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

Abstract

Purpose 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. Methods 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. Results 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. Conclusion 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.

RPE65-related retinal dystrophy: mutational and phenotypic spectrum in 45 affected patients

“…Pathogenic variations in RPE65 are causative of different IRD such as LCA, EORP or cone-rod dystrophies with AR pattern of heritance. RPE65 variants explained the 2.5% of the AR non-syndromic IRD families genetically characterized in our 1042 families cohort [22], similar to the incidence (2.1%) found in previous studies of RPE65 -associated IRD in European and North American populations [34] and higher than the prevalence of 0.8% recently reported in a Chinese cohort [19]. Besides, RPE65 has been related to a considerable percentage (3-16%) of LCA cases worldwide [14–16, 19], in accordance to the near to 16% of RPE65 -associated LCA found in our cohort.…”

“…RPE65 variants explained the 2.5% of the AR non-syndromic IRD families genetically characterized in our 1042 families cohort [22], similar to the incidence (2.1%) found in previous studies of RPE65 -associated IRD in European and North American populations [34] and higher than the prevalence of 0.8% recently reported in a Chinese cohort [19]. Besides, RPE65 has been related to a considerable percentage (3-16%) of LCA cases worldwide [14–16, 19], in accordance to the near to 16% of RPE65 -associated LCA found in our cohort. As LCA is the earliest and most severe form of IRD [2, 3], the better knowledge of RPE65 pathogenic variants and their phenotypic spectrum is particularly relevant owing to the severity of the disease, the available therapeutic intervention and the ongoing clinical trials [25].…”

“…So far, more than 200 different RPE65 variants have been identified in public databases [17]. Despite of most affected individuals showing a severe progression, with a 50% of patients legally blind by age 20 years, a clear correlation between phenotypic severity and genotype has not been established yet [1, 18, 19].…”

Findings from a Genotyping Study of over 1000 People with Inherited Retinal Disorders in Ireland

“…Mutations in the RPE65 gene were initially found to be causative of some cases of autosomal recessive LCA, a severe and clinically distinct IRD [66][67][68]. This was subsequently expanded to include a milder, dominant form of retinopathy and more recently, to include less severe autosomal recessive retinopathies [35,37]. Luxturna, the first ocular gene therapy approved by the FDA, is for biallelic RPE65 retinal disease [16].…”

“…Initial reports and phenotype characterisation of this mutation were based on several pedigrees originating from Ireland [35,36]. The dominant c.1430A>G (p.Asp477Gly) variant remains to be probed for, yet is undetected, in large RPE65 screening studies (n > 2000) of non-Irish ethnicity [37]. Currently in the Target 5000 cohort, there are 23 genetically confirmed affected individuals, with many patients from these pedigrees that are pending recruitment.…”