Hereditary diseases such as macular dystrophy and retinitis pigmentosa have been regarded as representative refractory ocular diseases for which no fundamental therapy has been established to date. However, prospects for treating hereditary retinal diseases have recently been proposed, including the initiation of gene therapy for diseases whose genetic pathophysiology is clear. It is critical to accurately understand the pathophysiology of individual patients to establish treatment and therefore to conduct novel genetic pathophysiologic research on large-scale cohorts of Japanese patients whose genetic background differs from Westerners.
In 2014, the National Institute of Sensory Organs located in Tokyo, Japan, established the Japan Eye Genetics Consortium (JEGC, a nationwide joint research team for hereditary chorioretinal diseases) and has been trying to elucidate the genetic pathophysiology of chorioretinal dystrophy and establish a patient data bank. The present review reports the nationwide collaborative research system and the latest findings on hereditary chorioretinal diseases obtained from this research.
1. Establishment of a nationwide collaborative research system for managing refractory ocular diseases
Clinical data and peripheral blood from patients with hereditary chorioretinal and optic nerve diseases (34 diseases, 56 subclassifications) and their unaffected families were collected from 33 ophthalmologic collaborative research institutions nationwide. The anonymized clinical data included basic information such as disease name, age at onset, subjective symptoms, and visual acuity as well as visual field, fundus photography, and imaging data such as optical coherence tomography, fundus autofluorescence, and electroretinography. For causative gene search, comprehensive genetic analyses were performed using whole-exome sequencing. Clinical and genetic information were entered into the JEGC patient database and 2450 patients from 1488 families have been registered as of April 2019. Using this database, it is possible to search and display relevant patients based on keywords such as disease name, age at onset, and causative genes. Additionally, clinical information, including images, of all the patients can be freely viewed.
2. Current findings on hereditary chorioretinal diseases
As of April 2019, the genetic analysis results of 1302 patients from 729 families in the JEGC patient database have been reported. A total of 301 genes, including all the genes registered as retinal disease-related genes in RetNet™ (https://sph.uth.edu/retnet/home.htm; accessed on August 1, 2015), were included in the whole-exome sequencing. Causative genes were identified in 366 (50.2%) of the 729 families. A total of 49 retina-associated genes were identified to be causative, 28% of all the families had known gene mutations (309 mutations) and 22% had novel mutations in known genes (159 mutations). In the remaining 49.8%, the cause could not be identified among the known retina-associated gene candidates. The frequencies of genes identified were as follows with the top five genes accounting for approximately 40% of the total genes identified: EYS 16%; RP1 L1 8%; USH2A 6%; ABCA4 5%; and BEST1 4%. Thereafter, CRX, GUCY2D, PRPH2, RPGR, CYP4V2, RP1, RS1, and SAG each accounted for 3% of the total genes identified, and the top 13 genes accounted for 63%.
Analyses of the ophthalmologic pathogenicity of each disease revealed genotype-phenotype relationship features in Japanese patients. Some of these diseases were similar to those reported previously in Europe and the United States, whereas other diseases such as Miyake's disease and POC1B-related retinopathy were disease concepts that were first identified in JECG cohorts, and diseases such as EYS-related retinopathy were newly characterized based on clinical findings. This new information can be used not only for predicting the long-term progress and daily care of Japanese patients with chorioretinal dystrophy but can also serve as an important guideline for the genetic treatment to be performed in the future. Furthermore, a new national patient registry needs to be developed to allow this information to be shared with patients to facilitate the introduction of genetic therapies.
Nippon Ganka Gakkai Zasshi (J Jpn Ophthalmol Soc) 124: 247-284, 2020.