TY - JOUR
T1 - Clinical and genetic characteristics of 15 affected patients from 12 Japanese families with GUCY2D-associated retinal disorder
AU - Liu, Xiao
AU - Fujinami, Kaoru
AU - Kuniyoshi, Kazuki
AU - Kondo, Mineo
AU - Ueno, Shinji
AU - Hayashi, Takaaki
AU - Mochizuki, Kiyofumi
AU - Kameya, Shuhei
AU - Yang, Lizhu
AU - Fujinami-Yokokawa, Yu
AU - Arno, Gavin
AU - Pontikos, Nikolas
AU - Sakuramoto, Hiroyuki
AU - Kominami, Taro
AU - Terasaki, Hiroko
AU - Katagiri, Satoshi
AU - Mizobuchi, Kei
AU - Nakamura, Natsuko
AU - Yoshitake, Kazutoshi
AU - Miyake, Yozo
AU - Li, Shiying
AU - Kurihara, Toshihide
AU - Tsubota, Kazuo
AU - Iwata, Takeshi
AU - Tsunoda, Kazushige
AU - Consortium, Japan Eye Genetics
N1 - Funding Information:
We thank Kazuki Yamazawa and Satomi Inoue, National Institute of Sensory Organs, National Tokyo Medical Center, Japan, for their help in the clinical genetic data analysis. The laboratory of Visual Physiology, Division for Vision Research, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan is supported by grants from Astellas Pharma Inc. (NCT03281005), outside the submitted work. Supported by grants from Grant-in-Aid for Young Scientists (A) of the Ministry of Education, Culture, Sports, Science and Technology, Japan (16H06269); grants from Grant-in-Aid for Scientists to support international collaborative studies of the Ministry of Education, Culture, Sports, Science and Technology, Japan (16KK01930002); grants from the National Hospital Organization Network Research Fund (H30-NHO-Sensory Organs-03); grants from FOUNDATION FIGHTING BLINDNESS ALAN LATIES CAREER DEVELOPMENT PROGRAM (CF-CL-0416-0696-UCL); grants from Health Labour Sciences Research Grant, the Ministry of Health, Labour and Welfare (201711107A); and grants from the Great Britain Sasakawa Foundation Butterfield Awards (KF). Supported by grants from Grant-in-Aid for Young Scientists of the Ministry of Education, Culture, Sports, Science and Technology, Japan (18K16943) (YF-Y). Supported by a Fight for Sight (UK) early career investigator award, NIHR-BRC at Moorfields Eye Hospital and the UCL Institute of Ophthalmology, NIHR-BRC at Great Ormond Street Hospital and UCL Institute of Child Health, and Great Britain Sasakawa Foundation Butterfield Award, UK (GA). Funded by the NIHR-BRC at Moorfields Eye Hospital and the UCL Institute of Ophthalmology (NP). Supported by Tsubota Laboratory, Inc, Fuji Xerox Co., Ltd, Kirin Company, Ltd, Kowa Company, Ltd, Novartis Pharmaceuticals, Santen Pharmaceutical Co. Ltd, and ROHTO Pharmaceutical Co.,Ltd. (TK). Supported by the Japan Agency for Medical Research and Development (AMED) (18ek0109282h0002) (TI). Supported by AMED; the Ministry of Health, Labor and Welfare, Japan (18ek0109282h0002); Grants-in-Aid for Scientific Research, Japan Society for the Promotion of Science, Japan (H26-26462674); grants from the National Hospital Organization Network Research Fund, Japan (H30-NHO-Sensory Organs-03) and Novartis Research Grant (2018) (KT). The funding sources had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, and approval of the manuscript; or the decision to submit the manuscript for publication. Kaoru Fujinami has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Research design: Xiao Liu, Kaoru Fujinami, Lizhu Yang, Yu Fujinami-Yokokawa, Kazushige Tsunoda. Data acquisition and/or research execution: All authors. Data analysis and/or interpretation: All authors. Manuscript preparation: Xiao Liu, Kaoru Fujinami, Lizhu Yang, Yu Fujinami-Yokokawa, Gavin Arno, Nikolas Pontikos, Kazushige Tsunoda.
Funding Information:
The laboratory of Visual Physiology, Division for Vision Research, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan is supported by grants from Astellas Pharma Inc. (NCT03281005), outside the submitted work. Supported by grants from Grant-in-Aid for Young Scientists (A) of the Ministry of Education, Culture, Sports, Science and Technology, Japan (16H06269); grants from Grant-in-Aid for Scientists to support international collaborative studies of the Ministry of Education, Culture, Sports, Science and Technology, Japan (16KK01930002); grants from the National Hospital Organization Network Research Fund (H30-NHO-Sensory Organs-03); grants from FOUNDATION FIGHTING BLINDNESS ALAN LATIES CAREER DEVELOPMENT PROGRAM (CF-CL-0416-0696-UCL); grants from Health Labour Sciences Research Grant, the Ministry of Health, Labour and Welfare (201711107A); and grants from the Great Britain Sasakawa Foundation Butterfield Awards (KF). Supported by grants from Grant-in-Aid for Young Scientists of the Ministry of Education, Culture, Sports, Science and Technology, Japan (18K16943) (YF-Y). Supported by a Fight for Sight (UK) early career investigator award, NIHR-BRC at Moorfields Eye Hospital and the UCL Institute of Ophthalmology, NIHR-BRC at Great Ormond Street Hospital and UCL Institute of Child Health, and Great Britain Sasakawa Foundation Butterfield Award, UK (GA). Funded by the NIHR-BRC at Moorfields Eye Hospital and the UCL Institute of Ophthalmology (NP). Supported by Tsubota Laboratory, Inc, Fuji Xerox Co., Ltd, Kirin Company, Ltd, Kowa Company, Ltd, Novartis Pharmaceuticals, Santen Pharmaceutical Co. Ltd, and ROHTO Pharmaceutical Co.,Ltd. (TK). Supported by the Japan Agency for Medical Research and Development (AMED) (18ek0109282h0002) (TI). Supported by AMED; the Ministry of Health, Labor and Welfare, Japan (18ek0109282h0002); Grants-in-Aid for Scientific Research, Japan Society for the Promotion of Science, Japan (H26-26462674); grants from the National Hospital Organization Network Research Fund, Japan (H30-NHO-Sensory Organs-03) and Novartis Research Grant (2018) (KT). The funding sources had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, and approval of the manuscript; or the decision to submit the manuscript for publication.
