TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome

Nat Genet. 2012 Jul 8;44(8):916-21. doi: 10.1038/ng.2348.


A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.

Publication types

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

MeSH terms

  • Aortic Aneurysm, Thoracic / genetics*
  • Aortic Aneurysm, Thoracic / metabolism
  • Aortic Aneurysm, Thoracic / pathology
  • Aortic Dissection / genetics*
  • Aortic Dissection / metabolism
  • Aortic Dissection / pathology
  • Codon, Nonsense
  • Exome
  • Female
  • Frameshift Mutation
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Haploinsufficiency
  • Humans
  • Lod Score
  • Male
  • Marfan Syndrome / genetics*
  • Mutation*
  • Pedigree
  • Transforming Growth Factor beta2 / genetics*
  • Transforming Growth Factor beta2 / metabolism


  • Codon, Nonsense
  • TGFB2 protein, human
  • Transforming Growth Factor beta2