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

Lookup NU author(s): Dr Edwin Wong, Professor David KavanaghORCiD


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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 x 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.

Publication metadata

Author(s): Yu Y, Triebwasser MP, Wong EKS, Schramm EC, Thomas B, Reynolds R, Mardis ER, Atkinson JP, Daly M, Raychaudhuri S, Kavanagh D, Seddon JM

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2014

Volume: 23

Issue: 19

Pages: 5283-5293

Print publication date: 01/10/2014

Online publication date: 20/05/2014

Acceptance date: 06/05/2014

Date deposited: 30/01/2015

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddu226


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Funder referenceFunder name
P30 AR48335NIH-Arthritis and Musculoskeletal and Skin Diseases
U54 HL112303NIH
Arnold and Mabel Beckman Initiative for Macular Research
Doris Duke Clinical Scientist Development Award
Massachusetts Lions Eye Research Fund, Inc.
Ruth L. Kirschstein National Research Service Award (National Heart, Lung and Blood Institute)
American Macular Degeneration Foundation
Edward N. & Della L.Thome Memorial Foundation
Facility of the Rheumatic Diseases Core
Foundation Fighting Blindness
Macular Degeneration Research Fund of the Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine
Macular Vision Research Foundation
Research to Prevent Blindness Challenge Grant