Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield
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Published version
OA Location
Author(s)
Type
Journal Article
Abstract
PURPOSE: Increasing numbers of genes are being implicated in Mendelian disorders and incorporated into clinical test panels. However, lack of evidence supporting the gene-disease relationship can hinder interpretation. We explored the utility of testing 51 additional genes for hypertrophic cardiomyopathy (HCM), one of the most commonly tested Mendelian disorders. METHODS: Using genome sequencing data from 240 sarcomere gene negative HCM cases and 6229 controls, we undertook case-control and individual variant analyses to assess 51 genes that have been proposed for HCM testing. RESULTS: We found no evidence to suggest that rare variants in these genes are prevalent causes of HCM. One variant, in a single case, was categorized as likely to be pathogenic. Over 99% of variants were classified as a variant of uncertain significance (VUS) and 54% of cases had one or more VUS. CONCLUSION: For almost all genes, the gene-disease relationship could not be validated and lack of evidence precluded variant interpretation. Thus, the incremental diagnostic yield of extending testing was negligible, and would, we propose, be outweighed by problems that arise with a high rate of uninterpretable findings. These findings highlight the need for rigorous, evidence-based selection of genes for clinical test panels.
Date Issued
2019-07-01
Date Acceptance
2018-11-08
Citation
Genetics in Medicine, 2019, 21, pp.1576-1584
ISSN
1098-3600
Publisher
Springer Nature [academic journals on nature.com]
Start Page
1576
End Page
1584
Journal / Book Title
Genetics in Medicine
Volume
21
Copyright Statement
© The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0InternationalLicense,whichpermitsuse,sharing, adaptation, distribution and reproduction in any medium or format, as long as yougiveappropriate creditto theoriginalauthor(s)andthesource,provide alink 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 notincluded inthe article ’ sCreative 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
Wellcome Trust
British Heart Foundation
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/30531895
PII: 10.1038/s41436-018-0375-z
Grant Number
107469/Z/15/Z
SP/10/10/28431
Subjects
HCM
VUS
evidence-based
genetic testing
variant interpretation
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2018-12-11