Genetic abnormalities in bicuspid aortic valve root phenotype: preliminary results

OBJECTIVES: Genetic defects associated with bicuspid aortopathy have been infrequently analysed. Our goal was to examine the prevalence of rare genetic variants in patients with a bicuspid aortic valve (BAV) with a root phenotype using next-generation sequencing technology. METHODS: We investigated a total of 124 patients with BAV with a root dilatation phenotype who underwent aortic valve +/- proximal aortic surgery at a single institution (BAV database, n = 812) during a 20-year period (1995-2015). Cross-sectional follow-up revealed 63 (51%) patients who were still alive and willing to participate. Systematic follow-up visits were scheduled from March to December 2015 and included aortic imaging as well as peripheral blood sampling for genetic testing. Next-generation sequencing libraries were prepared using a custom-made HaloPlex HS gene panel and included 20 candidate genes known to be associated with aortopathy and BAV. The primary end-point was the prevalence of genetic defects in our study cohort. RESULTS: A total of 63 patients (mean age 46 +/- 10 years, 92% men) with BAV root phenotype and mean post-aortic valve replacement follow-up of 10.3 +/- 4.9 years were included. Our genetic analysis yielded a wide spectrum of rare, potentially or likely pathogenic variants in 19 (30%) patients, with NOTCH1 variants being the most common (n = 6). Moreover, deleterious variants were revealed in AXIN1 (n = 3), NOS3 (n = 3), ELN (n = 2), FBN1 (n = 2), FN1 (n = 2) and rarely in other candidate genes. CONCLUSIONS: Our preliminary study demonstrates a high prevalence and a wide spectrum of rare genetic variants in patients with the BAV root phenotype, indicative of the potentially congenital origin of associated aortopathy in this specific BAV cohort.