Clinical and Genetic Characteristics of 18 Patients from 13 Japanese Families with CRX-associated retinal disorder: Identification of Genotype-phenotype Association

Yu Fujinami‐Yokokawa ,Taro Kominami,Kei Mizobuchi,Michio Ohta ,Hiroaki Matsubara ,Kaoru Fujinami,Xiao Liu,Nikolas Pontikos,Takeshi Iwata,Kei Shinoda,Satoshi Katagiri,Kazuki Kuniyoshi,Shinji Ueno,Yoichi Miyake ,Hiroko Terasaki,Kazutoshi Yoshitake,Shuhei Kameya,Lizhu Yang,Hiroyuki Sakuramoto,Atsushi Mizota,Gavin Arno,Natsuko Nakamura,Takaaki Hayashi,Kazushige Tsunoda

doi:10.1038/s41598-020-65737-z

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.

Highlights

CRX, denoted as a cone–rod homeobox-containing gene (OMIM: 602225) with high homology to the OTX family of homeobox genes, is located on 19q13.33 and contains four exons encoding a 299-amino acid homeodomain transcription factor crucial for the development and survival of photoreceptors[18]
Eighteen affected subjects from 13 Japanese families with a clinical diagnosis of Inherited retinal disorder (IRD) and harbouring CRX variants were identified in this study
Diverse clinical presentations with different inheritance patterns were identified in CRX-associated retinal disorder (CRX-RD), including nine families with molecularly confirmed ADCORD, one family with ADMD, two families with ARRP, and one family with ADRP

Summary

Introduction

CRX, denoted as a cone–rod homeobox-containing gene (OMIM: 602225) with high homology to the OTX family of homeobox genes, is located on 19q13.33 and contains four exons encoding a 299-amino acid homeodomain transcription factor crucial for the development and survival of photoreceptors[18]. The predominant mode of inheritance in reported families is AD, and in a few patients, including Japanese with RP or LCA caused by homozygous CRX variants was reported[29,36]. Studies of CRX-associated retinal disorder (CRX-RD) have often been separately conducted for each phenotype, such as CORD or RP/LCA16,24,26,27,32,36; it has been hard to comprehensively understand the disorder in consideration of different phenotypes and different modes of inheritance. To solve such a problem, large cohort studies with standardized clinical and genetic investigations for IRDs are required.

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