Mutational profile of the most common genes causing inherited retinal diseases in a large molecularly characterized cohort from the United Kingdom

Abstract

Purpose : Inherited retinal diseases are an important cause of blindness, and due to the recent advancement of gene-directed trials it is increasingly important to understand the molecular basis of these disorders. The aim of this study was to examine the mutation spectrum of the 5 most common genes involved in inherited retinal disease in a large molecularly characterized cohort from the United Kingdom.

Methods : We performed a retrospective study of electronic patient records of the Genetics Service of Moorfields Eye Hospital. The 5 most common genes, by persons affected, causing inherited retinal disease in this cohort have previously been reported (Pontikos et al., 2020) as ABCA4, USH2A, RPGR, PRPH2, and BEST1. The electronic records database was interrogated, and all patients with a molecular diagnosis due to one of the above 5 genes were analyzed. A total of 1870 patients from 1720 families were included. For autosomal recessive disorders where 2 or more likely pathogenic or pathogenic changes were reported, all mutant alleles were included.

Results : The most common pathogenic or likely pathogenic mutations in our cohort for ABCA4 were c.5882G>A (p.Gly1961Glu) and c.5461-10T>C (212 and 119 of 2024 mutant ABCA4-alleles, respectively). The five most frequent mutant alleles (c.5882G>A (p.Gly1961Glu), c.5461-10T>C, c.2588G>C (p.Gly863Ala), c.4139C>T (p.Pro1380Leu), c.5714+5G>A) account for more than 25% of disease-associated variants in ABCA4. In USH2A the c.2299del (p.Glu767Serfs*21) mutation was most commonly involved (130/749 mutant USH2A-alleles), c.2405_2406del (p.Glu802Glyfs*32) and c.2426_2427del (p.Glu809Glyfs*25) were most prevalent in RPGR (23 and 21/239 mutant RPGR-alleles, repectively), while c.514C>T (p.Arg172Trp) was the most common in PRPH2 (40/194 mutant PRPH2-alleles). In BEST1 the most commonly observed mutations were c.728C>T (p.Ala243Val) and c.652C>T (p.Arg218Cys) (11 and 10 of 201 mutant BEST1-alleles, respectively).

Conclusions : Our findings provide meaningful population-based data of the mutation spectrum of ABCA4, USH2A, RPGR, PRPH2, and BEST1 from a large cohort of patients with a molecular diagnosis from the United Kingdom.

This is a 2021 ARVO Annual Meeting abstract.