In the case of thoracic aortic disease associated with a bicuspid aortic valve, is genetic screening appropriate?

Background Bicuspid aortic valve (BAV) affects more than 1% of the general population, mainly men, and is associated with dilation of the ascending aorta in half of cases. BAV may be more common in hereditary thoracic aortic diseases (HTAD), mainly in syndromic forms linked to a pathogenic variation in the TGFbeta pathway. In addition, thoracic aortic disease (TAD) and/or BAV are not uncommon in first-degree relatives of individuals with BAV. The question of whether genetic testing should be performed in patients with BAV associated with a non-syndromic form of thoracic aortic disease remains to be determined. Objectives To assess the prevalence of likely pathogenic or pathogenic (LP/P) variants in individuals with BAV and thoracic aortic disease, namely dissection or dilation of the ascending aorta, and without extra-aortic signs suggestive of Marfan syndrome or HTAD. Methods Consecutive individuals with BAV and TAD (history of ascending aortic dissection, surgery for ascending aortic dilation, or ascending aortic enlargement with a Z-score > 2) underwent clinically evaluation for the diagnosis of MFS or a related disorder and were offered genetic testing. Individuals without clinical suspicion of MFS or related disorders, presenting with BAV and TAD and who underwent genetic testing were included in this analysis. Results 189 individuals were included in this analysis. This cohort consisted mainly of men (145/189; 76%) with a mean age of 48.8 ± 14.9 years. The predominant morphology of the BAV was a fused BAV with 3 sinuses and a right-left cup fusion (99/189; 52.3%). The median diameter of the root and ascending aorta was 42.0 ± 7.5 mm and 42.0 ± 8.1 mm, respectively. Eight patients had a history of aortic dissection and 36 had a history of preventive surgery. LP/P variants were present in only 6/189 patients (3.1%): FBN1 in 3, MFAP5 in 1, COL5A1 in 1, and FBN2 in 1. Variants of unknown significance were found in 14/189 (7.4%). In 5 of the 6 patients with LP/P variants, positive family history would have led to genetic testing anyway. Only one patient, with no extra-aortic features or family history, was found to carry a pathogenic missense variant in the FBN1 gene. Conclusion In individuals with BAV and thoracic aortic disease, namely dissection or dilation of the ascending aorta, who have no extra-aortic signs or family history of thoracic aortic disease, likely pathogenic or pathogenic variants are rare. In this context, systematic genetic screening seems inappropriate.