Syndromic Inherited Retinal Diseases: Genetic, Clinical and Diagnostic Aspects
Abstract
:1. Introduction
2. Syndromic IRD Types
3. Genetic Heterogeneity in Syndromic IRDs
4. Phenotypic Overlap in Syndromic IRDs
4.1. Phenotypic Overlap between Different IRD Syndromes
4.2. Syndromic Versus Non-Syndromic IRD Caused by the Same Genes
4.3. Co-Existence of Non-Syndromic IRD and Additional Non-Ocular Diseases
5. Diagnostic Challenges
6. Summary and Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Syndrome (MIM/Reference) | Gene | Inheritance * | Main Ocular Phenotypes # | Main Extra-Ocular Phenotypes ¶ |
---|---|---|---|---|
Abetalipoproteinemia; ABL (#200100) | MTTP | AR | RP | Fat malabsorption, neurodegeneration, acanthocytosis |
Aicardi Syndrome; AIC (#304050) | Xp22 abnormalities | XLD | Chorioretinopathy, OA, microphthalmia, optic nerve coloboma, cataract | Callosal agenesis, PGR, microcephaly, ID, skeletal anomalies, neoplasia |
Alagille Syndrome 1; ALGS1 (#118450) | JAG1 | AD | Iris stromal hypoplasia, posterior embryotoxon, microcornea, anomalous optic disc, peripapillary retinal depigmentation, chorioretinopathy | Liver disease, skeletal and renal involvement, characteristic facial features, ID, FTT |
Alport Syndrome 1; ATS1 (#3010150) | COL4A5 | XLD | Fleck retinopathy, cataract, myopia, corneal abnormalities | HL, renal disease |
Alstrom Syndrome; ALMS (#203800) | ALMS1 | AR | CRD, MD, cataract | DD, SS, obesity, HL, cardiac, skeletal, hepatic, renal and endocrine involvement |
Alpha-Methylacyl-CoA Racemase Deficiency; AMACRD (#614307) | AMACR | AR | RP | Neurodegeneration |
Autoimmune Polyendocrine Syndrome, Type I, with or without Reversible Metaphyseal Dysplasia; APS1 (#240300) | AIRE | AD, AR | RP, keratopathy, keratoconjunctivitis | Multiple autoantibodies, anemia, hepatic, gastrointestinal, dental, skin, hair and endocrine involvement, hypogonadism |
Bardet–Biedl Syndrome; BBS (#209900, #615981, #600151, #615982, #615983, #605231, #615984, #615985, #615986, #615987, #615988, #615989, #615990, #615991, 615992, #615993, #615994, #615995, #615996, #617119, #617406) [7] | BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, PTHB1, BBS10, TRIM32, BBS12, MKS1, CEP290, WDPCP, SDCCAG8, LZTFL1, BBIP1, IFT27, IFT74, C8ORF37, CEP164 | AR | RP, strabismus, cataract | ID, SS, obesity, hypogonadism, renal disease, polydactyly |
Cerebellar Atrophy with Pigmentary Retinopathy [8] | MSTO1 | AR | RD | Cerebellar atrophy, ID, PGR |
Congenital Disorder of Glycosylation; CDG (#212065, #617082, #613861, #608799, #300896) | PMM2, NUS1, DHDDS, DPM1, SLC35A2 | AR | RP | FTT, microcephaly, ID, neurodegeneration, cardiac, hepatic, gastrointestinal, renal and hematological involvement |
Congenital Disorder of Glycosylation with Defective Fucosylation 2; CDGF2 (#618324) | FCSK | AR | MD, OA, strabismus | FTT, ID, hypotonia, neurodegeneration, gastrointestinal anomalies |
Cranioectodermal Dysplasia 4; CED4 (#614378) | WDR19 | AR | RP | Skeletal anomalies, SS, respiratory, hepatic and renal involvement |
Ceroid Lipofuscinosis, Neuronal; CLN (#256730, #204500, #204200, #256731, #601780, #610951, #600143, #610127, #614706) | PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, GRN | AR | RP, CRD, OA | Microcephaly, ID, neurodegeneration |
Cohen Syndrome; COH1 (#216550) | VPS13B | AR | RD, OA, strabismus, high myopia | ID, DD, microcephaly, SS, obesity, skeletal, cardiac, hematological and endocrine involvement |
