SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium

J Med Genet. 2019 Apr;56(4):252-260. doi: 10.1136/jmedgenet-2018-105583. Epub 2019 Jan 19.


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.

Keywords: cardiovascular medicine; clinical genetics; connective tissue disease; genetics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Amino Acid Substitution
  • Aortic Aneurysm, Thoracic / complications
  • Aortic Aneurysm, Thoracic / diagnosis*
  • Aortic Aneurysm, Thoracic / genetics*
  • Child
  • Child, Preschool
  • Female
  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Phenotype*
  • Prognosis
  • Protein Domains / genetics
  • Risk Factors
  • Smad3 Protein / chemistry
  • Smad3 Protein / genetics*


  • SMAD3 protein, human
  • Smad3 Protein