Identification of rare and penetrant gene mutations for bicuspid aortic valve (BAV)

二叶式主动脉瓣（BAV）是最常见的先天性心脏病，并导致主动脉夹层、主动脉瓣狭窄和主动脉瓣关闭不全，这是发病率和死亡率的显著原因。从遗传学上讲，BAV代表了一种异质性表型，包括具有中度影响的常见风险变异和具有更明显影响的罕见突变。我们建立了科学网络GUARD（www.guard-net.de）。通过GUARD，我们可以访问欧洲最大的生物样本库，其中包括来自1,000多名BAV患者的DNA样本，以及详细的临床信息。使用该样本，我们最近进行了一项全基因组关联研究（GWAS），从而确定了常见的BAV风险变异。GWAS的发现目前得到了斑马鱼功能研究的补充，斑马鱼是一种研究心血管发育的成熟动物模型。在这个项目中，我们的目标是检测BAV发展的遗传因素的全谱，包括新的罕见和渗透突变。为此，我们将使用来自GUARD的500例BAV患者进行全外显子组测序（WES）分析，这些患者富集了一级亲属中具有额外先天性心脏缺陷和/或先天性心脏缺陷的病例。随后，最有希望和新鉴定的BAV疾病基因将在剩余的BAV患者和受影响的一级亲属中进行测序。这将证实基因在BAV发育中的作用。此外，使用详细的临床数据和受影响的一级亲属将允许定义由BAV疾病基因/突变引起的表型谱，并探索其在家庭背景中的相关性。最后，我们将在功能上的特点，选择BAV疾病基因的影响流出道瓣膜发育，采用全面的敲除实验在斑马鱼。总之，我们项目的结果将为BAV发展中涉及的病理生理机制提供深入见解，并将允许定义由BAV疾病基因/突变引起的临床谱。

Bicuspid aortic valve (BAV) is the most common congenital heart disease and leads to aortic dissection, aortic valve stenosis and aortic insufficiency in later life, which represent a notable cause of morbidity and mortality. Genetically, BAV represents a heterogeneous phenotype involving common risk variants with moderate effects and rare mutations with more penetrant effects. We have established the scientific network GUARD (www.guard-net.de). Through GUARD we have access to the largest biobank in Europe comprising DNA samples from > 1,000 BAV patients with detailed clinical information. Using this sample, we have recently conducted a genome-wide association study (GWAS) which led to the identification of common BAV risk variants. The GWAS findings are currently complemented by functional studies in zebrafish, a well-established animal model for studying cardiovascular development. Within this project we aim at detecting the full spectrum of genetic factors underlying BAV-development including novel rare and penetrant mutations. For this, we will perform whole exome sequencing (WES) analyses using 500 BAV patients from GUARD, which are enriched for cases with additional congenital heart defects and/or congenital heart defects in first-degree relatives. Subsequently, the most promising and newly identified BAV disease genes will be sequenced in the remaining BAV patients and affected first-degree relatives. This will confirm the contribution of the genes in BAV-development. Furthermore, using the detailed clinical data and affected first-degree relatives will allow to define the phenotypic spectrum that is caused by BAV disease genes/mutations as well as to explore their relevance in the family context. Finally, we will functionally characterize the effect of selected BAV disease genes on the outflow tract valvulogenesis using comprehensive knock-down experiments in zebrafish. In summary, the results of our project will provide deep insights into the pathophysiological mechanisms involved in BAV development and will allow to define the clinical spectrum that is caused by BAV disease genes/mutations.