Retinal Dystrophies, Genomic Applications in Diagnosis and Prospects for Therapy

Overview

Journal Transl Pediatr

Publisher AME Publishing Company

Specialty Pediatrics

Date 2016 Feb 3

PMID 26835369

Citations 44

Authors

Benjamin M Nash

Dale C Wright

John R Grigg

Bruce Bennetts

Robyn V Jamieson

Affiliations

Soon will be listed here.

Abstract

Retinal dystrophies (RDs) are degenerative diseases of the retina which have marked clinical and genetic heterogeneity. Common presentations among these disorders include night or colour blindness, tunnel vision and subsequent progression to complete blindness. The known causative disease genes have a variety of developmental and functional roles with mutations in more than 120 genes shown to be responsible for the phenotypes. In addition, mutations within the same gene have been shown to cause different disease phenotypes, even amongst affected individuals within the same family highlighting further levels of complexity. The known disease genes encode proteins involved in retinal cellular structures, phototransduction, the visual cycle, and photoreceptor structure or gene regulation. This review aims to demonstrate the high degree of genetic complexity in both the causative disease genes and their associated phenotypes, highlighting the more common clinical manifestation of retinitis pigmentosa (RP). The review also provides insight to recent advances in genomic molecular diagnosis and gene and cell-based therapies for the RDs.

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References

Sergouniotis P, Davidson A, Mackay D, Li Z, Yang X, Plagnol V . Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis. Am J Hum Genet. 2011; 89(1):183-90. PMC: 3135807. DOI: 10.1016/j.ajhg.2011.06.002. View

Wu H, Cowing J, Michaelides M, Wilkie S, Jeffery G, Jenkins S . Mutations in the gene KCNV2 encoding a voltage-gated potassium channel subunit cause "cone dystrophy with supernormal rod electroretinogram" in humans. Am J Hum Genet. 2006; 79(3):574-9. PMC: 1559534. DOI: 10.1086/507568. View

Corton M, Avila-Fernandez A, Vallespin E, Lopez-Molina M, Almoguera B, Martin-Garrido E . Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population. Ophthalmology. 2013; 121(1):399-407. DOI: 10.1016/j.ophtha.2013.08.028. View

den Hollander A, McGee T, Ziviello C, Banfi S, Dryja T, Gonzalez-Fernandez F . A homozygous missense mutation in the IRBP gene (RBP3) associated with autosomal recessive retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2008; 50(4):1864-72. PMC: 2823395. DOI: 10.1167/iovs.08-2497. View

Liu X, Jian X, Boerwinkle E . dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations. Hum Mutat. 2013; 34(9):E2393-402. PMC: 4109890. DOI: 10.1002/humu.22376. View

Maw M, Kennedy B, Knight A, Bridges R, Roth K, Mani E . Mutation of the gene encoding cellular retinaldehyde-binding protein in autosomal recessive retinitis pigmentosa. Nat Genet. 1997; 17(2):198-200. DOI: 10.1038/ng1097-198. View

Thiadens A, den Hollander A, Roosing S, Nabuurs S, Zekveld-Vroon R, Collin R . Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders. Am J Hum Genet. 2009; 85(2):240-7. PMC: 2725240. DOI: 10.1016/j.ajhg.2009.06.016. View

Morimura H, Fishman G, Grover S, Fulton A, Berson E, Dryja T . Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proc Natl Acad Sci U S A. 1998; 95(6):3088-93. PMC: 19699. DOI: 10.1073/pnas.95.6.3088. View

Luo J, Baranov P, Patel S, Ouyang H, Quach J, Wu F . Human retinal progenitor cell transplantation preserves vision. J Biol Chem. 2014; 289(10):6362-6371. PMC: 3945303. DOI: 10.1074/jbc.M113.513713. View

10.

Nishiguchi K, Friedman J, Sandberg M, Swaroop A, Berson E, Dryja T . Recessive NRL mutations in patients with clumped pigmentary retinal degeneration and relative preservation of blue cone function. Proc Natl Acad Sci U S A. 2004; 101(51):17819-24. PMC: 535407. DOI: 10.1073/pnas.0408183101. View

11.

MacLaren R, Groppe M, Barnard A, Cottriall C, Tolmachova T, Seymour L . Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014; 383(9923):1129-37. PMC: 4171740. DOI: 10.1016/S0140-6736(13)62117-0. View

12.

Khan A, Bolz H . Pediatric Cone-Rod Dystrophy with High Myopia and Nystagmus Suggests Recessive PROM1 Mutations. Ophthalmic Genet. 2014; 36(4):349-52. DOI: 10.3109/13816810.2014.886266. View

13.

Seyedahmadi B, Rivolta C, Keene J, Berson E, Dryja T . Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa. Exp Eye Res. 2004; 79(2):167-73. DOI: 10.1016/j.exer.2004.03.005. View

14.

Zuchner S, Dallman J, Wen R, Beecham G, Naj A, Farooq A . Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa. Am J Hum Genet. 2011; 88(2):201-6. PMC: 3035708. DOI: 10.1016/j.ajhg.2011.01.001. View

15.

Demirci F, Rigatti B, Wen G, Radak A, Mah T, Baic C . X-linked cone-rod dystrophy (locus COD1): identification of mutations in RPGR exon ORF15. Am J Hum Genet. 2002; 70(4):1049-53. PMC: 379101. DOI: 10.1086/339620. View

16.

Dryja T, McGee T, Berson E, Fishman G, Sandberg M, Alexander K . Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6. Proc Natl Acad Sci U S A. 2005; 102(13):4884-9. PMC: 555731. DOI: 10.1073/pnas.0501233102. View

17.

Langmann T, Di Gioia S, Rau I, Stohr H, Maksimovic N, Corbo J . Nonsense mutations in FAM161A cause RP28-associated recessive retinitis pigmentosa. Am J Hum Genet. 2010; 87(3):376-81. PMC: 2933350. DOI: 10.1016/j.ajhg.2010.07.018. View

18.

Chakarova C, Papaioannou M, Khanna H, Lopez I, Waseem N, Shah A . Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy. Am J Hum Genet. 2007; 81(5):1098-103. PMC: 2265653. DOI: 10.1086/521953. View

19.

Ran F, Hsu P, Lin C, Gootenberg J, Konermann S, Trevino A . Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell. 2013; 154(6):1380-9. PMC: 3856256. DOI: 10.1016/j.cell.2013.08.021. View

20.

Roepman R, Bauer D, Rosenberg T, van Duijnhoven G, van de Vosse E, Platzer M . Identification of a gene disrupted by a microdeletion in a patient with X-linked retinitis pigmentosa (XLRP). Hum Mol Genet. 1996; 5(6):827-33. DOI: 10.1093/hmg/5.6.827. View