SMAD6 was first reported in relation to autosomal dominant syndromic craniosynostosis in 2016 (Timberlake et al., PMID: 27606499). Syndromic craniosynostosis is the presentation of craniosynostosis with congenital heart defects and/or radioulnar synostosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in [molecular mechanism and inheritance pattern. Variants in SMAD6 causing Aortic valve disease, craniosynostosis, and radioulnar synostosis were located throughout the gene. Reports have also shown various syndromic presentations of SMAD6 variants. Therefore, the following disease entities have been lumped into one disease entity, Aortic Valve Disease 2 (OMIM:614823), Craniosynostosis 7 (OMIM:617439), and Radioulnar Synostosis (OMIM:179300). 28 variants (missense, nonsense, and frameshift) that have been reported in 28 probands in 3 publications (PMIDs: 34953066, 32499606, 27606499) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by animal models and expression studies (PMIDs: 21681813, 10655064). SMAD6 was found to be expressed in developing cardiac tissue and bones, and mice deficient in SMAD6 were found to exhibit phenotypes similar to Aortic Valve Disorder and Craniosynostosis. In summary, SMAD6 is definitively associated with autosomal dominant syndromic craniosynostosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 06/15/2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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