Coenzyme Q10 Deficiency, Primary, 1; COQ10D1 (#607426) | COQ2 | AR | RP | ID, cerebellar atrophy, HL, cardiac, hepatic, renal and muscular involvement |
Combined Oxidative Phosphorylation Deficiency 29; COXPD29 (#616811) | TXN2 | AR | RD, OA | Microcephaly, hypotonia, DD, ID, neurodegeneration |
Charcot–Marie–Tooth Disease, X-linked recessive, 5; CMTX5 (#311070) | PRPS1 | XLR | RP, OA | Peripheral neuropathy, HL |
Cone–Rod Dystrophy and Hearing Loss 1; CRDHL1 (#617236) | CEP78 | AR | CRD | HL |
Cockayne Syndrome; CS (#216400, #133540) | ERCC8, ERCC6 | AR | RD, OA, cataract, strabismus | IUGR, PGR, microcephaly, ID, neurodegeneration, HL, renal, skeletal and skin involvement |
Cystinosis, Nephropathic; CTNS (#219800, #219900) | CTNS | AR | RD, corneal crystals | Renal disease, neurodegeneration, skeletal and endocrine anomalies |
Danon Disease (#300257) | LAMP2 | XLD | RD | Cardiac disease, myopathy, ID |
Diabetes and Deafness, Maternally Inherited; MIDD (#520000) | MTTL1, MTTE, MTTK, mitochondrial DNA rearrangements | Mi | RD, MD, ophthalmoplegia | HL, cardiac and neurological anomalies, diabetes mellitus |
Dyskeratosis Congenita, Autosomal Dominant 3; DKCA3 (#613990) | TINF2 | AD | RD, blockage of lacrimal ducts | IUGR, SS, microcephaly, ID, HL, respiratory, skin, skeletal and hematological involvement, neoplasia |
Hypobetalipoproteinemia, Familial, 1; FHBL1 (#615558) | APOB | AR | RP | Fat malabsorption, neurodegeneration, acanthocytosis |
Hypobetalipoproteinemia, Acanthocytosis, Retinitis Pigmentosa and Pallidal Degeneration; HARP (#607236) | PANK2 | AR | RP | Fat malabsorption, neurodegeneration, acanthocytosis |
Hypotrichosis, Congenital, with Juvenile Macular Dystrophy; HJMD (#601553) | CDH3 | AR | MD | Hypotrichosis |
Hermansky–Pudlak Syndrome; HPS (#614072, #614073, #614077) | HPS3, HPS4, BLOC1S3 | AR | Hypopigmentation of retina and choroid, foveal hypoplasia, nystagmus, iris transillumination | Skin and hair hypopigmentation, bleeding diathesis |
Hyper-IgD Syndrome; HIDS (#260920) | MVK | AR | RP | Hematological anomalies, gastrointestinal and skeletal involvement, periodic fever |
Hyperoxaluria, Primary, Type I; HP1 (#259900) | AGXT | AR | RD, OA | Renal disease, dental, cardiovascular and skin involvement, peripheral neuropathy |
Intellectual Developmental Disorder and Retinitis Pigmentosa; IDDRP (#618195) | SCAPER | AR | RP, MD, cataract | ID, skeletal abnormalities, male sterility |
Jalili Syndrome (#217080) | CNNM4 | AR | CRD | Amelogenesis imperfecta |
Joubert Syndrome; JBTS (#213300, #608091, #608629, #610188, #610688, #611560, #612291, #612285, #614464, #614465, #614844, #614970, #615636, #615665, #616781, #617121, #617562, #617622, #618161, #300804) | INPP5E, TMEM216, AHI1, CEP290, TMEM67, RPGRIP1L, ARL13B, CC2D2A, CEP41, TMEM138, ZNF423, TMEM231, CSPP1, PDE6D, CEP104, MKS1, TMEM107, ARMC9, ARL3 | AR | RD, chorioretinal coloboma, optic nerve coloboma, microphthalmia, oculomotor apraxia, esotropia, ptosis | Brain structural anomalies, FTT, macrocephaly, ID, neurodegeneration, genitourinary, hepatic, respiratory and skeletal involvement |
OFD1 | XLR | |||
Kearns–Sayre Syndrome; KSS (#530000) | Mitochondrial DNA deletions | Mi | RD, ophthalmoplegia | SS, microcephaly, neurodegeneration, cardiac, renal and endocrine involvement |
Laurence–Moon Syndrome; LNMS (#245800) | PNPLA6 | AR | Chorioretinal degeneration | ID, neurodegeneration, genitourinary abnormalities |
