Genetic characteristics of retinitis pigmentosa and allied diseases in 2063 Japanese patients

Abstract

Purpose : As the development of gene therapy for inherited retinal dystrophy accelerates, the detection of pathogenic genes and variants is becoming increasingly important. The purpose of this study was to evaluate the pathogenicity of variants in a large number of patients with retinitis pigmentosa (RP) and allied diseases according to the American College of Medical Genetics and Genomics (ACMG) guidelines and to detect the pathogenic genes and variants in each patient.

Methods : We recruited 2063 probands with RP and allied diseases from eight Japanese facilities from the Japan Retinitis Pigmentosa Registry Project. Multiple PCR-based target sequencing was performed on 83 genes associated with RP that were registered on the Retinal Information Network (RetNet). The detected variants were interpreted according to the ACMG guidelines. Genetic diagnosis was made using the variants interpreted as “(Likely) Pathogenic”.

Results : There were 1985 patients with non-syndromic RP and 78 with allied diseases, such as Usher syndrome, Leber congenital amaurosis (LCA), cone-rod dystrophy (CRD), choroideremia, and Oguchi disease with retinal degeneration. A total of 3853 variants were detected, and 545 variants, including 135 novel variants, were interpreted as “(Likely) Pathogenic”. In the non-syndromic RP group, 691 patients (34.8%) were genetically diagnosed with 263 pathogenic variants in 41 genes. EYS was the most common causative gene among the genetically solved patients (49.5%), followed by USH2A (7.1%), RHO (5.4%), RPGR (4.9%), and RP1 (4.2%). In particular, the p.S1653Kfs*2 in EYS was detected in 210 (30.4%) solved patients and 81 (6.3%) unsolved patients with non-syndromic RP. The genetic diagnosis rates of allied diseases were 10% for Usher syndrome, 11.1% for LCA, 13% for CRD, 14.3% for choroideremia, and 88.9% for Oguchi disease with retinal degeneration, respectively.

Conclusions : Our genetic analysis of large-scale samples based on the ACMG guidelines identified a large number of novel pathogenic variants and calculated the latest genetic diagnosis rates of RP and allied diseases in Japan. The East Asian-specific p.S1653Kfs*2 in EYS was the most frequent pathogenic variant, which may serve as a therapeutic target for patients with non-syndromic RP in Japanese population.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.