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

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

Author information

1
University of Michigan (B.N.W., W.E.H., L.F., J.M., A.D., X.W., M.R.M., S.K.G., N.J.D., C.M.B., J.K., Y.E.C., K.K., G.M.D., H.P., K.A.E., C.J.W., B.Y.), Michigan Medicine, University of Michigan, Ann Arbor.
2
Department of Computational Medicine and Bioinformatics (B.N.W., C.J.W.), Michigan Medicine, University of Michigan, Ann Arbor.
3
Department of Internal Medicine (W.E.H., J.M., S.K.G., K.A.E., C.J.W.), Michigan Medicine, University of Michigan, Ann Arbor.
4
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth) (D.G., D.M.M.).
5
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston (W.Z.).
6
Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA (W.Z.).
7
Department of Bioinformatics and Genomics, University of North Carolina at Charlotte (M.L.).
8
Department of Cardiac Surgery (L.F., X.W., K.K., G.M.D., H.P., B.Y.), Michigan Medicine, University of Michigan, Ann Arbor.
9
Office of Research-Precision Health, Ann Arbor, MI (A.D.).
10
Open Targets, Wellcome Sanger Institute, Cambridge, United Kingdom (E.M.S.).
11
Creighton University School of Medicine, Omaha, NE (E.L.N.).
12
Department of Anesthesiology (M.R.M., N.J.D., C.M.B.), Michigan Medicine, University of Michigan, Ann Arbor.
13
Department of Human Genetics (S.K.G., J.K., C.J.W.), Michigan Medicine, University of Michigan, Ann Arbor.
14
Department of Pharmacology (Y.E.C.), Michigan Medicine, University of Michigan, Ann Arbor.
15
Department of Molecular and Integrative Physiology (Y.E.C.), Michigan Medicine, University of Michigan, Ann Arbor.

Abstract

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

PMID:
31211624
PMCID:
PMC6582991
[Available on 2020-06-18]
DOI:
10.1161/CIRCGEN.118.002476

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