Leber Congenital Amaurosis with Early-Onset Deafness; LCAEOD (#617879) | TUBB4B | AD | LCA | HL |
Lipodystrophy, familial partial, type7; FPLD7 (#606721) | CAV1 | AD | RD, cataract | Lack of facial fat, orthostatic hypotension, neurological and skin involvement |
Methylmalonic Aciduria and Homocystinuria, cblC type; MAHCC (#277400) | MMACHC | AR | RP, CRD | FTT, microcephaly, ID, neurodegeneration, renal and hematological involvement |
Mevalonic Aciduria; MEVA (#610377) | MVK | AR | RP, OA, cataract | FTT, DD, neurodegeneration, spleen, hepatic, skeletal, skin and hematological involvement |
Microcephaly and Chorioretinopathy, autosomal recessive; MCCRP (#251270, #616171, #616335) | TUBGCP6, PLK4, TUBGCP4 | AR | Chorioretinopathy, OA, microphthalmia, microcornea, cataract | IUGR, microcephaly, brain structural anomalies, DD, ID, neurodegeneration, SS |
Microcephaly with or without Chorioretinopathy, Lymphedema or Mental Retardation; MCLMR (#152950) | KIF11 | AD | Chorioretinopathy, myopia, hypermetropia, corneal opacity, microcornea, microphthalmia, cataract | Microcephaly, ID, neurodegeneration, lymphedema |
Microphthalmia, Syndromic 5; MCOPS5 (#610125) | OTX2 | AD | RD, microphthalmia, anophthalmia, optic nerve hypoplasia or agenesis, microcornea, cataract | Brain structural anomalies, hypotonia, pituitary dysfunction, DD, SS, cleft palate, abnormal genitalia, joint laxity |
Mitochondrial Complex II Deficiency (#252011) | SDHA, SDHD, SDHAF1 | AR | RD, OA, ptosis, ophthalmoplegia | SS, cardiac, skeletal, muscular and neurological involvement |
Mitochondrial Complex IV Deficiency (#220110) | APOPT1, COA3, COX6A2, COX6B1, COX8A, COX10, COX14, COX20, PET100, TACO1 | AR | RD, OA, ptosis | FTT, brain structural anomalies, ID, HL, cardiac, respiratory, hepatic, renal and muscular involvement |
Mucolipidosis III alpha/beta; MLIII A/B (#252600) | GNPTAB | AR | RD, corneal clouding | Neurodegeneration, ID, SS, coarse facies, skeletal, cardiac and skin involvement |
Mucolipidosis IV; ML4 (#252650) | MCOLN1 | AR | RD, OA, corneal disease, strabismus | Microcephaly, ID, neurodegeneration |
Mucopolysaccharidosis; MPS (#309900, #252930, #607014, #253000, #253010) | IDS | XLR | RP, ptosis, corneal clouding | Neurodegeneration, ID, SS, coarse facies, HL, skeletal, cardiac, respiratory, hepatic, gastrointestinal and skin involvement |
HGSNAT, IDUA, GALN5, GLB1 | AR | |||
Nephronophthisis 15; NPHP15 (#614845) | CEP164 | AR | LCA | Renal disease |
Neurodegeneration with Brain Iron Accumulation 1; NBIA1 (#234200) | PANK2 | AR | RD, OA, eyelid apraxia | Neurodegeneration, gastrointestinal, skeletal, skin and muscular involvement |
Neuropathy, Ataxia and Retinitis Pigmentosa; NARP (#551500) | MTATP6 | Mi | RP | Neurodegeneration, ataxia |
Norrie Disease; ND (#310600) | NDP | XLR | Retinal dysgenesis, retinal dysplasia, OA, microphthalmia, vitreous atrophy, corneal opacities, iris atrophy, cataract | HL, ID, neurodegeneration |
Oculoauricular Syndrome; OCACS (#612109) | HMX1 | AR | RP, microphthalmia, microcornea, cataract, microphakia, sclerocornea, increased intraocular pressure | External ear abnormalities |
Orofaciodigital Syndrome XVI; OFD16 (#617563) | TMEM107 | AR | RD, oculomotor apraxia, ptosis | Facial anomalies, breathing abnormalities, polydactyly, hypotonia, ID, neurological anomalies |
