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

Purpose: Inherited 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 United Kingdom (UK) IRD patient cohort.

Design: Retrospective study of electronic patient records.

Participants: Patients with IRD who attended the Genetics Service at Moorfields Eye Hospital between 2003 and July 2020, in whom a molecular diagnosis was identified.

Methods: Genetic 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). 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 Measures: Detailed analysis was performed for variants in the 5 most frequent genes (ABCA4, USH2A, RPGR, PRPH2, and BEST1), as well as for the most common variants encountered in the IRD study cohort.

Results: We identified 4415 individuals from 3953 families with molecularly diagnosed IRD (variants in 166 genes). Of the families, 42.7% had variants in 1 of the 5 most common 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. Of the RPGR variants, 71% 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, 5 were not in the most common genes; these included founder variants in CNGB3, BBS1, TIMP3, EFEMP1, and RP1.

Conclusions: We describe the most common pathogenic IRD alleles in a large single-center multiethnic 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 help delineate the cohort of patients eligible for gene-directed therapies under development.

Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.