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

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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.

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Most cited references 20

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2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).

Henning Bundgaard (2015)

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InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines.

Quan Li, Kai Wang (2017)

In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published updated standards and guidelines for the clinical interpretation of sequence variants with respect to human diseases on the basis of 28 criteria. However, variability between individual interpreters can be extensive because of reasons such as the different understandings of these guidelines and the lack of standard algorithms for implementing them, yet computational tools for semi-automated variant interpretation are not available. To address these problems, we propose a suite of methods for implementing these criteria and have developed a tool called InterVar to help human reviewers interpret the clinical significance of variants. InterVar can take a pre-annotated or VCF file as input and generate automated interpretation on 18 criteria. Furthermore, we have developed a companion web server, wInterVar, to enable user-friendly variant interpretation with an automated interpretation step and a manual adjustment step. These tools are especially useful for addressing severe congenital or very early-onset developmental disorders with high penetrance. Using results from a few published sequencing studies, we demonstrate the utility of InterVar in significantly reducing the time to interpret the clinical significance of sequence variants.

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Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.

Pascale Richard, Philippe Charron, Lucie Carrier … (2003)

Hypertrophic cardiomyopathy is an autosomal-dominant disorder in which 10 genes and numerous mutations have been reported. The aim of the present study was to perform a systematic screening of these genes in a large population, to evaluate the distribution of the disease genes, and to determine the best molecular strategy in clinical practice. The entire coding sequences of 9 genes (MYH7, MYBPC3, TNNI3, TNNT2, MYL2, MYL3, TPM1, ACTC, andTNNC1) were analyzed in 197 unrelated index cases with familial or sporadic hypertrophic cardiomyopathy. Disease-causing mutations were identified in 124 index patients ( approximately 63%), and 97 different mutations, including 60 novel ones, were identified. The cardiac myosin-binding protein C (MYBPC3) and beta-myosin heavy chain (MYH7) genes accounted for 82% of families with identified mutations (42% and 40%, respectively). Distribution of the genes varied according to the prognosis (P=0.036). Moreover, a mutation was found in 15 of 25 index cases with "sporadic" hypertrophic cardiomyopathy (60%). Finally, 6 families had patients with more than one mutation, and phenotype analyses suggested a gene dose effect in these compound-heterozygous, double-heterozygous, or homozygous patients. These results might have implications for genetic diagnosis strategy and, subsequently, for genetic counseling. First, on the basis of this experience, the screening of already known mutations is not helpful. The analysis should start by testing MYBPC3 and MYH7 and then focus on TNNI3, TNNT2, and MYL2. Second, in particularly severe phenotypes, several mutations should be searched. Finally, sporadic cases can be successfully screened.

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Author and article information

Contributors

Francesco Mazzarotto: +39 055 2758272 , francesco.mazzarotto@unifi.it , f.mazzarotto@imperial.ac.uk

Journal

Journal ID (nlm-ta): Genet Med

Journal ID (iso-abbrev): Genet. Med

Title: Genetics in Medicine

Publisher: Nature Publishing Group US (New York )

ISSN (Print): 1098-3600

ISSN (Electronic): 1530-0366

Publication date (Electronic): 6 June 2018

Publication date PMC-release: 6 June 2018

Publication date (Print): 2019

Volume: 21

Issue: 2

Pages: 284-292

Affiliations

[1 ]ISNI 0000 0004 1759 9494, GRID grid.24704.35, Cardiomyopathy Unit, , Careggi University Hospital, ; Florence, Italy

[2 ]ISNI 0000 0000 9216 5443, GRID grid.421662.5, Cardiovascular Research Center, , Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, ; London, UK

[3 ]ISNI 0000 0004 1757 2304, GRID grid.8404.8, Department of Clinical and Experimental Medicine, , University of Florence, ; Florence, Italy

[4 ]ISNI 0000 0004 1759 9494, GRID grid.24704.35, Genetic Unit, , Careggi University Hospital, ; Florence, Italy

[5 ]ISNI 0000 0004 1757 2304, GRID grid.8404.8, Department NEUROFARBA, , University of Florence, ; Firenze, Italy

[6 ]ISNI 0000 0004 0620 9905, GRID grid.419385.2, National Heart Centre, ; Singapore, Singapore

[7 ]ISNI 0000 0004 0385 0924, GRID grid.428397.3, Duke–National University of Singapore Medical School, ; Singapore, Singapore

Article

Publisher ID: 46

DOI: 10.1038/s41436-018-0046-0

PMC ID: 6752309

PubMed ID: 29875424

SO-VID: 9327b288-d04f-457e-8197-f3fa030fd0a4

License:

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/.

History

Date received : 27 November 2017

Date accepted : 9 April 2018

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ScienceOpen disciplines: Genetics

Keywords: diagnostic effectiveness,hcm mimics,hypertrophic cardiomyopathy,mendelian hcm genetics,ngs

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ScienceOpen disciplines: Genetics

Keywords: diagnostic effectiveness, hcm mimics, hypertrophic cardiomyopathy, mendelian hcm genetics, ngs

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

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Abstract

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Conclusion

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G3: Genes|Genomes|Genetics

Most cited references 20

2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).

InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines.

Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.

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