Oliver–McFarlane Syndrome; OMCS (#275400) | PNPLA6 | AR | Chorioretinopathy, OA | SS, ID, neurodegeneration, obesity, male external genitalia abnormalities, endocrine anomalies |
Peroxisomal Acyl-CoA Oxidase Deficiency (#264470) | ACOX1 | AR | RD, OA, strabismus | Neurodegeneration, ID, HL, liver disease |
Peroxisome Biogenesis Disorder; PBD (#214100, #614866, #601539, #234580, #614879, #266510) | PEX1, PEX2, PEX5, PEX6, PEX7, PEX12 | AR | RD, OA, corneal clouding, cataract | FTT, neurodegeneration, ID, HL, dental, cardiac, hepatic, genitourinary and skeletal involvement |
Posterior Column Ataxia with Retinitis Pigmentosa; AXPC1 (#609033) | FLVCR1 | AR | RP, OA | Posterior column ataxia, neurodegeneration, gastrointestinal and skeletal involvement |
Polyneuropathy, Hearing Loss, Ataxia, Retinitis Pigmentosa and Cataract; PHARC (#612674) | ABHD12 | AR | RP, OA, cataract | Ataxia, neurodegeneration, HL |
Pseudoxanthoma Elasticum; PXE (#264800) | ABCC6 | AR | RD, MD, choroidal neovascularization | Skin lesions, cardiovascular disease, gastrointestinal and genitourinary involvement |
Refsum Disease, classic (#266500) | PHYH | AR | RP | Neurodegeneration, ataxia, HL, anosmia, cardiac, skeletal and skin involvement |
Retinal Dystrophy, Iris Coloboma and Comedogenic Acne Syndrome; RDCCAS (#615147) | RPB4 | AR | RD, coloboma of the iris, displacement of the pupil, microcornea, cataract | Comedogenic acne |
Retinal Dystrophy and Iris Coloboma with or without Cataract; RDICC (#616722) | MIR204 | AD | RD, coloboma of the iris, congenital cataract | |
Retinal Dystrophy, Juvenile Cataracts and Short Stature Syndrome; RDJCSS (#616108) | RDH11 | AR | RD, juvenile cataracts | SS, DD, ID, dental anomalies |
Retinal Dystrophy and Obesity; RDOB (#616188) | TUB | AR | RD | Obesity |
Revesz Syndrome (#268130) | TINF2 | AD | RD | IUGR, brain structural anomalies, neurodegeneration, ID, aplastic anemia, skin, hair and nail abnormalities |
Retinitis Pigmentosa–Deafness Syndrome (#500004) | MTTS2 | Mi | RP | HL |
Retinitis Pigmentosa and Erythrocytic Microcytosis; RPEM (#616959) | TRNT1 | AR | RP | Erythrocytic microcytosis and additional hematologic abnormalities |
Retinitis Pigmentosa, Hypopituitarism, Nephronophtisis and mild Skeletal Dysplasia; RHYNS (#602152) | TMEM67 | AR | RP | Hypopituitarism, renal disease, skeletal anomalies, HL |
Retinitis Pigmentosa 82 with or without Situs Inversus; RP82 (#615434) | ARL2BP | AR | RP | Situs inversus, male infertility |
Retinitis Pigmentosa with or without Skeletal Anomalies; RPSKA (#250410) | CWC27 | AR | RP | SS, skeletal anomalies, ID |
Retinitis Pigmentosa, X-linked and Sinorespiratory Infections, with or without Deafness (#300455) | RPGR | XL | RP | Recurrent respiratory infections, HL |
Senior–Løken Syndrome; SLSN (#266900, #606996, #609254, #610189, #613615, #616307, #616629) | NPHP1, NPHP4, IQCB1, CEP290, SDCCAG8, WDR19, TRAF3IP1 | AR | RP, LCA | Renal disease |
Short Stature, Hearing Loss, Retinitis Pigmentosa and Distinctive Facies; SHRF (#617763) | EXOSC2 | AR | RP, corneal dystrophy, glaucoma, strabismus | SS, facial anomalies, HL, neurodegeneration, DD, ID |
Sideroblastic Anemia with B-cell Immunodeficiency, Periodic Fevers and Developmental Delay; SIFD (#616084) | TRNT1 | AR | RP | Sideroblastic anemia, immunodeficiency, growth retardation, DD, periodic fever, HL, neurological, cardiac and renal involvement |
Spondylometaphyseal Dysplasia with Cone–Rod Dystrophy; SMDCRD (#608940) | PCYT1A | AR | CRD | Skeletal anomalies, PGR |
