Genetic Etiology of Bicuspid Aortic Valve Disease

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DESCRIPTION (provided by applicant): Bicuspid aortic valve (BAV) is the most frequent congenital cardiac malformation, occurring in 0.5-1.2% of the US population. Over 50% of patients with BAV develop early calcific aortic valve stenosis or incompetence in their lifetime and accounts for ~40% of the >30,000 aortic valve replacements (AVRs) performed in the US each year. Yet, we know little of the etiology, cellular biology and modifiers of disease progression for BAV to aortic valve stenosis and incompetence, and thoracic aortic aneurysm/dissection. Therefore, a critical goal of the proposed studies is to elucidate the genetic pathways involved in BAV pathology. There is very strong evidence for heritability of BAV, with estimates as high as 89%. In a few families, highly-penetrant dominant mutations of NOTCH1 have been associated with BAV. Additional susceptibility loci have also been identified but not replicated. However, a majority of individual with BAV do not report family members with BAV and ~94% do not possess a NOTCH1 mutation. We therefore aim to identify the genetic cause(s) of BAV by utilizing multiple cohorts of individuals with BAV who have, and have not, undergone AVR. The purpose of identifying BAV-associated mutations by whole-exome sequencing and subsequent genotyping is to establish the cause of BAV and importantly, the genetic background on which the clinical consequences of BAV are based, thus focusing research on pathways to attenuate the risk of calcific aortic valve disease in adulthood. We will support and expand the findings of sequencing and genotyping efforts by investigating the embryologic molecular biology of BAV, using Zebrafish morpholino models to mimic the identified human mutation(s). We will to attempt to identify genetic and non-genetic factors that impact on the progression of BAV calcific aortic valve disease using three methods. First, we will use BAV cohorts who have, and have not yet, undergone AVR for calcific aortic stenosis, to identify clinical and genetic factors that determine progression of aortic valve calcification. We will investigate these factors in an already-developed aging mouse GATA5 knockout model. The GATA5 knockout mouse has a 25% BAV penetrance, thus allowing investigation of the factors that alter calcification of the BAV on a common genetic background. We will also use a collection of human calcified aortic valve tissue from bicuspid and tricuspid aortic valves to identify expression differences between these different hemodynamic and genetic backgrounds. Our over-arching purpose is identification of genetic causes of bicuspid aortic valve disease and its subsequent calcific aortic stenosis. We believe that the RFA and this proposal provide a credible and best mechanism for attacking the issue of calcific aortic stenosis with BAV. We believe these methods will allow for critical advances in BAV research and potentially, patient management. (End of Abstract)