7 XLD 2
HESX1 601802 Septooptic dysplasia AD, AR 0
HEXA 606869 Tay-Sachs disease/ GM2-gangliosidosis AR 25
HGSNAT 610453 mucopolysaccharidosis type IIIC; retinitis pigmentosa type 73 AR 40
HK1 142600 Hemolytic anemia due to hexokinase deficiency; Neuropathy, hereditary motor and sensory, Russe type; Retinitis pigmentosa 79; Neurodevelopmental disorder with visual defects and brain anomalies AD, AR 4
HMX1 142992 AR 0
HPS1 604982 Hermansky-Pudlak syndrome type 1 AR 14
HPS3 606118 Hermansky-Pudlak syndrome type 3 AR 12
HPS4 606682 Hermansky-Pudlak syndrome type 4 AR 6
HPS5 607521 Hermansky-Pudlak syndrome type 5 AR 7
HPS6 607522 Hermansky-Pudlak syndrome type 6 AR 4
HSF4 602438 Cataract 5, multiple types AD 3
HTRA2 606441 Parkinson disease 13; 3-methylglutaconic aciduria, type VIII AR 4
IDH3B 604526 Retinitis pigmentosa 46 6
IFT140 614620 Mainzer-Saldino syndrome; retinitis pigmentosa type 80 AR 1
IFT172 607386 Short-rib thoracic dysplasia 10 with or without polydactyly AR 4
IFT27 615870 Bardet-Biedl syndrome 19 AR 0
IMPDH1 146690 Retinitis pigmentosa 10; Leber congenital amaurosis 11 AD 8
IMPG2 607056 Retinitis pigmentosa 56; vitelliform macular dystrophy-5 AD, AR 9
INPP5E 613037 Joubert syndrome 1; Mental retardation, truncal obesity, retinal dystrophy, and micropenis AR 18
IQCB1 609237 Senior-Loken syndrome 5 AR 19
KCNJ13 603208 AD, AR 0
KCNV2 607604 Retinal cone dystrophy 3B AR 3
KIF11 148760 Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation AD 30
KIF7 611254 Acrocallosal syndrome; Joubert syndrome 12; Hydrolethalus syndrome 2 AR 25
KIT 164920 Mast cell disease; Piebaldism; Spermatocytic seminoma, somatic; acute myeloid leukemia; gastrointestinal stromal tumor AD 14
KLHL7 611119 Retinitis pigmentosa 42; Cold-induced sweating syndrome 3 AD, AR 10
LCA5 611408 Leber congenital amaurosis type 5 AR 3
LEMD2 616312 AR 0
LEP 164160 Leptin deficiency AR 3
LEPR 601007 Morbid obesity due to leptin receptor deficiency AR 1
LIM2 154045 Cataract 19 AR 7
LMX1B 602575 Nail-patella syndrome AD 10
LOXL1 153456 Exfoliation syndrome AD 0
LRAT 604863 Leber congenital amaurosis 14 AR 0
LRMDA 614537 Albinism, oculocutaneous, type VII AR 3
LRP2 600073 Donnai-Barrow syndrome AR 10
LRP5 603506 Hyperostosis Corticalis Generalisata, Benign Form Of Worth, With Torus Palatinus; OSTEOPOROSIS; Osteoporosis-pseudoglioma syndrome; Exudative vitreoretinopathy 4; Bone Mineral Density Quantitative Trait Locus 1; autosomal dominant osteopetrosis type 1; van Buchem disease, type 2 AD, AR 35
LSS 600909 cataract 44 AR 0
LTBP2 602091 Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma; Glaucoma 3, primary congenital, D; Weill-Marchesani Syndrome 3 AR 4
LYST 606897 Chediak-Higashi syndrome AR 30
LZTFL1 606568 Bardet-Biedl syndrome 17 AR 5
MAB21L2 604357 Microphthalmia, syndromic 14 AD, AR 1
MAF 177075 Ayme-Gripp syndrome; Cataract, pulverulent or cerulean, with or without microcornea AD 4
MAK 154235 Retinitis pigmentosa 62 AR 9
MC1R 155555 oculocutaneous albinism type 2; skin/hair/eye pigmentation 2; Melanoma, cutaneous malignant, susceptibility to, 5 AR 9
