Fig. 1: Graphical representation of identified heterozygous SMAD6 variants in probands with bicuspid aortic valve-related aortopathy, congenital heart disease, (non-)syndromic craniosynostosis and non-syndromic radioulnar synostosis.

SMAD6 protein has several domains: MH1-domain (grey; inhibitory effect on signalling), PY motif (orange), PLDLDS motif (yellow), MH2-domain (grey; inhibitory effect on signalling) and L3-loop (blue; determines specificity for interaction with type I receptors)^88,89. Of note: (1) all variants were called “pathogenic” in the original publications but there is different criteria for calling “pathogenicity” (e.g., by applying different allele frequency thresholds, and/or using specific functional tests); (2) identical protein changes (underlined) are described in patients with distinctive phenotypes.