SMAD6, originally identified inmammals by homology-based cloning,5,6encodes one of two (with SMAD7) inhibitory members of the SMAD family required forregulated intracellular signal transduction by members of the transforming growthfactor β/bone morphogenetic protein (TGFβ/BMP) superfamily.7–9 Intriguingly, enrichment ofrare SMAD6 variants has also been reported inassociation with several other distinct phenotypes, namely congenital heartdisease,10–12 bicuspid aortic valve (BAV) and ascendingthoracic aortic aneurysm (TAA),13–15 intellectualdisability,16 and radioulnarsynostosis.17 The gene discussed is SMAD6; the disease is Bicuspid aortic valve.