Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection

Marjolijn Renard; Catherine Francis; Rajarshi Ghosh; Alan F Scott; P Dane Witmer; Lesley C Adès; Gregor U Andelfinger; Pauline Arnaud; Catherine Boileau; Bert L Callewaert; Dongchuan Guo; Nadine Hanna; Mark E Lindsay; Hiroko Morisaki; Takayuki Morisaki; Nicholas Pachter; Leema Robert; Lut Van Laer; Harry C Dietz; Bart L Loeys; Dianna M Milewicz; Julie De Backer

doi:10.1016/j.jacc.2018.04.089

Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection

J Am Coll Cardiol. 2018 Aug 7;72(6):605-615. doi: 10.1016/j.jacc.2018.04.089.

Authors

Marjolijn Renard¹, Catherine Francis², Rajarshi Ghosh³, Alan F Scott⁴, P Dane Witmer⁴, Lesley C Adès⁵, Gregor U Andelfinger⁶, Pauline Arnaud⁷, Catherine Boileau⁷, Bert L Callewaert¹, Dongchuan Guo⁸, Nadine Hanna⁷, Mark E Lindsay⁹, Hiroko Morisaki¹⁰, Takayuki Morisaki¹⁰, Nicholas Pachter¹¹, Leema Robert¹², Lut Van Laer¹³, Harry C Dietz¹⁴, Bart L Loeys¹³, Dianna M Milewicz⁸, Julie De Backer¹⁵

Affiliations

¹ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
² National Heart and Lung institute, Imperial College London, London, United Kingdom; NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom.
³ Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
⁴ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland.
⁵ Children's Hospital at Westmead, Sydney, New South Wales, Australia.
⁶ Cardiovascular Genetics, Department of Pediatrics, Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.
⁷ Département de Génétique et Centre de Référence Maladies Rares Syndrome de Marfan et pathologies apparentées, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France; LVTS, INSERM U1148, Université Paris Diderot, Hôpital Bichat, Paris, France.
⁸ Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas.
⁹ Thoracic Aortic Center and Cardiovascular Genetics Program, Departments of Medicine and Pediatrics, Massachusetts General Hospital, Boston, Massachusetts.
¹⁰ Department of Medical Genetics, Sakakibara Heart Institute, Tokyo, Japan; Tokyo University of Technology School of Health Sciences, Tokyo, Japan.
¹¹ Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia.
¹² Department of Clinical Genetics, Guys and St. Thomas' Hospital, London, United Kingdom.
¹³ Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
¹⁴ Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
¹⁵ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Department of Cardiology, Ghent University Hospital, Ghent, Belgium. Electronic address: [email protected].

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.

Keywords: ClinGen; gene curation; gene-disease relationship; thoracic aortic aneurysm; thoracic aortic dissection.

MeSH terms

Aortic Aneurysm, Thoracic / diagnosis*
Aortic Aneurysm, Thoracic / genetics*
Aortic Dissection / diagnosis*
Aortic Dissection / genetics*
Female
Genetic Predisposition to Disease / genetics*
Genetic Testing / methods
Genetic Testing / standards*
Humans
Male
Reproducibility of Results

Abstract

MeSH terms

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