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

Benjamin Landis, Jeffrey A. Schubert, Dongbing Lai, Anil G. Jegga, Amy R. Shikany, Tatiana Foroud, Stephanie Ware, Robert B. Hinton

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalJournal of Cardiovascular Translational Research
DOIs
StateAccepted/In press - May 26 2017

Fingerprint

Exome
Thoracic Aortic Aneurysm
Genes
Phenotype
Inborn Genetic Diseases
Penetrance
Retina
Familial Thoracic 1 Aortic Aneurysm
Dissection
Homeostasis

Keywords

  • Aneurysm
  • Aorta
  • Exome
  • Genetics
  • Marfan
  • Modifier

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmaceutical Science
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Cite this

Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity. / Landis, Benjamin; Schubert, Jeffrey A.; Lai, Dongbing; Jegga, Anil G.; Shikany, Amy R.; Foroud, Tatiana; Ware, Stephanie; Hinton, Robert B.

In: Journal of Cardiovascular Translational Research, 26.05.2017, p. 1-10.

Research output: Contribution to journalArticle

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AU - Jegga, Anil G.

AU - Shikany, Amy R.

AU - Foroud, Tatiana

AU - Ware, Stephanie

AU - Hinton, Robert B.

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