A roadmap to investigate the genetic basis of bicuspid aortic valve and its complications: insights from the International BAVCon (Bicuspid Aortic Valve Consortium)

Abstract

Bicuspid aortic valve (BAV) is the most common adult congenital heart defect and is found in 0.5% to 2.0% of the general population. The term "BAV" refers to a heterogeneous group of disorders characterized by diverse aortic valve malformations with associated aortopathy, congenital heart defects, and genetic syndromes. Even after decades of investigation, the genetic determinants of BAV and its complications remain largely undefined. Just as BAV phenotypes are highly variable, the genetic etiologies of BAV are equally diverse and vary from complex inheritance in families to sporadic cases without any evidence of inheritance. In this paper, the authors discuss current concepts in BAV genetics and propose a roadmap for unraveling unanswered questions about BAV through the integrated analysis of genetic and clinical data.

Keywords: bicuspid; consortium; roadmap; valve.

FIGURE 1. Genetic Variants on the Spectrum

(A) The diversity of genetic variants in the human genome. (Left) A single-nucleotide variant at a specific location in the genome in 2 different individuals. Single-nucleotide variants are classified as single-nucleotide polymorphisms (SNPs), which are found in 1% or more of the general population, or rare variants, including disease-causing mutations. (Right) A chromosomal duplication that results in a copy gain of a chromosomal segment. Structural variants in the human genome include copy-number variants (CNVs) such as duplications and deletions, as well as copy-neutral events such as inversions and translocations. (B) The genetic spectrum of bicuspid aortic valve (BAV) disease. The allele frequency equals the proportion of subjects harboring a genetic variant. Single-gene disorders with high penetrance tend to cause genetic syndromes with BAV or familial forms of BAV. Rare mutations such as CNVs are expected to cause early onset forms of BAV with severe manifestations but may not be recognizable as genetic syndromes. Common variation in genes that regulate aortic valve calcification or connective tissue integrity can modify the phenotype of BAV disease progression but are unlikely to cause disease on their own. Any combination of these variants may predispose to BAV in individual cases. TAAD = thoracic aortic aneurysms and dissections. Figure 1B is adapted from McCarthy MI, Abecasis GR, Cardon LR, et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 2008;9:356–69.

FIGURE 2. Experimental Designs to Identify Disease-Causing and Susceptibility Genetic Variants

(A) Example of a 3-generation pedigree with autosomal-dominant inheritance. Affected patients are gray. Mutation carriers (MT) and subjects without mutations (WT) are highlighted in red and green, respectively. In this instance, the penetrance of the mutation is complete, and the mutant gene can be mapped to a segment of the genome using linkage analysis. (B) Example of a trio. De novo mutations in the affected offspring that are not found in the parents may be prioritized for analysis in independent groups of cases. In this situation, the penetrance of the phenotype in the parents is uncertain and may confound the results. (C) Example of a case-control association study. The genotypes of large groups of cases (gray) and controls (white) are compared at sites across the genome. The red border identifies subjects who carry the risk allele that is being tested for association. Variants that are enriched in cases compared with controls are considered to be associated with the disease. In this case, there is a 4-fold enrichment of the variant among the cases compared with controls.

CENTRAL ILLUSTRATION. Roadmap to Translate Genetic Discoveries Into Clinical Applications

“Knock-out” models include tissue-specific and whole-organism deletion of genes. “Knock-in” models are generated by introducing a specific human sequence variant into an orthologous gene. In real time, these processes would most likely occur simultaneously. CNV = central nervous system; GWA = genome-wide analysis.