Martin LJ, Pilipenko V, Kaufman KM, Cripe L, Kottyan LC, Keddache M, Dexheimer P, Weirauch MT, Benson DW
BACKGROUND: -Bicuspid aortic valve (BAV) is the most common congenital cardiovascular malformation (CVM). 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 (WES) a multiplex BAV kindred. METHODS AND RESULTS: -WES was performed on 17 individuals from a single family (BAV = 3, other CVM = 3). Post variant calling error control metrics (ECM) 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 ECM, we evaluated three variant selection strategies frequently used in WES studies plus extended family linkage. No putative rare, high impact variants were identified in all affected but no unaffected individuals. Eight high impact variants were identified by at least two 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. On the other hand, using extended family linkage three noncoding variants were identified; all three variants were identified by at least one other strategy. CONCLUSIONS: -These results suggest that traditional WES 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 utilization of segregation within families.