Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center

PURPOSE: Genetic testing in hypertrophic cardiomyopathy (HCM) has long relied on Sanger sequencing of sarcomeric genes. The advent of next-generation sequencing (NGS) has catalyzed routine testing of additional genes of dubious HCM-causing potential. We used 19 years of genetic testing results to de...

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Autores principales: Mazzarotto, Francesco, Girolami, Francesca, Boschi, Beatrice, Barlocco, Fausto, Tomberli, Alessia, Baldini, Katia, Coppini, Raffaele, Tanini, Ilaria, Bardi, Sara, Contini, Elisa, Cecchi, Franco, Pelo, Elisabetta, Cook, Stuart A., Cerbai, Elisabetta, Poggesi, Corrado, Torricelli, Francesca, Walsh, Roddy, Olivotto, Iacopo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2018
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Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752309/
https://www.ncbi.nlm.nih.gov/pubmed/29875424
http://dx.doi.org/10.1038/s41436-018-0046-0
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author Mazzarotto, Francesco
Girolami, Francesca
Boschi, Beatrice
Barlocco, Fausto
Tomberli, Alessia
Baldini, Katia
Coppini, Raffaele
Tanini, Ilaria
Bardi, Sara
Contini, Elisa
Cecchi, Franco
Pelo, Elisabetta
Cook, Stuart A.
Cerbai, Elisabetta
Poggesi, Corrado
Torricelli, Francesca
Walsh, Roddy
Olivotto, Iacopo
author_facet Mazzarotto, Francesco
Girolami, Francesca
Boschi, Beatrice
Barlocco, Fausto
Tomberli, Alessia
Baldini, Katia
Coppini, Raffaele
Tanini, Ilaria
Bardi, Sara
Contini, Elisa
Cecchi, Franco
Pelo, Elisabetta
Cook, Stuart A.
Cerbai, Elisabetta
Poggesi, Corrado
Torricelli, Francesca
Walsh, Roddy
Olivotto, Iacopo
author_sort Mazzarotto, Francesco
collection PubMed
description PURPOSE: Genetic testing in hypertrophic cardiomyopathy (HCM) has long relied on Sanger sequencing of sarcomeric genes. The advent of next-generation sequencing (NGS) has catalyzed routine testing of additional genes of dubious HCM-causing potential. We used 19 years of genetic testing results to define a reliable set of genes implicated in Mendelian HCM and assess the value of expanded NGS panels. METHODS: We dissected genetic testing results from 1,198 single-center HCM probands and devised a widely applicable score to identify which genes yield effective results in the diagnostic setting. RESULTS: Compared with early panels targeting only fully validated sarcomeric HCM genes, expanded NGS panels allow the prompt recognition of probands with HCM-mimicking diseases. Scoring by “diagnostic effectiveness” highlighted that PLN should also be routinely screened besides historically validated genes for HCM and its mimics. CONCLUSION: The additive value of expanded panels in HCM genetic testing lies in the systematic screening of genes associated with HCM mimics, requiring different patient management. Only variants in a limited set of genes are highly actionable and interpretable in the clinic, suggesting that larger panels offer limited additional sensitivity. A score estimating the relative effectiveness of a given gene’s inclusion in diagnostic panels is proposed.
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spelling pubmed-67523092019-09-23 Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center Mazzarotto, Francesco Girolami, Francesca Boschi, Beatrice Barlocco, Fausto Tomberli, Alessia Baldini, Katia Coppini, Raffaele Tanini, Ilaria Bardi, Sara Contini, Elisa Cecchi, Franco Pelo, Elisabetta Cook, Stuart A. Cerbai, Elisabetta Poggesi, Corrado Torricelli, Francesca Walsh, Roddy Olivotto, Iacopo Genet Med Article PURPOSE: Genetic testing in hypertrophic cardiomyopathy (HCM) has long relied on Sanger sequencing of sarcomeric genes. The advent of next-generation sequencing (NGS) has catalyzed routine testing of additional genes of dubious HCM-causing potential. We used 19 years of genetic testing results to define a reliable set of genes implicated in Mendelian HCM and assess the value of expanded NGS panels. METHODS: We dissected genetic testing results from 1,198 single-center HCM probands and devised a widely applicable score to identify which genes yield effective results in the diagnostic setting. RESULTS: Compared with early panels targeting only fully validated sarcomeric HCM genes, expanded NGS panels allow the prompt recognition of probands with HCM-mimicking diseases. Scoring by “diagnostic effectiveness” highlighted that PLN should also be routinely screened besides historically validated genes for HCM and its mimics. CONCLUSION: The additive value of expanded panels in HCM genetic testing lies in the systematic screening of genes associated with HCM mimics, requiring different patient management. Only variants in a limited set of genes are highly actionable and interpretable in the clinic, suggesting that larger panels offer limited additional sensitivity. A score estimating the relative effectiveness of a given gene’s inclusion in diagnostic panels is proposed. Nature Publishing Group US 2018-06-06 2019 /pmc/articles/PMC6752309/ /pubmed/29875424 http://dx.doi.org/10.1038/s41436-018-0046-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Mazzarotto, Francesco
Girolami, Francesca
Boschi, Beatrice
Barlocco, Fausto
Tomberli, Alessia
Baldini, Katia
Coppini, Raffaele
Tanini, Ilaria
Bardi, Sara
Contini, Elisa
Cecchi, Franco
Pelo, Elisabetta
Cook, Stuart A.
Cerbai, Elisabetta
Poggesi, Corrado
Torricelli, Francesca
Walsh, Roddy
Olivotto, Iacopo
Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center
title Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center
title_full Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center
title_fullStr Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center
title_full_unstemmed Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center
title_short Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center
title_sort defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752309/
https://www.ncbi.nlm.nih.gov/pubmed/29875424
http://dx.doi.org/10.1038/s41436-018-0046-0
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