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

二叶式主动脉瓣 (BAV) 罕见和渗透性基因突变的鉴定

• 批准号: 458896325
• 负责人: Professor Dr. Peter Krawitz
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/458896325?language=en
• 关键词: Identification; rare; penetrant; gene; mutations

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.

双刺主动脉瓣（BAV）是最常见的先天性心脏病，可导致主动脉夹层，主动脉瓣狭窄和后来的主动脉症不足，这是发病率和死亡率的显着原因。从遗传上讲，BAV代表了一种异质表型，涉及具有中等影响和稀有突变具有更渗透作用的常见风险变体。我们已经建立了科学网络卫队（www.guard-net.de）。通过警卫，我们可以进入欧洲最大的生物库，其中包括> 1,000名BAV患者的DNA样品，并具有详细的临床信息。使用此样本，我们最近进行了全基因组关联研究（GWAS），该研究导致了公共BAV风险变异的鉴定。 GWAS的发现目前与斑马鱼的功能研究相辅相成，斑马鱼是一种研究心血管发育的良好动物模型。在该项目中，我们旨在检测BAV开发基础的全部遗传因素，包括新型稀有和渗透突变。为此，我们将使用来自Guard的500名BAV患者进行整个外显子组测序（WES）分析，这些患者富含一级亲属的额外先天性心脏缺陷和/或先天性心脏缺陷的病例。随后，将在其余的BAV患者中测序最有前途和最新的BAV疾病基因并影响一级亲戚。这将确认基因在BAV开发中的贡献。此外，使用详细的临床数据和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，并在家庭环境中探索其相关性。最后，我们将使用斑马鱼中的综合敲低实验来表征选定的BAV疾病基因对流出瓣膜发生的影响。总而言之，我们项目的结果将为BAV发育中涉及的病理生理机制提供深入的见解，并将允许定义由BAV疾病基因/突变引起的临床光谱。