Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency

Abstract

Yoshitake 19 , Takeshi iwata 19 , Kazushige tsunoda 1 & JeGc study group † Biallelic variants in the EYS gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic EYS variants, to determine the clinical/genetic spectrum of EYS-associated retinal disease (EYS-RD), and to discover disease-associated variants with relatively high allele frequency (1%-10%) in a nationwide Japanese cohort. Sixty-six affected subjects from 61 families with biallelic or multiple pathogenic/disease-associated EYS variants were ascertained by whole-exome sequencing. Three phenotype groups were identified in EYS-RD: retinitis pigmentosa (RP; 85.94%), cone-rod dystrophy (CORD; 10.94%), and Leber congenital amaurosis (LCA; 3.12%). Twenty-six pathogenic/diseaseassociated EYS variants were identified, including seven novel variants. The two most prevalent variants, p.(Gly843Glu) and p.(Thr2465Ser) were found in 26 and twelve families (42.6%, 19.7%), respectively, for which the allele frequency (AF) in the Japanese population was 2.2% and 3.0%,

Identification of Novel EYS Mutations by Targeted Sequencing Analysis

“…The proband of family SCRP-18 exhibited rod-cone dystrophy symptoms and carried c.2545C>T and c.5802_5803insT. Similarly, Yang et al (2020) reported rod-cone dystrophy patients carrying EYS mutations in a Japanese population (Pagon, 1988). Therefore, different mutations in EYS could cause distinct phenotypes in patients.…”

“…R etinitis pigmentosa (RP, OMIM# 268000) refers to progressive degeneration of the retina, which exhibits genetic heterogeneity and a complex clinical phenotype (Daiger et al, 2013). Unfortunately, the pathogenesis of RP has not been completely elucidated (Pagon, 1988;Yang et al, 2020). RP is characterized by degeneration of rod cells, cone cells, and retinal pigment epithelial cells and by progressive functional impairment of the outer retina (Hamel, 2007).…”

“…EYS mutations account for 15.9% of arRP cases in a Spanish population (Barragán et al, 2010). A high prevalence (18-23%) of EYS-associated RP was reported in Japanese RP patients (Arai et al, 2015;Yang et al, 2020). In Chinese RP patients, the p.C2139Y mutation affecting the EGF-like domain of the EYS protein is a hotspot mutation (Gu et al, 2016;Xiao et al, 2019).…”

RP2‐associated retinal disorder in a Japanese cohort: Report of novel variants and a literature review, identifying a genotype–phenotype association

“…Patients with a clinical diagnosis of IRD and available whole‐exome sequencing (WES) genetic data were studied between 2008 and 2018. A total of 1,294 subjects from 730 families for whom genotype–phenotype association studies were completed, were surveyed, including 47 families with XLRP and 141 families with sporadic RP (Fujinami et al, 2016; Fujinami et al, 2019; Fujinami‐Yokokawa et al, 2019; Fujinami‐Yokokawa et al, 2020; Kameya et al, 2019; Katagiri et al, 2020; Kondo et al, 2019; Maeda‐Katahira et al, 2019; Mawatari et al, 2019; Mizobuchi et al, 2019; Nakamura et al, 2019; Nakanishi et al, 2016; Pontikos et al, 2020; Xiao Liu et al, 2020; Yang et al, 2020).…”

“…The called variants were filtered based on the allele frequencies in the general Japanese population (less than 1%) of the Human Genetic Variation Database (HGVD; http://www.hgvd.genome.med.kyoto-u.ac.jp/). Hypomorphic variants with high allele frequencies (>1%) were analyzed for three particular genes ( EYS, ABCA4 , USH2A ) (Yang et al, 2020). Depth and coverage for the target areas were assessed using the integrative Genomics Viewer (http://www.broadinstitute.org/igv/).…”