Confirmation of the role of pathogenic SMAD6 variants in bicuspid aortic valve-related aortopathy

Item does not contain fulltext Progressive dilatation of the thoracic aorta leads to thoracic aortic aneurysm (TAA), which is often asymptomatic but predisposes to lethal aortic dissections and ruptures. TAA is a common complication in patients with bicuspid aortic valve (BAV). Recently, rare loss-of-function SMAD6 variants were shown to contribute significantly to the genetic aetiology of BAV/TAA. Intriguingly, patients with craniosynostosis have also been reported to be explained molecularly by similar loss-of-function SMAD6 variants. While significantly reduced penetrance of craniosynostosis has been reported for the SMAD6 variants as such, near-complete penetrance is reached upon co-occurrence with a common BMP2 SNP risk allele. Here, we report on the results of a SMAD6-variant analysis in 473 unrelated non-syndromic TAA patients, of which the SMAD6-positive individuals were also studied for the presence of the BMP2 risk allele. Although only 14% of the TAA patients also presented BAV, all novel likely pathogenic SMAD6 variants (N = 7) were identified in BAV/TAA individuals, further establishing the role of SMAD6 variants to the aetiology of BAV/TAA and revealing limited contribution to TAA development in patients with a tricuspid aortic valve. Familial segregation studies confirmed reduced penetrance (82%) and variable clinical expressivity, with coarctation of the aorta being a common comorbidity. None of our six BMP2+/SMAD6+ patients presented with craniosynostosis. Hence, the proposed digenic model for craniosynostosis was not supported in the presented BAV/TAA cohort, suggesting that additional factors are at play. Finally, our data provide improved insights into the clinical spectrum of SMAD6-related BAV/TAA and has important implications for molecular diagnostics.