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Human molecular genetics 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, EK, Schramm, EC, Thomas, B, Reynolds, R, Mardis, E, Atkinson, JP, Daly, M, Raychaudhuri, S, Kavanagh, D, Seddon, JM
JournalHuman molecular genetics
Date Published2014/05/20

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=6.7x10(-7)). In an independent cohort, 4 out of 1,676 cases but none of the 745 examined controls or the 4300 NHBLI ESP samples carried the R53C mutation (P=0.0039). In another family of 6 siblings, D90G similarly segregated with AMD in 5 cases and 1 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.