Abstract
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.
Highlights
Age-related macular degeneration (AMD), a multifactorial disorder of the central retina, is the commonest cause of vision loss among the elderly in the developed world [1]
At least one proband in each family manifested early-AMD featuring before 65 years
As described in detail below, in Phase-1 we have identified by mutation screening three additional families (Families 4, 5, 8) of Tunisian (North-African) Jews ancestry who carry the previously reported
Summary
Age-related macular degeneration (AMD), a multifactorial disorder of the central retina, is the commonest cause of vision loss among the elderly in the developed world [1]. AMD prevalence rises dramatically in the eighth decade; some patients exhibit early onset of disease manifestations and rapid progression (e.g., early-AMD) [2]. Environmental risk factors associated with AMD progression, such as smoking [3], fail to account for the phenotypic diversity of the disease. Two decades of research unraveled a complex influence of a handful of genes on disease pathogenesis. Genome-wide association studies (GWAS) have initially discovered the role of the common complement factor-H (CFH) p.Y402H variant (rs1061170) as an AMD risk factor [4]; followed by many other variants in complement system genes CFI, C3, C2, and factor-B [5,6,7].
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