Bicuspid aortic valve (BAV), which affects 1% of the general population, is the most common congenital valvular heart disorder. In affected individuals, the aortic valve (the structure that allows blood to flow from the left ventricle to the aorta) consists of two rather than three leaflets. Despite usually having a benign presentation, BAV is associated with serious cardiovascular complications later in life including aortic valve stenosis, aneurysm of the thoracic aorta and infective endocarditis. More than 50% of patients with BAV need an open-heart surgery during their lifetime.
BAV clusters within families following an autosomal dominant pattern of inheritance and causative mutations in several genes including NOTCH1, TGFBR2, GATA5 and SMAD6 have been identified, however, mutations in these genes only explain a small proportion of BAV cases. In addition, up to 85% of all BAV patients are sporadic i.e. do not have any affected relatives. The reason for this phenomenon has not been elucidated but incomplete penetrance of genetic variants and variable clinical presentation of the disease have been hypothesized.
We have recruited a large cohort of patients with BAV as part of the University of Leicester NIHR Bicuspid aoRtic vAlVe gEnetic research (BRAVE) study. The BRAVE cohort comprises more than 700 patients with sporadic BAV disease and over 20 extended pedigrees with multiple affected members. In this PhD the student will utilise this resource to identify new genes causing BAV via analysis of new sequencing data, perform functional validation and characterisation analyses of novel BAV genes and screen patients with sporadic disease to gain a better understanding of penetrance of BAV causal mutations.
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