Whole Exome Sequencing for Familial Bicuspid Aortic Valve Identifies Putative Variants

Abstract

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. (Circ Cardiovasc Genet. 2014;7:677-683.)

Trends in Congenital Heart Disease

“…Using techniques such as whole genome sequencing, the role of noncoding sequences of the genome that regulate gene transcription is likely to further add to our understanding of genetic determinants of CHD, and the identification of DNA variants in cardiac transcription factor binding sites, enhancers, promoters, and other regulatory elements in causing CHD. [30][31][32] Transcriptome analyses of discarded CHD tissues may disclose transcriptional changes that accompany abnormal hemodynamic load and define posttranscriptional RNA processing that regulates cardiac development. [33][34][35][36][37] We can expect the future to bring the identification of new classes of CHD mutations and novel insights into the pathways that these mutations impact and a better understanding of genes that modify the responses to hemodynamic and environmental stress, as well.…”

Bicuspid aortic valve syndrome: a multidisciplinary approach for a complex entity

“…The inability to identify simple mendelian loci with whole-exome approaches may suggest a polygenic influence rather than simply incomplete penetrance (31).…”

Genetics of congenital heart disease: the contribution of the noncoding regulatory genome

“…However, this variant was identified in all but one affected family member. Likewise, Martin et al 43 failed to identify the causal variant in a multiplex family with bicuspid aortic valve and other cardiovascular malformations using WES. They could not find a single likelycausal coding variant shared by all affected.…”