Clinical and Genetic Characteristics of 15 Affected Patients From 12 Japanese Families with GUCY2D-Associated Retinal Disorder

Xiao Liu; Kaoru Fujinami; Kazuki Kuniyoshi; Mineo Kondo; Shinji Ueno; Takaaki Hayashi; Kiyofumi Mochizuki; Shuhei Kameya; Lizhu Yang; Yu Fujinami-Yokokawa; Gavin Arno; Nikolas Pontikos; Hiroyuki Sakuramoto; Taro Kominami; Hiroko Terasaki; Satoshi Katagiri; Kei Mizobuchi; Natsuko Nakamura; Kazutoshi Yoshitake; Yozo Miyake; Shiying Li; Toshihide Kurihara; Kazuo Tsubota; Takeshi Iwata; Kazushige Tsunoda; Japan Eye Genetics Consortium

doi:10.1167/tvst.9.6.2

Clinical and Genetic Characteristics of 15 Affected Patients From 12 Japanese Families with GUCY2D-Associated Retinal Disorder

Transl Vis Sci Technol. 2020 May 11;9(6):2. doi: 10.1167/tvst.9.6.2. eCollection 2020 May.

Authors

Xiao Liu^{1

2

3}, Kaoru Fujinami^{1

2

4

5}, Kazuki Kuniyoshi⁶, Mineo Kondo⁷, Shinji Ueno⁸, Takaaki Hayashi⁹, Kiyofumi Mochizuki¹⁰, Shuhei Kameya¹¹, Lizhu Yang^{1

2}, Yu Fujinami-Yokokawa^{1

12

13}, Gavin Arno^{1

4

5

14}, Nikolas Pontikos^{4

5}, Hiroyuki Sakuramoto⁶, Taro Kominami⁸, Hiroko Terasaki⁸, Satoshi Katagiri⁹, Kei Mizobuchi⁹, Natsuko Nakamura^{1

15}, Kazutoshi Yoshitake¹⁶, Yozo Miyake^{1

17}, Shiying Li³, Toshihide Kurihara², Kazuo Tsubota², Takeshi Iwata¹⁶, Kazushige Tsunoda¹; Japan Eye Genetics Consortium

Affiliations

¹ Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Meguro-ku, Tokyo, Japan.
² Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
³ Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
⁴ UCL Institute of Ophthalmology, London, UK.
⁵ Moorfields Eye Hospital, London, UK.
⁶ Department of Ophthalmology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
⁷ Department of Ophthalmology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
⁸ Department of Ophthalmology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
⁹ Department of Ophthalmology, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
¹⁰ Department of Ophthalmology, Gifu University Graduate School of Medicine, Gifu-shi, Gifu, Japan.
¹¹ Department of Ophthalmology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan.
¹² Graduate School of Health Management, Keio University, Shinjuku-ku, Tokyo, Japan.
¹³ Division of Public Health, Yokokawa Clinic, Suita, Osaka, Japan.
¹⁴ North East Thames Regional Genetics Service, UCL Great Ormond Street Institute of Child Health, Great Ormond Street NHS Foundation Trust, London, UK.
¹⁵ Department of Ophthalmology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
¹⁶ Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization National Tokyo Medical Center, Meguro-ku, Tokyo, Japan.
¹⁷ Aichi Medical University, Nagakute, Aichi, Japan.

Abstract

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) measurement, 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.

Keywords: GUCY2D; Leber congenital amaurosis; autosomal dominant; cone rod dystrophy; macular dystrophy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Asia, Eastern
Cohort Studies
Guanylate Cyclase* / genetics
Humans
Japan / epidemiology
Receptors, Cell Surface* / genetics

Substances

Receptors, Cell Surface
Guanylate Cyclase