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

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.

SUBMITTER: Wolford BN

PROVIDER: S-EPMC6582991 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Wolford Brooke N BN Hornsby Whitney E WE Guo Dongchuan D Zhou Wei W Lin Maoxuan M Farhat Linda L McNamara Jennifer J Driscoll Anisa A Wu Xiaoting X Schmidt Ellen M EM Norton Elizabeth L EL Mathis Michael R MR Ganesh Santhi K SK Douville Nicholas J NJ Brummett Chad M CM Kitzman Jacob J Chen Y Eugene YE Kim Karen K Deeb G Michael GM Patel Himanshu H Eagle Kim A KA Milewicz Dianna M DM J Willer Cristen C Yang Bo B

Circulation. Genomic and precision medicine 20190618 6

<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>T ...[more]

PMID: 31211624

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Project description:BACKGROUND:Thoracic aortic aneurysms progressively enlarge and predispose to acute aortic dissections. Up to 25% of individuals with thoracic aortic disease harbor an underlying Mendelian pathogenic variant. An evidence-based strategy for selection of genes to test in hereditary thoracic aortic aneurysm and dissection (HTAAD) helps inform family screening and intervention to prevent life-threatening thoracic aortic events. OBJECTIVES:The purpose of this study was to accurately identify genes that predispose to HTAAD using the Clinical Genome Resource (ClinGen) framework. METHODS:We applied the semiquantitative ClinGen framework to assess presumed gene-disease relationships between 53 candidate genes and HTAAD. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable, triggering routine aortic surveillance, intervention, and family cascade screening. All gene-disease assertions were evaluated by a pre-defined curator-expert pair and subsequently discussed with an expert panel. RESULTS:Genes were classified based on the strength of association with HTAAD into 5 categories: definitive (n = 9), strong (n = 2), moderate (n = 4), limited (n = 15), and no reported evidence (n = 23). They were further categorized by severity of associated aortic disease and risk of progression. Eleven genes in the definitive and strong groups were designated as "HTAAD genes" (category A). Eight genes were classified as unlikely to be progressive (category B) and 4 as low risk (category C). The remaining genes were recent genes with an uncertain classification or genes with no evidence of association with HTAAD. CONCLUSIONS:The ClinGen framework is useful to semiquantitatively assess the strength of gene-disease relationships for HTAAD. Gene categories resulting from the curation may inform clinical laboratories in the development, interpretation, and subsequent clinical implications of genetic testing for patients with aortic disease.

Dataset Information

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

Publications

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

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