MERTK 604705 Retinitis pigmentosa 38 AR 24
MFN2 608507 hereditary motor and sensory neuropathy type VIA with optic atrophy; axonal Charcot-Marie-Tooth disease type 2A2A; axonal Charcot-Marie-Tooth disease type 2A2B AD, AR 24
MFRP 606227 Nanophthalmos 2; isolated microphthalmia 5 AR 0
MFSD8 611124 neuronal ceroid lipofuscinosis type 7; macular dystrophy with central cone involvement AR 14
MIP 154050 AD 0
MITF 156845 Albinism, Ocular, With Sensorineural Deafness; Tietz Syndrome; Waardenburg syndrome type 2A; Melanoma, Cutaneous Malignant, Susceptibility To, 8 AD, AR 11
MKKS 604896 McKusick-Kaufman syndrome; Bardet-Biedl syndrome type 6 AR 6
MKS1 609883 Meckel syndrome type 1; Bardet-Biedl syndrome type 13; Joubert syndrome type 28 AR 7
MLPH 606526 Griscelli syndrome, type 3 AR 2
MYH9 160775 Fechtner syndrome; Macrothrombocytopenia and progressive sensorineural deafness; May-Hegglin anomaly; Sebastian syndrome; deafness type 17 AD 8
MYO5A 160777 Griscelli syndrome, type 1 AR 31
MYO7A 276903 Usher syndrome type 1B; deafness type 2; autosomal dominant deafness type 11 AD, AR 31
MYOC 601652 Glaucoma 1, Open Angle, A AD 1
NAA10 300013 Ogden syndrome; Microphthalmia, syndromic 1 XL, XLD, XLR 1
NDP 300658 Exudative Vitreoretinopathy 2, X-Linked; Norrie disease XLD, XLR 8
NF2 607379 neurofibromatosis type 2; Schwannomatosis; Meningioma, familial, susceptibility to AD 16
NHS 300457 Nance-Horan syndrome XL, XLD 8
NMNAT1 608700 Leber congenital amaurosis 9 AR 2
NPHP1 607100 nephronophthisis 1; Joubert syndrome 4 AR 19
NPHP3 608002 Renal-hepatic-pancreatic dysplasia 1; Meckel syndrome 7; nephronophthisis 3 AR 16
NPHP4 607215 nephronophthisis 4 AR 14
NR0B2 604630 OBESITY AD, AR 0
NR2F1 132890 Bosch-Boonstra-Schaaf optic atrophy syndrome AD 5
NRL 162080 Retinitis pigmentosa 27 AD 0
NTF4 162662 Glaucoma 1, open angle, 1O 0
OCA2 611409 oculocutaneous albinism type 2 AR 23
OCRL 300535 Dent disease type 2; Lowe oculocerebrorenal syndrome XLR 13
OFD1 300170 Simpson-Golabi-Behmel syndrome type 2; Retinitis pigmentosa 23; Joubert syndrome 10; oral-facial-digital syndrome 1 XLD, XLR 22
OPA1 605290 Optic atrophy plus syndrome; optic atrophy type 1; Behr syndrome; Glaucoma, normal tension, susceptibility to; Mitochondrial DNA depletion syndrome 14 AD, AR 46
OPA3 606580 Optic atrophy type 3 with cataract; 3-methylglutaconic aciduria type III AD, AR 15
OPN1LW 300822 Blue cone monochromacy XL, XLR 2
OPN1MW 300821 Blue cone monochromacy XL, XLR 0
OPTN 602432 Adult-onset primary open angle glaucoma; Glaucoma, normal tension, susceptibility to; amyotrophic lateral sclerosis 12 AD 10
OSTM1 607649 Osteopetrosis, autosomal recessive 5 AR 12
OTX2 600037 Microphthalmia, syndromic 5; Pituitary hormone deficiency, combined, 6 AD 2
P3H2 610341 AR 0
PAX2 167409 Papillorenal syndrome AD 5
PAX3 606597 Waardenburg syndrome, type 3; Waardenburg syndrome type 1 AD, AR 13
PAX6 607108 Aniridia 1; foveal hypoplasia type 1 AD 17
PCARE 613425 Retinitis pigmentosa 54 4
PCDH15 605514 Usher syndrome type 1D; Usher syndrome type 1F; deafness type 23 AR, DiR 30