Publisher Copyright:
© 2020 The Authors.
PY - 2020/5
Y1 - 2020/5
N2 - Purpose: To determine the clinical and genetic characteristics of patients with GUCY2D-associated retinal disorder (GUCY2D-RD). Methods: Fifteen patients from 12 families with inherited retinal disorder (IRD) and harboring GUCY2D variants were ascertained from 730 Japanese families with IRD. Comprehensive ophthalmological examinations, including visual acuity (VA) measure-ment, retinal imaging, and electrophysiological assessment were performed to classify patients into three phenotype subgroups; macular dystrophy (MD), cone-rod dystrophy (CORD), and Leber congenital amaurosis (LCA). In silico analysis was performed for the detected variants, and the molecularly confirmed inheritance pattern was determined (autosomal dominant/recessive [AD/AR]). Results: The median age of onset/examination was 22.0/38.0 years (ranges, 0-55 and 1-73) with a median VA of 0.80/0.70 LogMAR units (ranges, 0.00-1.52 and 0.10-1.52) in the right/left eye, respectively. Macular atrophy was identified in seven patients (46.7%), and two had diffuse fundus disturbance (13.3%), and six had an essentially normal fundus (40.0%). There were 11 patients with generalized cone-rod dysfunction (78.6%), two with entire functional loss (14.3%), and one with confined macular dysfunction (7.1%). There were nine families with ADCORD, one with ARCORD, one with ADMD, and one with ARLCA. Ten GUCY2D variants were identified, including four novel variants (p.Val56GlyfsTer262, p.Met246Ile, p.Arg761Trp, p.Glu874Lys). Conclusions: This large cohort study delineates the disease spectrum of GUCY2D-RD. Diverse clinical presentations with various severities of ADCORD and the early-onset severe phenotype of ARLCA are illustrated. A relatively lower prevalence of GUCY2D-RD for ADCORD and ARLCA in the Japanese population was revealed. Translational Relevance: The obtained data help to monitor and counsel patients, especially in East Asia, as well as to design future therapeutic approaches.
AB - Purpose: To determine the clinical and genetic characteristics of patients with GUCY2D-associated retinal disorder (GUCY2D-RD). Methods: Fifteen patients from 12 families with inherited retinal disorder (IRD) and harboring GUCY2D variants were ascertained from 730 Japanese families with IRD. Comprehensive ophthalmological examinations, including visual acuity (VA) measure-ment, retinal imaging, and electrophysiological assessment were performed to classify patients into three phenotype subgroups; macular dystrophy (MD), cone-rod dystrophy (CORD), and Leber congenital amaurosis (LCA). In silico analysis was performed for the detected variants, and the molecularly confirmed inheritance pattern was determined (autosomal dominant/recessive [AD/AR]). Results: The median age of onset/examination was 22.0/38.0 years (ranges, 0-55 and 1-73) with a median VA of 0.80/0.70 LogMAR units (ranges, 0.00-1.52 and 0.10-1.52) in the right/left eye, respectively. Macular atrophy was identified in seven patients (46.7%), and two had diffuse fundus disturbance (13.3%), and six had an essentially normal fundus (40.0%). There were 11 patients with generalized cone-rod dysfunction (78.6%), two with entire functional loss (14.3%), and one with confined macular dysfunction (7.1%). There were nine families with ADCORD, one with ARCORD, one with ADMD, and one with ARLCA. Ten GUCY2D variants were identified, including four novel variants (p.Val56GlyfsTer262, p.Met246Ile, p.Arg761Trp, p.Glu874Lys). Conclusions: This large cohort study delineates the disease spectrum of GUCY2D-RD. Diverse clinical presentations with various severities of ADCORD and the early-onset severe phenotype of ARLCA are illustrated. A relatively lower prevalence of GUCY2D-RD for ADCORD and ARLCA in the Japanese population was revealed. Translational Relevance: The obtained data help to monitor and counsel patients, especially in East Asia, as well as to design future therapeutic approaches.
KW - Autosomal dominant
KW - Cone rod dystrophy
KW - GUCY2D
KW - Leber congenital amaurosis
KW - Macular dystrophy
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U2 - 10.1167/tvst.9.6.2
DO - 10.1167/tvst.9.6.2
M3 - Article
AN - SCOPUS:85084759414
SN - 2164-2591
VL - 9
JO - Translational Vision Science and Technology
JF - Translational Vision Science and Technology
IS - 6
M1 - 2
ER -