SMAD2 was first reported in relation to autosomal dominant congenital heart disease in 2017 (Jin et al., PMID 28991257). At least 9 rare variants (4 missense, 5 loss-of-function) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. SMAD2 has been noted to be associated with the following disease entities: atrial septal defect, ventricular septal defect, dextrocardia, atrial isomerism, double-outlet right ventricle, unbalanced complete atrioventricular canal, unbalanced right-dominant complete atrioventricular canal, pulmonary stenosis, pulmonary atresia, mitral atresia and hypoplastic left ventricle (OMIM 619657). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. Therefore, these disease entities have been lumped into one disease entity, Autosomal Dominant SMAD2-related Congenital Heart Disorders with or without Heterotaxy. Variants in this gene have been reported in at least 9 probands in 9 publications (PMIDs 28991257, 36803080, 30157302, 30622330, 29786156, 34328347), using an allele frequency threshold of 1x10-5. This gene-disease relationship is supported by animal models, expression studies, and functional assays. Expression studies confirmed that SMAD2 is expressed during mouse embryogenesis (PMID 24064296). Multiple mouse models of congenital heart disease had abnormal SMAD2 expression and/or phosphorylation (PMIDs 15528466, 33801433, 18952608, 26821812, 35894043). Hypomorphic alleles of Smad2 resulted in impaired mouse embryo formation (PMID 12432092), while overexpression led to increased cardiac differentiation (PMID 27818139). In summary, there is strong evidence to support this gene-disease relationship. The association has been replicated over time, supporting a definitive gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 11/6/23 (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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.