Related Experiment Video
Updated: Jan 30, 2026
Aortic Ring Assay
Published on: November 24, 2009
SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic
Ellen M Hostetler1, Ellen S Regalado1, Dong-Chuan Guo1
1Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, Texas, USA.
Insights
Pathogenic SMAD3 variants cause aortic dissections, with MH2 missense variants leading to earlier events than haploinsufficiency variants. This highlights the importance of gene-specific management for SMAD3-related aortic disease.
Area of Science:
- Genetics and cardiovascular disease research.
- Molecular mechanisms of aortic aneurysm and dissection.
Background:
- Pathogenic variants in SMAD3 are linked to thoracic aortic aneurysms and dissections.
- These variants can also affect other arteries, leading to aneurysms and rupture.
Purpose of the Study:
- To investigate how age and specific SMAD3 variant types influence the clinical presentation of aortic events.
- To analyze differences in aortic event timing and frequency based on SMAD3 variant characteristics.
Main Methods:
- Retrospective review of medical records for 212 individuals with 51 unique SMAD3 variants.
- Categorization of variants included haploinsufficiency (HI), MH2 missense, MH1 in-frame deletions, and MH1 missense variants.
Main Results:
- Aortic events occurred in 37% of individuals, with dissections comprising 70% of these events.
- The median age of the first aortic event was significantly lower for MH2 missense variants (42 years) compared to HI variants (49 years).
- No significant difference in aortic event frequency by variant type was observed; cumulative risk reached 50% by age 54, with no childhood events.
Conclusions:
- SMAD3 pathogenic variants cause aortic aneurysms and dissections with variable onset and reduced penetrance.
- The type of SMAD3 variant contributes to the variation in clinical presentation, including age of onset.
- Later onset and absence of childhood events support tailored, gene-specific management strategies for SMAD3-related disorders.
Background:
Pathogenic variants in SMAD3 cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Here, we 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 individuals with SMAD3 variants.
Methods:
Aortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 unique SMAD3 variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain.
Results:
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 HI variants (42years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type. The cumulative risk of an aortic event was 50% at 54 years of age. No aortic events in childhood were observed.
Conclusions:
SMAD3 pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. Of the covariates examined, the type of underlying SMAD3 variant was responsible for some of this variation. Later onset of aortic events and the absence of aortic events in children associated with SMAD3 variants support gene-specific management of this disorder.
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