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

Eur J Hum Genet. 2019 Jul;27(7):1044-1053. doi: 10.1038/s41431-019-0363-z. Epub 2019 Feb 22.


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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aneurysm, Dissecting / genetics*
  • Aortic Aneurysm, Thoracic / genetics*
  • Aortic Valve / abnormalities*
  • Bicuspid Aortic Valve Disease
  • Bone Morphogenetic Protein 2 / genetics
  • Craniosynostoses / genetics
  • Female
  • Genetic Variation*
  • Heart Valve Diseases / genetics*
  • Humans
  • Male
  • Middle Aged
  • Smad6 Protein / genetics*


  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • SMAD6 protein, human
  • Smad6 Protein