Genetic Basis of Early Onset Bicuspid Aortic Valve Disease

二叶式主动脉瓣（BAV）可因主动脉瓣狭窄而导致过早死亡， 导致急性主动脉夹层的主动脉瓣返流或胸主动脉瘤 （TAAD）。BAV的遗传原因在很大程度上仍然是未知的，由于大量的 BAV相关并发症的遗传和临床异质性。我们确定 罕见的拷贝数变异体（CNVs）在BAV患者中显著富集， 出现早期临床并发症。我研究的总体目标是 确定负责BAV及其 并发症，并建立与每种并发症相关的临床表型 新基因我的建议的具体目标是：1）表征一组BAV 有严重和早发性并发症的患者，2）识别罕见的CNV， 与严重的BAV相关并发症相关，以及3）识别罕见外显子组 具有严重表型或独特临床特征的患者中的序列变异， 有父母或受影响的亲属。我们的发现可以提供新的见解 BAV疾病的病因学，也可能有助于风险分层或临床 关于BAV患者的监测和选择性干预的决策。

Bicuspid Aortic Valves (BAV) can cause premature deaths due to aortic stenosis, aortic regurgitation or Thoracic Aortic Aneurysms leading to acute aortic Dissections (TAAD). The genetic causes of BAV remain largely unknown due to the substantial genetic and clinical heterogeneity of complications related to BAV. We determined that rare Copy Number Variants (CNVs) are significantly enriched in BAV patients who experienced early onset clinical complications. The overall goal of my research is to identify causal genetic variants that are responsible for both the BAV and its complications, and to establish the clinical phenotypes that are associated with each new gene. The specific aims of my proposal are: 1) to characterize a cohort of BAV patients with severe and early onset complications, 2) to identify rare CNVs that are associated with severe BAV-related complications and 3) to identify rare exome sequence variants in patients with severe phenotypes or distinctive clinical features who have available parents or affected relatives. Our discoveries could provide new insights into the etiology of BAV disease and may also be useful for risk stratification or clinical decision-making about surveillance and elective interventions for BAV patients.