Submission Details

Variants in SMAD2 have been reported in individuals with the following disease entities: congenital heart disease, Loeys-Dietz syndrome, and thoracic aortic aneurysm and dissection. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism and phenotypic variability. Therefore, Loeys-Dietz syndrome 6 (MIM: 619656) and familial thoracic aortic aneurysm and dissection (FTAAD) have been lumped into one disease entity, whereas Congenital heart defects, multiple types, 8, with or without heterotaxy (MIM: 619657) remains separate. This current curation will be for the lumped disease entity of SMAD2-related autosomal dominant Loeys-Dietz syndrome and thoracic aortic aneurysm and dissection. The split curation for SMAD2-related autosomal dominant congenital heart disorder has been assessed separately by the ClinGen Congenital Heart Disease GCEP.

SMAD2 was first reported in relation to autosomal dominant inheritance of Loeys-Dietz syndrome (LDS) and thoracic aortic aneurysm and dissection (TAAD) in 2015 when Micha et al. described individuals carrying heterozygous SMAD2 variants affected by aneurysms and dissections in the vertebral arteries and thoracic aorta while also presenting with tall stature, hip dysplasia, ptosis, scoliosis, high palate, and osteoarthrosis (PMID: 26247899).

Evidence supporting this gene-disease relationship includes case-level data and experimental data. Fourteen variants (nine missense, three nonsense, and two frameshift) that have been reported in sixteen probands from five publications (PMIDs: 26247899, 28283438, 29967133, 30157302, 31915033) and five ClinVar submissions (ClinVar IDs: SCV002581277.2, SCV004501205.2, SCV005729311.1, SCV004399167.2, SCV006083335.1) are included in this curation. The nine missense variants reported in patients with arterial or aortic aneurysms are primarily localized to the MH2 domain while the null variants are distributed across all three domains of SMAD2. Only probands with aneurysm or dissection were considered for this curation.

This gene-disease association is also supported by protein interaction, animal model, and expression studies. SMAD2 is ubiquitously expressed in tissues with high expression in aorta and skin tissue (PMID: 23715323, dbGaP Accession phs000424.v10.p2). Using a transgenic mouse model, Xie et al. reported Smad2 deficiency in neural crest cells (NCC) caused reduction in differentiated vascular smooth muscle cell layers along with distortion and thinning of elastic lamina, resulting in thinner vessel walls within carotid arteries of Smad2 NCC-specific knockout mice (PMID: 23817199). Furthermore, coimmunoprecipitation assays by Marcias-Silva et al. showed SMAD2 interacts with TGFBR1, a gene previously determined to be Definitively associated with Loeys-Dietz syndrome and familial thoracic aortic aneurysm and dissections (PMID: 8980228, 9311995).

Using isogenic induced pluripotent stem cells (iPSC) models with heterozygous or homozygous loss-of-function and missense SMAD2 variants, Ward et al. in 2025 (PMID: 40028843) showed SMAD2-mutant iPSCs reduced SMAD2 protein expression and reduced expression of target genes in the TGF‐beta/BMP pathway. However, the variants used in these SMAD2 mutant iPSC models were only reported in patients with clinical presentations of congenital heart disease with no indication of aortopathy (PMID: 40028843). In contrast, Smad2 mRNA upregulation as well as increased phosphorylated Smad2 have been shown in aneurysmal vascular smooth muscle cells (PMID: 19224541). Fukuda et al. (2018, PMID: 29682117) reported increased phosphorylated Smad2 immunostaining in aortic tissues of individuals with thoracic aortic aneurysms while Micha et al. (2015, PMID: 26247899) reported increased levels of both phosphorylated Smad2 and phosphorylated Smad3 in cultured dermal fibroblasts from individuals with SMAD2 missense variants and affected by arterial aneurysms and dissections. However, the direct functional impact of pathogenic variants in SMAD2 on the TGF-beta-signaling Smad2 pathway in aneurysms is unclear. Therefore, the mechanism of pathogenicity of SMAD2-related LDS with thoracic aortic aneurysm and dissection remains to be unclear.

In summary, there is definitive evidence to support the relationship between SMAD2 and autosomal dominant Loeys Dietz Syndrome with thoracic aortic aneurysm and dissection. 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 Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Disease GCEP on August 1st, 2025 (SOP Version 11).