Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration.
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.
Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, MA, USA.
Yi
Y
Yu
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
Michael P
MP
Triebwasser
Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK.
Edwin K S
EK
Wong
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
Elizabeth C
EC
Schramm
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Brett
B
Thomas
Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, MA, USA.
Robyn
R
Reynolds
The Genome Institute at Washington University, Saint Louis, MO, USA.
Elaine R
ER
Mardis
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
John P
JP
Atkinson
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
Mark
M
Daly
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA, USA Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
Soumya
S
Raychaudhuri
Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK.
David
D
Kavanagh
Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, MA, USA Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, USA Sackler School of Graduate Medical Sciences, Tufts University, Boston, MA, USA jseddon@tuftsmedicalcenter.org.
Johanna M
JM
Seddon
D000483:Alleles; D003179:Complement C3b / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007700:Kinetics; D008126:Lod Score; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D011487:Protein Conformation
D003179:Complement C3b; D017242:Complement Factor H