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.

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. - In: GENETICS IN MEDICINE. - ISSN 1098-3600. - ELETTRONICO. - (2018), pp. 1-9. [10.1038/s41436-018-0046-0]

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;Barlocco, Fausto;Tomberli, Alessia;Coppini, Raffaele;Contini, Elisa;Cecchi, Franco;Pelo, Elisabetta;Cerbai, Elisabetta;Poggesi, Corrado;Torricelli, Francesca;Olivotto, Iacopo
2018

Abstract

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.
2018
1
9
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
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1136153
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