Indexed on: 21 Mar '19Published on: 09 Mar '19Published in: Molecular Genetics & Genomic Medicine
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. 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. 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. 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. © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.