ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000015.9) (NC_000015.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
30661052 Hostetler et al. (2019) examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of 212 individuals with 51 SMAD3 variants, including more than 10 nonsense, partial gene deletions and frame shift variants, as well as many missense and in-frame variants in MH2 and MH1 domain of the gene. Aortic events were documented in 37% of cases, with dissections accounting for 70% of events. The median age at first aortic event was significantly lower in individuals with SMAD3 MH2 missense variants than those with haploinsufficient variants (42 years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type.
29907982 Overwater et al. (2018) did a targeted NGS analysis of 21 Hereditary Thoracic Aortic Disease (H?TAD) associated genes, including SMAD3 in 810 suspected patients. Out of 66 patients with pathogenic or likely pathogenic variant, 11 patients (11.7%) had SMAD3 variants (3 frame shift, 1 splicing, an in-frame deletion in exon 6 (part of MH2 domain) and a loss of initiation codon). Regarding the in-frame deletion of exon 6 was likely familial since the Proband's father and paternal grandmother were both affected and died in their 30s.
29392890 Schepers et al. (2018) did a case review study of patients with reported and novel SMAD2/3 and TGFB2/3 variants, and summarized diagnostic criteria in the absence of known family history of LDS. Among the novel variants were multiple nonsense, frame shift and splicing variants in SMAD3 gene.

Haploinsufficiency phenotype comments:

Many other HI variants have been reported and listed in HGMD database, for example: Nevidomskyte et al (2017)(PMID: 28286188) reported 2 sisters with splicing variant of SMAD3 gene who both had internal mammary artery aneurysms. Courtois et al. (2017) (PMID:28185953) reported a frame shift variant in SMAD3 gene in a patient with multiple visceral arteries and abdominal aortic aneurysms but without dissection of the thoracic aorta and without any sign of osteoarthritis. The same mutation was found in the proband's mother and sister who had open surgery for abdominal aortic aneurysm and in one of his children. van de Laar 2011 (PMID: 21217753): Three pathogenic SMAD3 variants associated with aortic dissection/aneurysm were described in independent families. One was a 2bp deletion leading to a frameshift and premature termination at exon7 (removing nearly all of the MH2 oligomerization domain). This variant segregated faithfully in 22 family members, though not all reported aortic involvement. The truncated mRNA was shown to be sensitive to nonsense-mediated RNA decay, suggesting a haploinsufficiency mechanism. The other two variants described were missense variants of highly conserved residues in the MH2 domain. See also PMID: 22167769 for a second publication from this group with mutliple additional nonsense, frameshift, and missense mutation described. Regalado 2011 (PMID:21778426): Four novel SMAD3 variants in independent families were shown to segregate with aneurysm phenotypes (aortic, cranial). One frame shift variant segregating in a large family was found in exon 5, which would remove all of the MH2 domain (supporting a haploinsufficiency, rather than dominant negative mechanism). Three other substitution mutations were described; two in the MH2 domain. Hilhorst-Hofstee 2012 (PMID:22803640): A large deletion described in multiple family members. This deletion involves all but exon 1 of SMAD3 (plus two additional genes). The proband also had a 22q11.2 duplication (related to indication for study), but further family follow-up revealed the SMAD3 deletion in multiple adult family members with aortic aneurysms. While this deletion does involve AAGAB and IQCH in additon to SMAD3, it is consistent with the phenotypes in the SMAD3-only mutation cases. Plus, the large deletion supports haploinsufficiency as the mechanism for pathogenicity. While no full gene deletions were found in the current literature search, multiple nonsense and frameshift mutations as well as partial gene deletions have been described. Haploinsufficiency as well as disruption of trimer formation due to specific MH2 domain mutations have been implicated as genetic mechanisms.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

No focal duplications were found at the time of this review.