Whole Exome Sequencing Uncovers the Genetic Complexity of Bicuspid Aortic Valve in Families with Early Onset Complications

Abstract

Bicuspid Aortic Valve (BAV) is the most common adult congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that early onset complications of BAV (EBAV) are driven by specific impactful genetic variants. We analyzed whole exome sequences (WES) to identify rare coding variants that contribute to BAV disease in 215 EBAV families. Predicted pathogenic variants of causal genes were present in 111 EBAV families (51% of total), including genes that cause BAV (8%) or heritable thoracic aortic disease (HTAD, 17%). After appropriate filtration, we also identified 93 variants in 26 novel genes that are associated with autosomal dominant congenital heart phenotypes, including recurrent deleterious variation of FBN2, MYH6, channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants contribute to early onset complications of BAV disease.

Keywords: Bicuspid Aortic Valve; Cardiovascular Genetics; Congenital Heart Disease; Thoracic Aortic Aneurysm; Whole Exome Sequencing.

Figure 1:. Distribution of predicted deleterious variants in 111 EBAV families and in candidate genes.

A. Distribution of variants in EBAV families; B. Distribution of variants in candidate genes.

Figure 2:. Filtration workflow to select candidate EBAV variants.

The initial seqr project variant search generated 4790 candidates. Missense variants that were not rated as deleterious by at least three functional predictors, had normalized CADD scores < 20, and had the same base position in two different families were removed. We prioritized novel genes that had predicted deleterious variants in three or more families. We removed genes that are known to cause recessive or noncardiac phenotypes.

Figure 3.. Enrichment of EBAV candidate gene variants.

The number of rare deleterious loss of function and missense variants, selected according to the criteria defined in the Methods, were compared to the number of variants with equivalent functional classifications from European ancestry populations in gnomAD v2. Circles: enrichment vs. gnomAD (0–100X); horizontal lines: 95% confidence intervals; orange boxes: segregates with BAV in more than one EBAV family; purple boxes: also enriched in JRRP and GenTAC datasets; red boxes: at least one de novo variant.

Figure 4.. Gene ontology enrichment analysis of EBAV candidate genes.

Plot was generated using Over-Representation Analysis of gene ontologies in WebGestalt 2019. The −log10 of false discovery rates (FDR) were plotted against the log2 of enrichment ratios.