Spectrum of Genetic Variants in the Most Common Genes Causing Inherited Retinal Disease in a Large Molecularly Characterized United Kingdom Cohort

Abstract

PurposeInherited retinal disease (IRD) is a leading cause of blindness. Recent advances in gene-directed therapies highlight the importance of understanding the genetic basis of these disorders. This study details the molecular spectrum in a large UK IRD patient cohort. DesignRetrospective study of electronic patient records. ParticipantsPatients with IRD who have attended the Genetics Service at Moorfields Eye Hospital between 2003 and July 2020, in whom a molecular diagnosis has been identified. MethodsGenetic testing was undertaken via a combination of single-gene testing, gene panel testing, whole exome sequencing, and more recently, whole genome sequencing. Likely disease-causing variants were identified from entries within the genetics module of the hospital electronic patient record (OpenEyes Electronic Medical Record, UK). Analysis was restricted to only genes listed in the Genomics England PanelApp R32 Retinal disorders panel (Version 3.24), which includes 412 genes associated with IRD. Manual curation ensured consistent variant annotation and included only plausible disease-associated variants. Main outcome measuresDetailed analysis was performed for variants in the five most frequent genes (ABCA4, USH2A, RPGR, PRPH2, BEST1), as well as for the commonest variants encountered in the IRD study cohort. ResultsWe identified 4415 individuals from 3953 families with molecularly diagnosed IRD (variants in 166 genes). 42.7% of families had variants in one of the five commonest IRD genes. Complex disease alleles contributed to disease in 16.9% of affected families with ABCA4-associated retinopathy. USH2A exon 13 variants were identified in 43% of affected individuals with USH2A-associated IRD. 71% of RPGR variants were clustered in the ORF15 region. PRPH2 and BEST1 variants were associated with a range of dominant and recessive IRD phenotypes. Of the 20 most prevalent variants identified, five were not in the commonest genes; these included founder variants in CNGB3, BBS1, TIMP3, EFEMP1 and RP1. ConclusionsWe describe the commonest pathogenic IRD alleles in a large single-center multi-ethnic UK cohort, and the burden of disease, in terms of families affected, attributable to these variants. Our findings will inform IRD diagnoses in future patients and helps delineate the cohort of patients eligible for gene-directed therapies under development.