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Hum Mol Genet DOI:10.1093/hmg/ddu226

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

Publication TypeJournal Article
Year of Publication2014
AuthorsYu, Y, Triebwasser, MP, Wong, EKS, Schramm, EC, Thomas, B, Reynolds, R, Mardis, ER, Atkinson, JP, Daly, M, Raychaudhuri, S, Kavanagh, D, Seddon, JM
JournalHum Mol Genet
Date Published2014 Oct 01
KeywordsAlleles, Complement C3b, Complement Factor H, Exome, Female, Gene Frequency, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Kinetics, Lod Score, Macular Degeneration, Male, Models, Molecular, Pedigree, Polymorphism, Single Nucleotide, Protein Binding, Protein Conformation

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.


Alternate JournalHum. Mol. Genet.
PubMed ID24847005
PubMed Central IDPMC4159152
Grant ListK08AR055688 / 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