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

Yi Yu, Michael P. Triebwasser, Edwin K.S. Wong, Elizabeth C. Schramm, Brett Thomas, Robyn Reynolds, Elaine R. Mardis, John P. Atkinson, Mark Daly, Soumya Raychaudhuri, David Kavanagh, Johanna M. Seddon

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


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.

Original languageEnglish
Pages (from-to)5283-5293
Number of pages11
JournalHuman molecular genetics
Issue number19
StatePublished - Oct 1 2014


Dive into the research topics of 'Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration'. Together they form a unique fingerprint.

Cite this