Pontikos, N;
Arno, G;
Jurkute, N;
Schiff, E;
Ba-Abbad, R;
Malka, S;
Gimenez, A;
... Mahroo, OA; + view all
(2020)
Genetic basis of inherited retinal disease in a molecularly characterised cohort of over 3000 families from the United Kingdom.
Ophthalmology
10.1016/j.ophtha.2020.04.008.
(In press).
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Abstract
Purpose: In our cohort of >3000 molecularly characterised inherited retinal disease (IRD) families, we investigated proportions with disease attributable to causative variants in each gene. Design: Retrospective study of electronic patient record 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 whole cohort, a cohort <18 years, and a “current” cohort (at least one patient encounter between 1 Jan 2017 and 2 Aug 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 pediatric cohort showed some differences, including a higher proportion of families with X-linked disease. The 20 most frequently implicated genes overall were as follows: ABCA4 (20.8% of families); 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%); MYO7A (1.7%); OPA1 (1.6%); CNGB3 (1.4%); RPE65 (1.2%); EYS (1.2%); GUCY2D (1.2%); PROM1 (1.2%); CNGA3 (1.1%); 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 quantify the burden of inherited retinal disease attributable to each gene. Over 70% of families had pathogenic variants in one of 20 genes. Transcript length (relevant to gene delivery strategies) correlated significantly with numbers of affected families (but not for dominant disease).
| Type: | Article |
|---|---|
| Title: | Genetic basis of inherited retinal disease in a molecularly characterised cohort of over 3000 families from the United Kingdom |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ophtha.2020.04.008 |
| Publisher version: | https://doi.org/10.1016/j.ophtha.2020.04.008 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10096370 |
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