Clinical and Genetic Characteristics of 18 Patients from 13 Japanese Families with CRX-associated retinal disorder: Identification of Genotype-phenotype Association
Authors: Fujinami-Yokokawa Yu , Fujinami Kaoru , Kuniyoshi Kazuki , Hayashi Takaaki , Ueno Shinji , Mizota Atsushi , Shinoda Kei , Arno Gavin , Pontikos Nikolas , Yang Lizhu , Liu Xiao , Sakuramoto Hiroyuki , Katagiri Satoshi , Mizobuchi Kei , Kominami Taro , Terasaki Hiroko , Nakamura Natsuko , Kameya Shuhei , Yoshitake Kazutoshi , Miyake Yozo , Kurihara Toshihide , Tsubota Kazuo , Miyata Hiroaki , Iwata Takeshi , Tsunoda Kazushige ,   Japan Eye Genetics Consortium, Nishimura Toshihide , Hayashizaki Yoshihide , Kondo Mineo , Shimozawa Nobuhiro , Horiguchi Masayuki , Yamamoto Shuichi , Kuze Manami , Naoi Nobuhisa , Machida Shigeki , Shimada Yoshiaki , Nakamura Makoto , Fujikado Takashi , Hotta Yoshihiro , Takahashi Masayo , Mochizuki Kiyofumi , Murakami Akira , Kondo Hiroyuki , Ishida Susumu , Nakazawa Mitsuru , Hatase Tetsuhisa , Matsunaga Tatsuo , Maeda Akiko , Noda Kosuke , Tanikawa Atsuhiro , Yamamoto Syuji , Yamamoto Hiroyuki , Araie Makoto , Aihara Makoto , Nakazawa Toru , Sekiryu Tetuju , Kashiwagi Kenji , Kosaki Kenjiro , Piero Carninci , Fukuchi Takeo , Hayashi Atsushi , Hosono Katsuhiro , Mori Keisuke , Tanaka Kouji , Furuya Koichi , Suzuki Keiichirou , Kohata Ryo , Yanagi Yasuo , Minegishi Yuriko , Iejima Daisuke , Suga Akiko , Rossmiller Brian P. , Pan Yang , Oshima Tomoko , Nakayama Mao , Teruyama Yu , Yamamoto Megumi , Minematsu Naoko , Sanbe Hideko , Mori Daisuke , Kijima Yusuke , Mawatari Go , Kurata Kentaro , Yamada Norihiro , Itoh Masayosi , Kawaji Hideya , Murakawa Yasuhiro 
Published: June 2020

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.