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

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

Author information

1
Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, 1044 W. Walnut Street, R4-227, Indianapolis, IN, USA.
2
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
3
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
4
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
5
Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati Children's Research Foundation, 3333 Burnet Ave, MLC 2003, Cincinnati, OH, 45229, USA.
6
Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, 1044 W. Walnut Street, R4-227, Indianapolis, IN, USA. stware@iu.edu.
7
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. stware@iu.edu.
8
Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati Children's Research Foundation, 3333 Burnet Ave, MLC 2003, Cincinnati, OH, 45229, USA. bingrbh@icloud.com.

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.

KEYWORDS:

Aneurysm; Aorta; Exome; Genetics; Marfan; Modifier

PMID:
28550590
PMCID:
PMC5702585
DOI:
10.1007/s12265-017-9753-1
[Indexed for MEDLINE]
Free PMC Article

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