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Open AccessArticle

Rare Genetic Variants in Jewish Patients Suffering from Age-Related Macular Degeneration

The Matlow’s Ophthalmo-Genetics Laboratory, Department of Ophthalmology, Shamir (formerly Assaf-Harofeh) Medical Center, Zerifin 70300, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
Variantyx Inc., Framingham, MA 01701, USA
Author to whom correspondence should be addressed.
Genes 2019, 10(10), 825;
Received: 24 August 2019 / Revised: 2 October 2019 / Accepted: 15 October 2019 / Published: 18 October 2019
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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. View Full-Text
Keywords: degeneration; genetics; macula; WES (whole-exome sequencing) degeneration; genetics; macula; WES (whole-exome sequencing)
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Shoshany, N.; Weiner, C.; Safir, M.; Einan-Lifshitz, A.; Pokroy, R.; Kol, A.; Modai, S.; Shomron, N.; Pras, E. Rare Genetic Variants in Jewish Patients Suffering from Age-Related Macular Degeneration. Genes 2019, 10, 825.

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