Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency
Lizhu Yang, Kaoru Fujinami, Shinji Ueno, Kazuki Kuniyoshi, Takaaki Hayashi, Mineo Kondo, Atsushi Mizota, Nobuhisa Nao‐i, Kei Shinoda, Shuhei Kameya, Yu Fujinami‐Yokokawa, Xiao Liu, Gavin Arno, Nikolas Pontikos, Taro Kominami, Hiroko Terasaki, Hiroyuki Sakuramoto, Satoshi Katagiri, Kei Mizobuchi, Natsuko Nakamura, Go Mawatari, Toshihide Kurihara, Kazuo Tsubota, Yozo Miyake, Kazutoshi Yoshitake, Takeshi Iwata, Kazushige Tsunoda, JEGC study group, Toshihide Nishimura, Yoshihide Hayashizaki, Nobuhiro Shimozawa, Masayuki Horiguchi, Shuichi Yamamoto, Manami Kuze, Shigeki Machida, Yoshiaki Shimada, Makoto Nakamura, Takashi Fujikado, Yoshihiro Hotta, Masayo Takahashi, Kiyofumi Mochizuki, Akira Murakami, Hiroyuki Kondo, Susumu Ishida, Mitsuru Nakazawa, Tetsuhisa Hatase, Tatsuo Matsunaga, Akiko Maeda, Kosuke Noda, Atsuhiro Tanikawa, Syuji Yamamoto, Hiroyuki Yamamoto, Makoto Araie, Makoto Aihara, Toru Nakazawa, Tetsuju Sekiryu, Kenji Kashiwagi, Kenjiro Kosaki, Carninci Piero, Takeo Fukuchi, Atsushi Hayashi, Katsuhiro Hosono, Keisuke Mori, Kouji Tanaka, Koichi Furuya, Keiichirou Suzuki, Ryo Kohata, Yasuo Yanagi, Yuriko Minegishi, Daisuke Iejima, Akiko Suga, Brian Rossmiller, Yang Pan, Tomoko Oshima, Mao Nakayama, Megumi Yamamoto, Naoko Minematsu, Daisuke Mori, Yusuke Kijima, Kentaro Kurata, Norihiro Yamada, Masayoshi Itoh, Hideya Kawaji, Yasuhiro Murakawa
Abstract
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/disease-associated 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%, respectively. These results expand the phenotypic and genotypic spectrum of EYS-RD, accounting for a high proportion of EYS-RD both in autosomal recessive RP (23.4%) and autosomal recessive CORD (9.9%) in the Japanese population. The presence of EYS variants with relatively high AF highlights the importance of considering the pathogenicity of non-rare variants in relatively prevalent Mendelian disorders.