1. Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection
- Author
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Julie De Backer, Takayuki Morisaki, Harry C. Dietz, Marjolijn Renard, Nadine Hanna, Bert Callewaert, Leema Robert, Hiroko Morisaki, Gregor Andelfinger, Pauline Arnaud, Lut Van Laer, Catherine Boileau, Catherine Francis, Dianna M. Milewicz, Rajarshi Ghosh, Lesley C. Adès, Mark E. Lindsay, Nicholas Pachter, Dongchuan Guo, Bart Loeys, P. Dane Witmer, and Alan F. Scott
- Subjects
ClinGen ,0301 basic medicine ,Candidate gene ,medicine.medical_specialty ,DILATION ,ARTERIAL ANEURYSMS ,FEATURES ,thoracic aortic aneurysm ,thoracic aortic dissection ,Disease ,030204 cardiovascular system & hematology ,gene curation ,Thoracic aortic aneurysm ,Genome ,Article ,DISEASE ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Internal medicine ,OF-FUNCTION MUTATIONS ,Medicine and Health Sciences ,medicine ,Humans ,gene disease relationship ,Gene ,SYNDROME TYPE-IV ,Genetic testing ,Aortic Aneurysm, Thoracic ,medicine.diagnostic_test ,business.industry ,GENOME RESOURCE ,DEFECTS ,medicine.disease ,Aortic Dissection ,Phenotype ,030104 developmental biology ,Clinical validity ,Mendelian inheritance ,symbols ,Human medicine ,Cardiology and Cardiovascular Medicine ,business - Abstract
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, (C) 2018 the American College of Cardiology Foundation, Published by Elsevier. Alt rights reserved.
- Published
- 2018
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