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Inherited Retinal Disease

Researchers identify most common pathogenic IRD alleles

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A retrospective study describes the most common pathogenic inherited retinal disease (IRD) alleles in a large single-center multi-ethnic cohort, and the burden of disease, in terms of families affected, attributable to the variants. The findings inform IRD diagnoses in future patients and helps delineate the cohort of patients eligible for gene-directed therapies under development, according to the researchers.

Recent advances in gene-directed therapies have highlighted the importance of understanding the genetic basis of IRD and other disorders. The study of electronic patient records included participants with IRD in whom a molecular diagnosis has been identified who have attended the Genetics Service at Moorfields Eye Hospital between 2003 and July 2020.

Genetic testing was conducted using a combination of single-gene testing, gene panel testing, whole exome sequencing, and whole genome sequencing. Likely disease-causing variants were identified from entries within the genetics module of the hospital electronic patient 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 provided consistent variant annotation and only plausible disease-associated variants were included. For the main outcome measures, a detailed analysis was performed for variants in the 5 most frequent genes (ABCA4, USH2A, RPGR, PRPH2, BEST1), and the most common variants in the IRD study cohort.

The researchers identified 4,415 individuals from 3,953 families with molecularly diagnosed IRD (variants in 166 genes), with 42.7% of families having 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; 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, 5 were not in the commonest genes; these included founder variants in CNGB3, BBS1, TIMP3, EFEMP1 and RP1.

Reference
Lin S, Vermeirsch S, Pontikos N, et al. Spectrum of genetic variants in the commonest genes causing inherited retinal disease in a large molecularly characterised UK cohort. Ophthalmol Retina. 2024;S2468-6530(24)00013-7. doi:10.1016/j.oret.2024.01.012

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