Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. (360G-Wellcome-097453_Z_11_Z)

Congenital heart disease (CHD) is one of the most common birth defects. In the left ventricular outflow tract obstruction (LVOTO) subgroup, encompassing bicuspid aortic valve, aortic stenosis, coarctation of the aorta and hypoplastic left heart syndrome or a combination, the disease burden is among the highest. Although heritability analysis have indicated substantial genetic causation, none of the published loci have been shown to explain a high proportion of cases, pointing to genetic heterogeneity. Early studies have relied on findings in individual families, defined small subsets of candidate genes and animal models. Unfortunately, they can only explain a small proportion of the observed phenotypes in humans. We will therefore exome sequence parent- offspring trios with LVOTO and examine the inherited and de novo variants identified in the light of larger CNV datasets to provide further evidence for the role of rare variants in LVOTO. We anticipate to identify known and novel causal genes, the aim is to test these variants in zebrafish. Confident variants and a previously identified causal variant in ADAMTS19 will be studied in detail in conditional knockout mice. Therefore this study holds the potential to identify novel variants and to prevent progression and complications as well as enable prevention of the disease.