A novel SMAD6 variant in a patient with severely calcified bicuspid aortic valve and thoracic aortic aneurysm

Background: Bicuspid aortic valve (BAV) is the most common congenital heart defect with a prevalence of 1%–2% in the general population. NOTCH1, SMAD6, and GATA5 are associated with BAV in humans, but few cases have been reported that did not involve NOTCH1. Here, we identified novel in-frame variants in SMAD6 (c.1168_1173dup; p.Gly390_Ile391dup) in a BAV patient, who presented with dilatation of the ascending aorta and severe calcification of the aortic valve. Methods: Twenty BAV associated genes were screened by exome sequencing. Functional effects of SMAD6 variant were investigated using bone morphogenetic protein (BMP) signaling assays through in vitro functional study. Results: Exome sequencing revealed he had novel in-frame variants in the SMAD6 gene (c.1168_1173dup; p.Gly390_Ile391dup). SMAD6 is known to be an inhibitory protein in the BMP signaling pathway. In vitro functional study of the p.Gly390_Ile391dup variant revealed impaired inhibition of BMP signaling and BMP-induced alkaline phosphatase activity. Conclusion: In conclusion, we identified a novel SMAD6 variant causing a severely calcified BAV and TAA, which contributes to our understanding of the clinical and genetic background of SMAD6-related BAV.