The Genetic Landscape of Inherited Retinal Diseases in the Israeli Population

PURPOSE. Inherited retinal diseases (IRDs) are a group of more than 50 clinically and genetically heterogeneous diseases caused by variants in more than 300 genes. The Israeli population is composed of multiple ethnic groups with variable prevalence of IRD-causing variants. In the current study, we analyzed IRDs in different Israeli ethnic groups to establish the genetic landscape. METHODS. Patients were recruited by five genetic centers, and eight ophthalmic centers, located throughout the country, and belonging to the Israeli inherited retinal disease consortium (IIRDC). The information regarding the cause of disease in each solved family was tabulated. For each ethnic group, we listed the causing variants and their frequencies. RESULTS. We identified a total of 1062 disease-causing variants in Israeli patients with IRDs from 20 ethnic groups (13 of which are Jewish), with a total of 4,728 familial pathogenic alleles. Founder variants contributed the largest proportion of alleles in Yemenite Jews (75%), followed by Turkish Jews (67%), and North African Jews (66%). The most common disease-causing variant was ABCA4-c.5882G>A, a pan-ethnic variant, followed by FAM161A-c.1355_1356del, a founder variant in multiple Jewish ethnic groups. By performing haplotype analysis, 21 additional founder variants were identified. We generated a searchable online database (https://www.eyes.org.il/genecal) based on this data depicting the most common variants for each ethnic group and IRD. CONCLUSIONS. Our analysis provides a comprehensive list of common and founder variants for each ethnic group in Israel and is likely to allow more accurate and informative genetic counseling for Israeli families with IRDs.