Rare genetic variants in jewish patients suffering from age-related macular degeneration

Nadav Shoshany, Chen Weiner, Margarita Safir*, Adi Einan-Lifshitz, Russell Pokroy, Ayala Kol, Shira Modai, Noam Shomron, Eran Pras

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Purpose: To identify rare genetic variants in early age-related macular degeneration (AMD) utilizing whole-exome sequencing (WES). Methods: Eight non-related early-AMD families of different Jewish ethnicities were ascertained. Initial mutation screening (phase-1) included common complement factor-H (CFH) p.Y402H; and age related maculopathy susceptibility 2 (ARMS2) p.A69S; and rare variants complement factor-I (CFI) p.V412M; and hemicentin1 (HMCN1) c.4163delC identified previously in our population. Four families, whose initial screening for the aforementioned variants was negative, underwent WES (phase-2). Bioinformatics filtering was based on functionality (from a panel of 234 genes with proven or presumed association to AMD); predicted severity; and frequency (rare variants with minor allele frequency <1%). When applicable, further screening for specific rare variants was carried out on additional cases of similar ethnicities and phenotypes (phase-3). Results: Phase-1 identified three families carrying CFI p.V412M mutation. WES analysis detected probable disease-related variants in three out of the remaining families. These included: a family with a variant in PLEKHA1 gene p.S177N; a family with previously reported variant p.R1210C in CFH gene; and two families with the C3 p.R735W variant. Conclusions: Rare, high-penetrance variants have a profound contribution to early-AMD pathogenesis. Utilization of WES in genetic research of multifactorial diseases as AMD, allows a thorough comprehensive analysis with the identification of previously unreported rare variants.

Original languageEnglish
Article number825
Issue number10
StatePublished - Oct 2019


FundersFunder number
Claire and Amedee Maratier Institute for the Study of Blindness
Consortium for Mapping Retinal Degeneration Disorders in Israel
Sackler Faculty of Medicine
Sackler Faculty of Medicine, Tel-Aviv University7205
Visual Disorders
Tel Aviv University
Health and Medical Research Fund
Ministry of Health, State of Israel
Office of the Chief Scientist, Ministry of Health


    • Degeneration
    • Genetics
    • Macula
    • WES (whole-exome sequencing)


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