Clinical and Genetic Characteristics of 18 Patients from 13 Japanese Families with CRX-associated retinal disorder: Identification of Genotype-phenotype Association
Yu Fujinami‐Yokokawa, Kaoru Fujinami, Kazuki Kuniyoshi, Takaaki Hayashi, Shinji Ueno, Atsushi Mizota, Kei Shinoda, Gavin Arno, Nikolas Pontikos, Lizhu Yang, Xiao Liu, Hiroyuki Sakuramoto, Satoshi Katagiri, Kei Mizobuchi, Taro Kominami, Hiroko Terasaki, Natsuko Nakamura, Shuhei Kameya, Kazutoshi Yoshitake, Yozo Miyake, Toshihide Kurihara, Kazuo Tsubota, Hiroaki Miyata, Takeshi Iwata, Kazushige Tsunoda, Toshihide Nishimura, Yoshihide Hayashizaki, Mineo Kondo, Nobuhiro Shimozawa, Masayuki Horiguchi, Shuichi Yamamoto, Manami Kuze, Nobuhisa Nao‐i, 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, Tetuju 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, Yu Teruyama, Megumi Yamamoto, Naoko Minematsu, Hideko Sanbe, Daisuke Mori, Yusuke Kijima, Go Mawatari, Kentaro Kurata, Norihiro Yamada, Masayosi Itoh, Hideya Kawaji, Yasuhiro Murakawa
Abstract
Inherited retinal disorder (IRD) is a leading cause of blindness, and CRX is one of a number of genes reported to harbour autosomal dominant (AD) and recessive (AR) causative variants. Eighteen patients from 13 families with CRX-associated retinal disorder (CRX-RD) were identified from 730 Japanese families with IRD. Ophthalmological examinations and phenotype subgroup classification were performed. The median age of onset/latest examination was 45.0/62.5 years (range, 15-77/25-94). The median visual acuity in the right/left eye was 0.52/0.40 (range, -0.08-2.00/-0.18-1.70) logarithm of the minimum angle of resolution (LogMAR) units. There was one family with macular dystrophy, nine with cone-rod dystrophy (CORD), and three with retinitis pigmentosa. In silico analysis of CRX variants was conducted for genotype subgroup classification based on inheritance and the presence of truncating variants. Eight pathogenic CRX variants were identified, including three novel heterozygous variants (p.R43H, p.P145Lfs*42, and p.P197Afs*22). A trend of a genotype-phenotype association was revealed between the phenotype and genotype subgroups. A considerably high proportion of CRX-RD in ADCORD was determined in the Japanese cohort (39.1%), often showing the mild phenotype (CORD) with late-onset disease (sixth decade). Frequently found heterozygous missense variants located within the homeodomain underlie this mild phenotype. This large cohort study delineates the disease spectrum of CRX-RD in the Japanese population.