PDE6A 180071 Retinitis pigmentosa 43 22
PDE6B 180072 Night blindness, congenital stationary, autosomal dominant 2; Retinitis pigmentosa 40 AD, AR 17
PDE6C 600827 Cone dystrophy 4 AR 13
PDE6G 180073 Retinitis pigmentosa 57 AR 5
PDE6H 601190 Retinal cone dystrophy 3 AD, AR 0
PDZD7 612971 Usher syndrome type 2A; Usher syndrome type 2C; Deafness, autosomal recessive 57 AR, DiD 6
PEX1 602136 Peroxisome biogenesis disorder type 1A (Zellweger); Heimler syndrome type 1; peroxisome biogenesis disorder type 1B AR 42
PEX2 170993 peroxisome biogenesis disorder type 5A (Zellweger); peroxisome biogenesis disorder type 5B AR 4
PEX7 601757 Rhizomelic chondrodysplasia punctata type 1; peroxisome biogenesis disorder type 9B (Zellweger) AR 15
PHF6 300414 Borjeson-Forssman-Lehmann syndrome XLR 5
PHYH 602026 Refsum disease AR 15
PIK3R5 611317 Ataxia-oculomotor apraxia 3 AR 15
PITPNM3 608921 Cone-rod dystrophy 5 AD 5
PITX2 601542 Axenfeld-Rieger syndrome, type 1 AD 4
PITX3 602669 Anterior segment mesenchymal dysgenesis; Cataract 11, multiple types AD, AR 0
PLA2G5 601192 AR 0
PNKP 605610 type 2B2 Charcot-Marie-Tooth disease; early infantile epileptic encephalopathy 10 AR 28
PNPLA6 603197 Boucher-Neuhauser syndrome; spastic paraplegia 39 AR 55
POLG 174763 progressive external ophthalmoplegia; mitochondrial DNA depletion syndrome type 4A; autosomal recessive progressive external ophthalmoplegia; sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; mitochondrial DNA depletion syndrome type 4B AD, AR 50
POLG2 604983 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 AD, AR 18
POMC 176830 OBESITY; Proopiomelanocortin Deficiency AD, AR 2
POMGNT1 606822 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A3; congenital muscular dystrophy-dystroglycanopathy with mental retardation type B3; congenital limb-girdle muscular dystrophy-dystroglycanopathy type C3; retinitis pigmentosa type 76 AR 19
PPARG 601487 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; OBESITY; Lipodystrophy, familial partial, type 3 AD, AR 2
PPT1 600722 neuronal ceroid lipofuscinosis type 1 AR 16
PQBP1 300463 Renpenning Syndrome 1 XLR 2
PRCD 610598 Retinitis pigmentosa 36 9
PRKCG 176980 spinocerebellar ataxia 14 AD 32
PROM1 604365 Stargardt disease 4; Macular dystrophy, retinal, 2; Retinitis pigmentosa 41; Cone-rod dystrophy 12 AD, AR 27
PRPF3 607301 Retinitis pigmentosa 18 AD 5
PRPF31 606419 Retinitis pigmentosa 11 AD 10
PRPF6 613979 Retinitis pigmentosa 60 AD 6
PRPF8 607300 Retinitis pigmentosa 13 AD 18
PRPH2 179605 Retinitis punctata albescens; Patterned dystrophy of retinal pigment epithelium (macular dystrophy); Retinitis pigmentosa 7; vitelliform macular dystrophy-3; Choriodal dystrophy, central areolar 2 AD, AR 7
PRPS1 311850 Phosphoribosylpyrophosphate synthetase superactivity; Arts syndrome; deafness type 1; type X5 Charcot-Marie-Tooth XL, XLR 6
PRSS56 613858 isolated microphthalmia 6 AR 0
RAB18 602207 Warburg micro syndrome 3 AR 6
RAB27A 603868 Griscelli syndrome, type 2 AR 6
RAB3GAP1 602536 Warburg micro syndrome 1 AR 12
RAB3GAP2 609275 Martsolf syndrome; Warburg micro syndrome 2 AR 7
