Whole exome sequencing for familial bicuspid aortic valve identifies putative variants. Circ Cardiovasc Genet 2014 Oct;7(5):677-83
Date
08/03/2014Pubmed ID
25085919DOI
10.1161/CIRCGENETICS.114.000526Scopus ID
2-s2.0-84925848158 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
BACKGROUND: Bicuspid aortic valve (BAV) is the most common congenital cardiovascular malformation. Although highly heritable, few causal variants have been identified. The purpose of this study was to identify genetic variants underlying BAV by whole exome sequencing a multiplex BAV kindred.
METHODS AND RESULTS: Whole exome sequencing was performed on 17 individuals from a single family (BAV=3; other cardiovascular malformation, 3). Postvariant calling error control metrics were established after examining the relationship between Mendelian inheritance error rate and coverage, quality score, and call rate. To determine the most effective approach to identifying susceptibility variants from among 54 674 variants passing error control metrics, we evaluated 3 variant selection strategies frequently used in whole exome sequencing studies plus extended family linkage. No putative rare, high-effect variants were identified in all affected but no unaffected individuals. Eight high-effect variants were identified by ≥2 of the commonly used selection strategies; however, these were either common in the general population (>10%) or present in the majority of the unaffected family members. However, using extended family linkage, 3 synonymous variants were identified; all 3 variants were identified by at least one other strategy.
CONCLUSIONS: These results suggest that traditional whole exome sequencing approaches, which assume causal variants alter coding sense, may be insufficient for BAV and other complex traits. Identification of disease-associated variants is facilitated by the use of segregation within families.
Author List
Martin LJ, Pilipenko V, Kaufman KM, Cripe L, Kottyan LC, Keddache M, Dexheimer P, Weirauch MT, Benson DWMESH terms used to index this publication - Major topics in bold
AdultAortic Valve
Computational Biology
Exome
Family Health
Female
Genetic Linkage
Genetic Predisposition to Disease
Genetic Variation
Genotype
Heart Valve Diseases
Humans
Male
Models, Genetic
Pedigree
Phenotype
Reproducibility of Results
