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
Author(s)
Type
Journal Article
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.
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.
Date Issued
2019-02-01
Date Acceptance
2018-04-09
Citation
Genetics in Medicine, 2019, 21 (2), pp.284-292
ISSN
1098-3600
Publisher
Springer Nature [academic journals on nature.com]
Start Page
284
End Page
292
Journal / Book Title
Genetics in Medicine
Volume
21
Issue
2
Copyright Statement
© The Author(s) 2018 . 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/.
Sponsor
British Heart Foundation
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000458017600006&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
SP/10/10/28431
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
Diagnostic effectiveness
HCM mimics
Hypertrophic cardiomyopathy
Mendelian HCM genetics
NGS
GUIDELINES
MUTATIONS
VARIANTS
DISEASE
ESC
Publication Status
Published
Date Publish Online
2018-06-06