RARB 180220 syndromic microphthalmia, type 12 AD, AR 2
RAX 601881 isolated microphthalmia 3 AR 1
RAX2 610362 Cone-rod dystrophy 11; Macular degeneration, age-related, 6 AD 2
RBP3 180290 Retinitis pigmentosa 66 AR 2
RBP4 180250 Retinal dystrophy, iris coloboma, and comedogenic acne syndrome AD, AR 1
RD3 180040 Leber congenital amaurosis 12 AR 0
RDH12 608830 Leber congenital amaurosis type 13 AD, AR 9
RDH5 601617 Retinitis punctata albescens AD, AR 1
RGR 600342 Retinitis pigmentosa 44 6
RGS9 604067 Bradyopsia 17
RGS9BP 607814 Bradyopsia 0
RHO 180380 Retinitis punctata albescens; Night blindness, congenital stationary, autosomal dominant 1; Retinitis Pigmentosa 4 AD, AR 1
RIMS1 606629 Cone-rod dystrophy 7 4
RLBP1 180090 Retinitis punctata albescens AD, AR 4
ROM1 180721 Retinitis pigmentosa 7 AD, AR 4
RP1 603937 Retinitis pigmentosa 1 AD, AR 4
RP1L1 608581 occult macular dystrophy AD, AR 6
RP2 300757 Retinitis pigmentosa 2 XL 3
RPE65 180069 Leber congenital amaurosis type 2; retinitis pigmentosa type 20 AD, AR 8
RPGR 312610 Retinitis pigmentosa 3; Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness; Macular degeneration, X-linked atrophic; Cone-rod dystrophy, X-linked, 1 XL, XLR 22
RPGRIP1 605446 Cone-rod dystrophy 13; Leber congenital amaurosis 6 AR 20
RPGRIP1L 610937 COACH syndrome; Joubert syndrome 7; Meckel syndrome type 5 AR 18
RRM2B 604712 mitochondrial DNA depletion syndrome 8A; progressive external ophthalmoplegia with mitochondrial DNA deletions 5 AD, AR 21
RS1 300839 Retinoschisis XLR 3
RTN4IP1 610502 Optic atrophy 10 with or without ataxia, mental retardation, and seizures AR 2
SAG 181031 NIGHT BLINDNESS, CONGENITAL STATIONARY, OGUCHI TYPE 1; Retinitis pigmentosa 47 AR 10
SBF2 607697 type 4B2 Charcot-Marie-Tooth disease AR 29
SDCCAG8 613524 Senior-Loken syndrome 7; Bardet-Biedl syndrome 16 AR 12
SEMA4A 607292 Retinitis pigmentosa 35; Cone-rod dystrophy 10 AD, AR 7
SERAC1 614725 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL syndrome). AR 8
SETX 608465 amyotrophic lateral sclerosis 4; autosomal recessive spinocerebellar ataxia 1 AD, AR 81
SHH 600725 Holoprosencephaly 3; Solitary Median Maxillary Central Incisor; Schizencephaly; Microphthalmia, Isolated, With Coloboma 5 AD 5
SIL1 608005 Marinesco-Sjogren syndrome AR 7
SIX3 603714 Holoprosencephaly 2; Schizencephaly AD 9
SIX6 606326 Microphthalmia with cataract 2 AR 1
SLC16A12 611910 AD 0
SLC24A5 609802 Oculocutaneous albinism-6 AR 0
SLC25A4 103220 Progressive External Ophthalmoplegia With Mitochondrial Dna Deletions, Autosomal Dominant, 2; mitochondrial DNA depletion syndrome 12; mitochondrial DNA depletion syndrome type 12A AD, AR 11
SLC25A46 610826 Neuropathy, hereditary motor and sensory, type VIB AR 1
SLC33A1 603690 spastic paraplegia 42; Congenital cataracts, hearing loss, and neurodegeneration AD, AR 7
SLC45A2 606202 Oculocutaneous albinism, type IV AR 7
SLC9A6 300231 Christianson type of X-linked syndromic mental retardation XLD 14
SMCHD1 614982 Fascioscapulohumeral muscular dystrophy 2, digenic AD 3
SMOC1 608488 AR 0
