Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration.

Hum Mol Genet
Authors
Keywords
Abstract

We sequenced the whole exome of 35 cases and 7 controls from 9 age-related macular degeneration (AMD) families in whom known common genetic risk alleles could not explain their high disease burden and/or their early-onset advanced disease. Two families harbored novel rare mutations in CFH (R53C and D90G). R53C segregates perfectly with AMD in 11 cases (heterozygous) and 1 elderly control (reference allele) (LOD = 5.07, P = 6.7 × 10(-7)). In an independent cohort, 4 out of 1676 cases but none of the 745 examined controls or 4300 NHBLI Exome Sequencing Project (ESP) samples carried the R53C mutation (P = 0.0039). In another family of six siblings, D90G similarly segregated with AMD in five cases and one control (LOD = 1.22, P = 0.009). No other sample in our large cohort or the ESP had this mutation. Functional studies demonstrated that R53C decreased the ability of FH to perform decay accelerating activity. D90G exhibited a decrease in cofactor-mediated inactivation. Both of these changes would lead to a loss of regulatory activity, resulting in excessive alternative pathway activation. This study represents an initial application of the whole-exome strategy to families with early-onset AMD. It successfully identified high impact alleles leading to clearer functional insight into AMD etiopathogenesis.

Year of Publication
2014
Journal
Hum Mol Genet
Volume
23
Issue
19
Pages
5283-93
Date Published
2014 Oct 01
ISSN
1460-2083
URL
DOI
10.1093/hmg/ddu226
PubMed ID
24847005
PubMed Central ID
PMC4159152
Links
Grant list
K08AR055688 / AR / NIAMS NIH HHS / United States
MR/K023519/1 / Medical Research Council / United Kingdom
Medical Research Council / United Kingdom
R01-AI041592 / AI / NIAID NIH HHS / United States
P30 AR048335 / AR / NIAMS NIH HHS / United States
U54 HG003079 / HG / NHGRI NIH HHS / United States
U54HG00307910 / HG / NHGRI NIH HHS / United States
P30 AR 48335 / AR / NIAMS NIH HHS / United States
U54 HL112303 / HL / NHLBI NIH HHS / United States
U01HG0070033 / HG / NHGRI NIH HHS / United States
F30HL103072 / HL / NHLBI NIH HHS / United States
R01 EY11309 / EY / NEI NIH HHS / United States