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

Abstract

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).

Figure 1

Schematic of the retina showing site of expression of proteins encoded by the 20 most frequently implicated genes in the cohort. RPE = retinal pigment epithelium.

Figure 2

Bar graphs showing the 30 most frequently involved genes in the full cohort. A, Genes ranked by numbers of affected families. B, Genes ranked by numbers of affected individuals.

Figure 3

Graphs showing the numbers of affected families plotted against transcript length. A, Autosomal genes in which pathogenic variants act exclusively recessively (Spearman correlation coefficient, 0.27; P = 0.017). B, Autosomal genes in which pathogenic variants act exclusively dominantly (Spearman correlation coefficient, –0.17; P = 0.459). C, X-linked genes (Spearman correlation coefficient, 0.71; P = 0.047).

Figure 4

Bar graphs showing the 30 most frequently involved genes in the cohort younger than 18 years. A, Genes ranked by numbers of affected families. B, Genes ranked by numbers of affected individuals.

Figure 5

Bar graphs showing the 30 most frequently involved genes in the current cohort (in which a patient encounter had occurred within the preceding 2.5 years). A, Genes ranked by numbers of affected families. B, Genes ranked by numbers of affected individuals.