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

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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.