Elsevier

Ophthalmology

Volume 127, Issue 10, October 2020, Pages 1384-1394
Ophthalmology

Original Article
Genetic Basis of Inherited Retinal Disease in a Molecularly Characterized Cohort of More Than 3000 Families from the United Kingdom

https://doi.org/10.1016/j.ophtha.2020.04.008Get rights and content
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open access

Purpose

In a large cohort of molecularly characterized inherited retinal disease (IRD) families, we investigated proportions with disease attributable to causative variants in each gene.

Design

Retrospective study of electronic patient records.

Participants

Patients and relatives managed in the Genetics Service of Moorfields Eye Hospital in whom a molecular diagnosis had been identified.

Methods

Genetic screening used a combination of single-gene testing, gene panel testing, whole exome sequencing, and more recently, whole genome sequencing. For this study, genes listed in the Retinal Information Network online resource (https://sph.uth.edu/retnet/) were included. Transcript length was extracted for each gene (Ensembl, release 94).

Main Outcome Measures

We calculated proportions of families with IRD attributable to variants in each gene in the entire cohort, a cohort younger than 18 years, and a current cohort (at least 1 patient encounter between January 1, 2017, and August 2, 2019). Additionally, we explored correlation between numbers of families and gene transcript length.

Results

We identified 3195 families with a molecular diagnosis (variants in 135 genes), including 4236 affected individuals. The pediatric cohort comprised 452 individuals from 411 families (66 genes). The current cohort comprised 2614 families (131 genes; 3130 affected individuals). The 20 most frequently implicated genes overall (with prevalence rates per families) were as follows: ABCA4 (20.8%), USH2A (9.1%), RPGR (5.1%), PRPH2 (4.6%), BEST1 (3.9%), RS1 (3.5%), RP1 (3.3%), RHO (3.3%), CHM (2.7%), CRB1 (2.1%), PRPF31 (1.8%), MY07A (1.7%), OPA1 (1.6%), CNGB3 (1.4%), RPE65 (1.2%), EYS (1.2%), GUCY2D (1.2%), PROM1 (1.2%), CNGA3 (1.1%), and RDH12 (1.1%). These accounted for 71.8% of all molecularly diagnosed families. Spearman coefficients for correlation between numbers of families and transcript length were 0.20 (P = 0.025) overall and 0.27 (P = 0.017), –0.17 (P = 0.46), and 0.71 (P = 0.047) for genes in which variants exclusively cause recessive, dominant, or X-linked disease, respectively.

Conclusions

Our findings help to quantify the burden of IRD attributable to each gene. More than 70% of families showed pathogenic variants in 1 of 20 genes. Transcript length (relevant to gene delivery strategies) correlated significantly with numbers of affected families (but not for dominant disease).

Abbreviations and Acronyms

IRD
inherited retinal disease
RP
retinitis pigmentosa

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Supplemental material available at www.aaojournal.org.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Supported by the Wellcome Trust (grant nos.: 206619/Z/17/Z [O.M.] and 205174/Z/16/Z [M.M.]); Fight for Sight UK (Early Career Investigator Award [G.A.]); the National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology, London, United Kingdom; Moorfields Eye Charity, London, United Kingdom (Career Development Award no.: R190031A [N.P.]); Biomedical Research Centre at Great Ormond Street Hospital Institute of Child Health, London, United Kingdom (G.A.); Medical Research Council (UK) (Clinician Scientist Fellowship Award no.: G1002570 [P.Y.-W.-M.]); Fight for Sight UK (P.Y.-W.-M.); the Isaac Newton Trust (P.Y.-W.-M.); the UK National Institute of Health Research as part of the Rare Diseases Translational Research Collaboration (P.Y.-W.-M.); and Steven and Elizabeth Archer in memory of Marion Woods (N.P.). The funding organizations had no role in the design or conduct of this research. The views expressed are those of the authors and not the funding organizations.

HUMAN SUBJECTS: Human subjects were included in this study. The human ethics committees at Moorfields Eye Hospital and the Northwest London Research Ethics Committee approved the study. All research adhered to the tenets of the Declaration of Helsinki. All participants or their parents or guardians provided informed consent.

No animal subjects were included in this study.

Author Contributions:

Conception and design: Moore, Michaelides, Webster, Mahroo

Analysis and interpretation: Pontikos, Arno, Jurkute, Schiff, Ba-Abbad, Malka, Gimenez, Georgiou, Wright, Armengol, Knight, Katz, Moosajee, Yu-Wai-Man, Moore, Michaelides, Webster, Mahroo

Data collection: Pontikos, Arno, Jurkute, Schiff, Ba-Abbad, Malka, Gimenez, Georgiou, Wright, Armengol, Knight, Katz, Moosajee, Yu-Wai-Man, Moore, Michaelides, Webster, Mahroo

Obtained funding: Pontikos, Arno, Moosajee, Yu-Wai-Man, Moore, Michaelides, Webster, Mahroo

Overall responsibility: Moore, Michaelides, Webster, Mahroo

© 2020 by the American Academy of OphthalmologyThis is an open access article under the CC BY license (<inter-ref xlink: href=http://creativecommons.org/licenses/by/4.0/>http://creativecommons.org/licenses/by/4.0/</inter-ref>).