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Open AccessArticle

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

1
The Matlow’s Ophthalmo-Genetics Laboratory, Department of Ophthalmology, Shamir (formerly Assaf-Harofeh) Medical Center, Zerifin 70300, Israel
2
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
3
Variantyx Inc., Framingham, MA 01701, USA
*
Author to whom correspondence should be addressed.
Genes 2019, 10(10), 825; https://doi.org/10.3390/genes10100825
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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