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

被引:8
作者
Shoshany, Nadav [1 ]
Weiner, Chen [1 ,2 ]
Safir, Margarita [1 ,2 ]
Einan-Lifshitz, Adi [1 ,2 ]
Pokroy, Russell [1 ]
Kol, Ayala [1 ]
Modai, Shira [3 ]
Shomron, Noam [2 ,3 ]
Pras, Eran [1 ,2 ]
机构
[1] Shamir Formerly Assaf Harofeh Med Ctr, Matlows Ophthalmogenet Lab, Dept Ophthalmol, IL-70300 Zerifin, Israel
[2] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel
[3] Variantyx Inc, Framingham, MA 01701 USA
关键词
degeneration; genetics; macula; WES (whole-exome sequencing); HIGH-RISK; CFH; C3; COMMON;
D O I
10.3390/genes10100825
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
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页数:13
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