SNAI2 602150 Piebaldism; Waardenburg syndrome type 2d AD, AR 0
SNRNP200 601664 Retinitis pigmentosa 33 AD 8
SNX10 614780 Osteopetrosis, autosomal recessive 8 AR 4
SOX10 602229 PCWH syndrome; Waardenburg syndrome type 2E; Waardenburg syndrome, type 4C AD 20
SOX2 184429 Microphthalmia, Syndromic 3 AD 8
SPATA7 609868 Leber congenital amaurosis 3 13
SPG7 602783 spastic paraplegia 7 AD, AR 47
STRA6 610745 Microphthalmia, isolated, with coloboma 8 AR 12
TBC1D20 611663 Warburg micro syndrome 4 AR 1
TBK1 604834 Frontotemporal dementia and/or amyotrophic lateral sclerosis type 4; Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8 AD 0
TCIRG1 604592 osteopetrosis type 1 AR 15
TCTN1 609863 Joubert syndrome 13 AR 5
TCTN2 613846 Meckel syndrome 8; Joubert syndrome type 24 AR 19
TCTN3 613847 oral-facial-digital syndrome 4; Joubert syndrome 18 AR 2
TDRD7 611258 Cataract type 36 AR 7
TENM3 610083 microphthalmia with coloboma 9 AR 23
TFAP2A 107580 Branchiooculofacial syndrome AD 5
TIMM8A 300356 Mohr-Tranebjaerg syndrome XLR 3
TIMP3 188826 Sorsby fundus dystrophy AD 1
TK2 188250 mitochondrial DNA depletion syndrome 2 AR 7
TMEM126A 612988 Optic Atrophy 7 AR 0
TMEM138 614459 Joubert syndrome 16 AR 1
TMEM216 613277 Meckel Syndrome type 2; Joubert syndrome type 2 AR 0
TMEM231 614949 Joubert syndrome 20; Meckel syndrome, type 11 AR 10
TMEM237 614423 Joubert syndrome 14 AR 12
TMEM67 609884 COACH syndrome; Meckel Syndrome, Type 3; Joubert syndrome 6; nephronophthisis 11; Bardet-Biedl syndrome type 14 AR 22
TMEM70 612418 Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 AR 9
TNFRSF11A 603499 familial expansile osteolysis; Osteopetrosis, autosomal recessive 7 AD, AR 6
TNFSF11 602642 autosomal recessive osteopetrosis type 2 AR 4
TOPORS 609507 Retinitis pigmentosa 31 3
TPP1 607998 neuronal ceroid lipofuscinosis type 2; autosomal recessive spinocerebellar ataxia type 7 AR 31
TRIM32 602290 limb-girdle muscular dystrophy type 2H; Bardet-Biedl syndrome 11 AR 2
TRNT1 612907 Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay AR 0
TSPAN12 613138 Exudative vitreoretinopathy 5 AD 2
TTC21B 612014 Short-rib thoracic dysplasia 4 with or without polydactyly; nephronophthisis 12 AD, AR 24
TTC8 608132 retinitis pigmentosa type 51; Bardet-Biedl syndrome type 8 AR 13
TTPA 600415 ataxia with vitamin E deficiency AR 11
TULP1 602280 Retinitis pigmentosa 14 AR 21
TWNK 606075 Mitochondrial DNA depletion syndrome 7 (hepatocerebral type); Progressive external ophthalmoplegia, autosomal dominant, 3 AD, AR 4
TYMP 131222 mitochondrial DNA depletion syndrome 1 AR 13
TYR 606933 Albinism, Ocular, With Sensorineural Deafness; oculocutaneous albinism type 1A; Skin/hair/eye pigmentation 3; Albinism, oculocutaneous, type IB AD, AR 21
TYRP1 115501 Albinism, oculocutaneous, type III AR 8
UNC45B 611220 Cataract type 43 AD 2
USH1C 605242 Usher syndrome type IC; deafness type 18A AR 15
USH1G 607696 Usher syndrome type 1G AR 0
USH2A 608400 Usher syndrome type 2A; retinitis pigmentosa type 39 AR 48
VCAN 118661 Wagner syndrome 1 AD 9
VIM 193060 AD 0
VPS13B 607817 Cohen syndrome AR 28
