Bicuspid aortic valve (BAV) is the most common congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that specific gene variants predispose to early-onset complications of BAV (EBAV). We analyzed whole-exome sequences (WESs) to identify rare coding variants that contribute to BAV disease in 215 EBAV-affected families. Predicted damaging variants in candidate genes with moderate or strong supportive evidence to cause developmental cardiac phenotypes were present in 107 EBAV-affected families (50% of total), including genes that cause BAV (9%) or heritable thoracic aortic disease (HTAD, 19%). After appropriate filtration, we also identified 129 variants in 54 candidate 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 drive early-onset presentations of BAV disease.

中文翻译：

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全外显子组测序揭示了早发性并发症家系二叶式主动脉瓣的遗传复杂性


二叶式主动脉瓣 （BAV） 是最常见的先天性心脏病病变，估计人群患病率为 1%。我们假设特定基因变异易患 BAV 早发并发症 （EBAV）。我们分析了全外显子组序列 （WES），以鉴定导致 215 个 EBAV 影响家庭中 BAV 疾病的罕见编码变异。在 107 个受 EBAV 影响的家庭 （占总数的 50%） 中存在具有中等或强烈支持证据的候选基因的预测破坏性变异，包括导致 BAV （9%） 或遗传性胸主动脉疾病 （HTAD， 19%） 的基因。经过适当的过滤，我们还在 54 个候选基因中鉴定了 129 个与常染色体显性遗传先天性心脏病表型相关的变异，包括 FBN2 、 MYH6 、 通道病基因以及 1 型和 5 型胶原基因的复发性有害变异。这些发现证实了我们的假设，即独特的罕见遗传变异驱动 BAV 疾病的早发性表现。