Bicuspid aortic valve (BAV) is the most common congenital heart defect and its prevalence is estimated around 1% of the population. 50 to 70% of BAV are associated with ascending aorta dilatation. The issue of hemodynamic or genetic determinism of both conditions is still a matter of debate.

The aim of this study was to describe the genetic profile of 4 different families presenting with BAV and aortopathy (AP).

We included 4 families with BAV+AP from a prospective, mono-centric cohort of 381 BAV patients included from January 2014 to January 2020. We performed a whole exome sequencing of all index patients and available relatives in order to identify candidate genes, using the Varaft program. Once identified, polymerase chain reaction (PCR) were carried out in the remaining first-degree relatives to perform a segregation analysis. In case of a novel single nucleotide variant, in vitro models were used to examine its functional effect.

Family A includes 2 affected members linked to mutation in one gene implicated in the endothelial to mesenchymal transition (EMT) of the endothelial cells, not found in two unaffected relatives. In vitro culture using fibroblast from index patient confirmed the mutation involvement in loss of gene function. Family B includes 2 affected members with mutation in one gene known to activate the NOTCH signaling pathway implicated in EMT. Family C includes 2 members with a rare stop-gain variant in gene coding for one extracellular matrix protein essential for the structure of the aortic valve and ascending aorta. Family D includes 3 members with mutation in one gene involved in connective tissue disease.

Among a French prospective cohort of 381 BAV patients we identify 4 different families with non-syndromic BAV+AP. Whole exome sequencing analysis allows to reveal 4 distinct mutations of genes implicated in the EMT, the extracellular matrix structure and connective tissue disease.