期刊
OPHTHALMOLOGY
卷 127, 期 10, 页码 1384-1394出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ophtha.2020.04.008
关键词
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资金
- Wellcome Trust [206619/Z/17/Z, 205174/Z/16/Z]
- Fight for Sight UK (Early Career Investigator Award)
- National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital
- UCL Institute of Ophthalmology, London, United Kingdom
- Moorfields Eye Charity, London, United Kingdom [R190031A]
- Biomedical Research Centre at Great Ormond Street Hospital Institute of Child Health, London, United Kingdom
- Medical Research Council (UK) [G1002570]
- Fight for Sight UK
- Isaac Newton Trust
- UK National Institute of Health Research as part of the Rare Diseases Translational Research Collaboration
- Steven and Elizabeth Archer in memory of Marion Woods
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 co- efficients 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). (C) 2020 by the American Academy of Ophthalmology.
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