RPE65 mutation frequency and phenotypic variation according to exome sequencing in a tertiary centre for genetic eye...

Retinoid isomerohydrolase RPE65 has received a tremendous amount of attention due to successful clinical gene therapy for Leber congenital amaurosis (LCA) cases caused by RPE65 mutations. This study aimed to evaluate the frequency of RPE65 mutations and the associated phenotypes based on exome sequencing.

RPE65 variants were collected from exome sequencing data obtained from 2133 probands with different forms of hereditary retinal degeneration (HRD). Clinical data were collected from probands with homozygous or compound heterozygous variants in RPE65. Associated phenotypes were characterized based on clinical data.

Biallelic RPE65 mutations were detected in 18 families, including eight with LCA, five with early-onset retinal degeneration, four with fundus albipunctatus-like (FA-like) changes and one with high hyperopia. These cases accounted for approximately 3.0% (8/269) of LCA and 0.8% (18/2133) of HRD cases. An almost identical FA-like change was identified in seven patients from four unrelated families with RPE65 mutations. Classification of mutations suggested that FA-like changes may be associated with biallelic missense mutations in RPE65.

Fundus albipunctatus-like (FA-like) change, a common characteristic fundus sign in RPE65 biallelic mutations, was unexpected but was confirmed by the finding that affected siblings from different families exhibited similar phenotypes. These results enrich our understanding of RPE65 mutation frequencies and their associated phenotypic variants.