Spondylometaphyseal Dysplasia, Axial; SMDAX (#602271) | CFAP410 | AR | RP, CRD, OA | Skeletal anomalies, respiratory disease, reduced sperm motility |
Short-Rib Thoracic Dysplasia 9 with or without Polydactyly; SRTD9 (#266920) | IFT140 | AR | RP | Skeletal anomalies, renal disease, ID |
Thiamine-Responsive Megaloblastic Anemia Syndrome; TRMA (#249270) | SLC19A2 | AR | OA, RD | Megaloblastic anemia, diabetes mellitus, HL |
Usher Syndrome; USH (#276900, #276904, #601067, #602083, #606943, #614869, #276901, #605472, #611383, #276902, #614504) | MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2, USH2A, ADGRV1, WHRN, CLRN1, HARS1 | AR | RP | HL, vestibular dysfunction |
Wolfram Syndrome 1, WFS1 (#222300) | WFS1 | AR | OA, RD | Diabetes mellitus, diabetes insipidus, HL, neurodegeneration, genitourinary and neurologic involvement |
White–Sutton Syndrome, WHSUS (#616364) | POGZ | AD | RP, OA, cortical blindness | DD, characteristic facial features, hypotonia, HL, joint laxity, gastrointestinal anomalies |
Xeroderma Pigmentosum, group B; XPB (#610651) | ERCC3 | AR | RD, OA, micropathalmia | Neoplasia, skin anomalies, SS, microcephaly, HL, ID, brain structural anomalies, neurodegeneration |
Gene | Syndromic IRD | Non-Syndromic IRD (MIM) | Reference |
---|---|---|---|
ABHD12 | PHARC | arRP | [40] |
AHI1 | JBTS3 | arRP | [41] |
ALMS1 | ALMS | arCRD, arEORD | [42] |
ARL2BP | RP with situs inversus | arRP (#615434) | [43,44] |
ARL3 | JBTS35 | adRP (#618173) | [45] |
ARL6 | BBS3 | arRP (#613575) | [46] |
BBS2 | BBS2 | arRP (#616562) | [47] |
C8ORF37 | BBS21 | arCRD, arRP (#614500) | [48] |
CC2D2A | JBTS9, MKS6 | arRP | [49] |
CEP290 | BBS14, JBTS5, MKS4, SLSN6 | arLCA (#611755) | [50] |
CFAP410 | SMDAX | arRD with or without macular staphyloma (#617547) | [51,52] |
CLN3 | CLN3 | arRP | [53] |
CLRN1 | USH3A | arRP (#614180) | [54] |
CWC27 | RPSKA | arRP (#250410) | [55] |
DHDDS | CDG1BB | arRP (#613861) | [56,57] |
FLVCR1 | PCARP | arRP | [58] |
HGSNAT | MPS3C | arRP (#616544) | [59] |
IFT140 | SRTD9 with/without polydactyly | arRP (#617781) | [60] |
IQCB1 | SLSN5 | arLCA | [61] |
MFSD8 | CLN7 | arMD (#616170), arRD | [62] |
MMACHC | MAHCC | arMD | [63] |
MVK | HIDS, MEVA | arRP | [64] |
NDP | ND | XL EVR (#305390) | [65] |
OFD1 | JBTS10 | XL RP (#300424) | [66] |
OTX2 | RD with pituitary dysfunction | adPD (#610125) | [67] |
RPGR | RP, sinorespiratory infections and deafness | XL CRD (#304020), XL MD (#300834), XL RP (#300029) | [68] |
TTC8 | BBS8 | arRP (#613464) | [69] |
USH2A | USH2A | arRP (#613809) | [70] |
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Tatour, Y.; Ben-Yosef, T. Syndromic Inherited Retinal Diseases: Genetic, Clinical and Diagnostic Aspects. Diagnostics 2020, 10, 779. https://doi.org/10.3390/diagnostics10100779
Tatour Y, Ben-Yosef T. Syndromic Inherited Retinal Diseases: Genetic, Clinical and Diagnostic Aspects. Diagnostics. 2020; 10(10):779. https://doi.org/10.3390/diagnostics10100779
Chicago/Turabian StyleTatour, Yasmin, and Tamar Ben-Yosef. 2020. "Syndromic Inherited Retinal Diseases: Genetic, Clinical and Diagnostic Aspects" Diagnostics 10, no. 10: 779. https://doi.org/10.3390/diagnostics10100779
APA StyleTatour, Y., & Ben-Yosef, T. (2020). Syndromic Inherited Retinal Diseases: Genetic, Clinical and Diagnostic Aspects. Diagnostics, 10(10), 779. https://doi.org/10.3390/diagnostics10100779