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

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. LoeysDianna M. Milewicz, Julie De Backer

Research output: Contribution to journal › Article › peer-review

56 Scopus citations

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.

Original language	English (US)
Pages (from-to)	605-615
Number of pages	11
Journal	Journal of the American College of Cardiology
Volume	72
Issue number	6
DOIs	https://doi.org/10.1016/j.jacc.2018.04.089
State	Published - Aug 7 2018

Keywords

ClinGen
gene curation
gene-disease relationship
thoracic aortic aneurysm
thoracic aortic dissection

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1016/j.jacc.2018.04.089

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Renard, M., Francis, C., Ghosh, R., Scott, A. F., Witmer, P. D., Adès, L. C., Andelfinger, G. U., Arnaud, P., Boileau, C., Callewaert, B. L., Guo, D., Hanna, N., Lindsay, M. E., Morisaki, H., Morisaki, T., Pachter, N., Robert, L., Van Laer, L., Dietz, H. C., ... De Backer, J. (2018). Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection. Journal of the American College of Cardiology, 72(6), 605-615. https://doi.org/10.1016/j.jacc.2018.04.089

Renard, M, Francis, C, Ghosh, R, Scott, AF , Witmer, PD, Adès, LC, Andelfinger, GU, Arnaud, P, Boileau, C, Callewaert, BL, Guo, D, Hanna, N, Lindsay, ME, Morisaki, H, Morisaki, T, Pachter, N, Robert, L, Van Laer, L, Dietz, HC, Loeys, BL, Milewicz, DM & De Backer, J 2018, 'Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection', Journal of the American College of Cardiology, vol. 72, no. 6, pp. 605-615. https://doi.org/10.1016/j.jacc.2018.04.089

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title = "Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection",

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",

author = "Marjolijn Renard and Catherine Francis and Rajarshi Ghosh and Scott, {Alan F.} and Witmer, {P. Dane} and Ad{\`e}s, {Lesley C.} and Andelfinger, {Gregor U.} and Pauline Arnaud and Catherine Boileau and Callewaert, {Bert L.} and Dongchuan Guo and Nadine Hanna and Lindsay, {Mark E.} and Hiroko Morisaki and Takayuki Morisaki and Nicholas Pachter and Leema Robert and {Van Laer}, Lut and Dietz, {Harry C.} and Loeys, {Bart L.} and Milewicz, {Dianna M.} and {De Backer}, Julie",

note = "Publisher Copyright: {\textcopyright} 2018 American College of Cardiology Foundation",

year = "2018",

month = aug,

day = "7",

doi = "10.1016/j.jacc.2018.04.089",

language = "English (US)",

volume = "72",

pages = "605--615",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier USA",

number = "6",

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TY - JOUR

T1 - Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection

AU - Renard, Marjolijn

AU - Francis, Catherine

AU - Ghosh, Rajarshi

AU - Scott, Alan F.

AU - Witmer, P. Dane

AU - Adès, Lesley C.

AU - Andelfinger, Gregor U.

AU - Arnaud, Pauline

AU - Boileau, Catherine

AU - Callewaert, Bert L.

AU - Guo, Dongchuan

AU - Hanna, Nadine

AU - Lindsay, Mark E.

AU - Morisaki, Hiroko

AU - Morisaki, Takayuki

AU - Pachter, Nicholas

AU - Robert, Leema

AU - Van Laer, Lut

AU - Dietz, Harry C.

AU - Loeys, Bart L.

AU - Milewicz, Dianna M.

AU - De Backer, Julie

PY - 2018/8/7

Y1 - 2018/8/7

N2 - 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.

AB - 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.

KW - ClinGen

KW - gene curation

KW - gene-disease relationship

KW - thoracic aortic aneurysm

KW - thoracic aortic dissection

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Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection

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