Abstract
BackgroundBicuspid 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.MethodsTwenty 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.ResultsExome 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.ConclusionIn 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.
Highlights
Bicuspid aortic valve (BAV) is the most common congenital heart defect with a prevalence of 1%–2% in the general population (Michelena et al, 2014)
BAV is often associated with the occurrence of other cardiac manifestations such as a thoracic aortic aneurysm (TAA) or coarctation of the aorta (CoA) (Prakash et al, 2014)
We found that the SMAD6 in‐frame variant is related to severe calcification in the aortic valve
Summary
Bicuspid aortic valve (BAV) is the most common congenital heart defect with a prevalence of 1%–2% in the general population (Michelena et al, 2014). NOTCH1, SMAD6, and GATA5 have been known to be associated with BAV, but only a few human cases have been. Recent study using variant burden analysis had suggested that SMAD6 could be a significant contributor of BAV associated TAA in patients (Gillis et al, 2017). 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. We found that the SMAD6 in‐frame variant is related to severe calcification in the aortic valve
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