VSX2 142993 microphthalmia with coloboma 3; isolated microphthalmia 2 6
WDPCP 613580 Bardet-Biedl syndrome 15 AR 9
WDR19 608151 Short-rib thoracic dysplasia 5 with or without polydactyly; nephronophthisis 13; Cranioectodermal dysplasia 4; Senior-Loken syndrome 8 AR 1
WDR36 609669 Glaucoma 1, open angle, G 3
WFS1 606201 congenital nuclear cataract type 41; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Wolfram syndrome; Deafness, autosomal dominant 6/14/38; Wolfram-like syndrome AD, AR 22
WHRN 607928 deafness type 31; Usher syndrome type 2D AR 5
ZIC2 603073 Holoprosencephaly 5 AD 17
ZNF423 604557 nephronophthisis 14; Joubert syndrome 19 AD, AR 10
ZNF513 613598 Retinitis pigmentosa 58 AR 2

To date, there is no preventative or curative treatment for optic atrophy. However, symptomatic treatment that is initiated before the development of optic atrophy can be helpful in saving useful vision. The role of intravenous steroids was proven as helpful in cases with optic neuritis. Early diagnosis and prompt treatment can help patients with progressive and severe neuropathies. Development of therapeutic approaches based on stem cell therapy and gene therapy are in progress.

CENTOGENE offers sequencing and deletion/duplication analysis for the Optic atrophy panel (genes: ACO2, AFG3L2, C12ORF65, CISD2, MFN2, NR2F1, OPA1, OPA3, RTN4IP1, SLC25A46, SPG7, TIMM8A, TMEM126A, WFS1).


Differential diagnosis

The differential diagnosis of optic atrophy-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Leber hereditary optic neuropathy, caused by mutations in mtDNA (most commonly: m.11778G>A, m.14484T>C, m.3460G>A)
  • Wolfram´s syndrome, caused by mutations in WF1 or CISD2
  • Friedreich ataxia, caused by mutations in the FXN gene
  • Deafness-dystonia-optic neuronopathy syndrome, caused by mutations in the TIMM8A gene
  • Inborn errors of metabolism with 3-methylglutaconic aciduria
  • Acquired optic neuropathy caused by nutritional deficiencies, toxic exposures or certain medications.

Testing strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology.This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for optic atrophy using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Optic atrophy panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the optic atrophy panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.


Referral reasons

The following individuals are candidates for optic atrophy testing:

  • Individuals with a family history of optic atrophy and presentation of the most common symptoms
  • Individuals without a positive family history of optic atrophy, but with symptoms resembling the disease
  • Individuals with a negative but suspected family history of optic atrophy, in order to perform proper genetic counseling.

Test utility

Sequencing, deletion/duplication of the optic atrophy panel genes should be performed in all individuals suspected of having Maple syrup urine disease and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the optic atrophy and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.