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Molecular insights into bicuspid aortic valve development and the associated aortopathy

Center of Medical Genetics, Faculty of Medicine and Health Sciences University of Antwerp and Antwerp University Hospital, Antwerp, Belgium

Bicuspid Aortic valve (BAV) is one of the most common congenital cardiac malformations with a prevalence of 1–2% in the general population. Patients with BAV have a 9-fold increased risk of developing serious secondary complications including stenosis, endocarditis, regurgitation, dilation of the aorta, aortic aneurysms and subsequent dissection resulting in a significant increase in morbidity. Progressive decline in valve functionality and associated complications warrants surgical intervention in 27% of the affected individuals. The understanding of genetic and molecular mechanisms underlying disease pathology has been largely confounded by phenotypic heterogeneity, incomplete penetrance and variable expressivity. Additionally, the complex interplay between genetic, epigenetic and haemodynamic factors during and after development along with their dynamic expression depending on tissue type contribute to the elusiveness of the disease. While the exact mechanism of pathogenesis remains unclear, recent advances in genetics, propelled by large scale candidate gene discovery strategies employing next generation sequencing, epigenetics, haemodynamic modelling and imaging have provided insights into the development of BAV and associated aortopathy, thus accelerating advances in clinical management and diagnosis of the disease. This review aims at providing a comprehensive understanding of cardiac valve development and the underlying genetic and molecular mechanisms contributing to BAV associated aortopathy.
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