Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity

J Cardiovasc Transl Res. 2017 Aug;10(4):423-432. doi: 10.1007/s12265-017-9753-1. Epub 2017 May 26.


Thoracic aortic aneurysm (TAA) is a genetic disease predisposing to aortic dissection. It is important to identify the genetic modifiers controlling penetrance and expressivity to improve clinical prognostication. Exome sequencing was performed in 27 subjects with syndromic or familial TAA presenting with extreme phenotypes (15 with severe TAA; 12 with mild or absent TAA). Family-based analysis of a subset of the cohort identified variants, genes, and pathways segregating with TAA severity among three families. A rare missense variant in ADCK4 (p.Arg63Trp) segregated with mild TAA in each family. Genes and pathways identified in families were further investigated in the entire cohort using the optimal unified sequence kernel association test, finding significance for the gene COL15A1 (p = 0.025) and the retina homeostasis pathway (p = 0.035). Thus, we identified candidate genetic modifiers of TAA severity by exome-based study of extreme phenotypes, which may lead to improved risk stratification and development of new medical therapies.

Keywords: Aneurysm; Aorta; Exome; Genetics; Marfan; Modifier.

MeSH terms

  • Adolescent
  • Adult
  • Aortic Aneurysm, Thoracic / diagnostic imaging
  • Aortic Aneurysm, Thoracic / genetics*
  • Collagen / genetics
  • Exome Sequencing*
  • Female
  • Gene Regulatory Networks
  • Genes, Modifier*
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Heredity
  • Humans
  • Male
  • Middle Aged
  • Pedigree
  • Phenotype
  • Predictive Value of Tests
  • Prospective Studies
  • Risk Factors
  • Severity of Illness Index
  • Syndrome
  • Young Adult


  • COL15A1 protein, human
  • Collagen

Supplementary concepts

  • Aortic Aneurysm, Familial Thoracic 1