Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection

Circ Genom Precis Med. 2019 Jun;12(6):e002476. doi: 10.1161/CIRCGEN.118.002476. Epub 2019 Jun 18.


Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members.

Methods: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity.

Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age <50 (odds ratio [OR], 5.5; 95% CI, 1.6-19.7), no history of hypertension (OR, 5.6; 95% CI, 1.4-22.3), and family history of aortic disease (mother: OR, 5.7; 95% CI, 1.4-22.3, siblings: OR, 5.1; 95% CI, 1.1-23.9, children: OR, 6.0; 95% CI, 1.4-26.7).

Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.

Keywords: aortic disease; genetics; rupture; whole exome sequencing.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aortic Aneurysm, Thoracic / diagnosis
  • Aortic Aneurysm, Thoracic / genetics*
  • Aortic Aneurysm, Thoracic / physiopathology
  • Aortic Dissection / diagnosis
  • Aortic Dissection / genetics*
  • Aortic Dissection / physiopathology
  • Case-Control Studies
  • Collagen Type III / genetics
  • Cyclic GMP-Dependent Protein Kinase Type I / genetics
  • Exome Sequencing
  • Female
  • Fibrillin-1 / genetics
  • Genetic Testing
  • Humans
  • Hypertension
  • Male
  • Middle Aged
  • Pedigree
  • Protein-Lysine 6-Oxidase / genetics
  • Receptor, Transforming Growth Factor-beta Type II / genetics
  • Risk Factors
  • Smad3 Protein / genetics
  • Young Adult


  • COL3A1 protein, human
  • Collagen Type III
  • FBN1 protein, human
  • Fibrillin-1
  • SMAD3 protein, human
  • Smad3 Protein
  • LOX protein, human
  • Protein-Lysine 6-Oxidase
  • Cyclic GMP-Dependent Protein Kinase Type I
  • PRKG1 protein, human
  • Receptor, Transforming Growth Factor-beta Type II
  • TGFBR2 protein, human