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

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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.

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Abbreviations

ARS:

Aortic replacement surgery

CTD:

Connective tissue disorder

ECM:

Extracellular matrix

GO BP:

Gene Ontology biological process

MFS:

Marfan syndrome

MRI:

Magnetic resonance imaging

SKAT-O:

Optimal unified sequence kernel association test

TAA:

Thoracic aortic aneurysm

TGFβ:

Transforming growth factor beta

WES:

Whole exome sequencing

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Acknowledgments

We thank the Heart Institute Research Core (recruitment), the Genetic Variation and Gene Discovery Core (sequencing), Phil Dexheimer, Osniel Ramos-Gonzales, and Amy Opoka for their assistance.

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Authors and Affiliations

  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

    Benjamin J. Landis & Stephanie M. Ware

  2. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    Benjamin J. Landis, Jeffrey A. Schubert, Dongbing Lai, Tatiana Foroud & Stephanie M. Ware

  3. Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Jeffrey A. Schubert

  4. Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Anil G. Jegga

  5. Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati Children’s Research Foundation, 3333 Burnet Ave, MLC 2003, Cincinnati, OH, 45229, USA

    Amy R. Shikany & Robert B. Hinton

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  1. Benjamin J. Landis
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  2. Jeffrey A. Schubert
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Corresponding authors

Correspondence to Stephanie M. Ware or Robert B. Hinton.

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Sources of Funding

This study was supported by a National Institutes of Health (Bethesda, MD) K12HD068371 (BJL), a Burroughs Wellcome Fund (Research Triangle Park, NC) Clinical Scientist Award in Translational Research #1008496 (SMW), and an American Heart Association (Dallas, TX) Innovative Research Grant 14IRG18830027 (RBH).

Conflict of Interest

The authors declare that they have no conflict of interest.

Human Subjects/Informed Consent Statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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Landis, B.J., Schubert, J.A., Lai, D. et al. Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity. J. of Cardiovasc. Trans. Res. 10, 423–432 (2017). https://doi.org/10.1007/s12265-017-9753-1

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