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Clinical impact of re-evaluating genes and variants implicated in dilated cardiomyopathy

Abstract

Purpose

Accurate interpretation of variants detected in dilated cardiomyopathy (DCM) is crucial for patient care but has proven challenging. We applied a set of proposed refined American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria for DCM, reclassified all detected variants in robust genes, and associated these results to patients' phenotype.

Methods

The study included 902 DCM probands from the Maastricht Cardiomyopathy Registry who underwent genetic testing. Two gene panel sizes (extended n = 48; and robust panel n = 14) and two standards of variant classification (standard versus the proposed refined ACMG/AMP criteria) were applied to compare genetic yield.

Results

A pathogenic or likely pathogenic (P/LP) variant was found in 17.8% of patients, and a variant of uncertain significance (VUS) was found in 32.8% of patients when using method 1 (extended panel (n = 48) + standard ACMG/AMP), compared to respectively 16.9% and 12.9% when using method 2 (robust panel (n = 14) + standard ACMG/AMP), and respectively 14% and 14.5% using method 3 (robust panel (n = 14) + refined ACMG/AMP). Patients with P/LP variants had significantly lower event-free survival compared to genotype-negative DCM patients.

Conclusion

Stringent gene selection for DCM genetic testing reduced the number of VUS while retaining ability to detect similar P/LP variants. The number of genes on diagnostic panels should be limited to genes that have the highest signal to noise ratio.

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Fig. 1: Proportion of dilated cardiomyopathy (DCM) patients with either no variant, a variant of uncertain significance (VUS), a likely pathogenic, or pathogenic variant as result after genetic testing.
Fig. 2: Survival curves show freedom from combined endpoint (cardiac death or transplantation, heart failure hospitalization, or life-threatening arrhythmia) stratified on genetic status.

Data availability

The data that support the findings of this study are available from the corresponding author on request.

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Acknowledgements

The authors are grateful to Pablo Garcia-Pavia and Juan Pablo Ochoa (Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain) for their input and revising of the manuscript. J.W.: This work was supported by Wellcome Trust [107469/Z/15/Z], Medical Research Council (UK), British Heart Foundation [RE/18/4/34215], NIHR Royal Brompton Cardiovascular Biomedical Research Unit, and the NIHR Imperial College Biomedical Research Centre. S.H.: The research leading to these results has received funding from the European Union Commission’s Seventh Framework program under grant agreement number 305507 (HOMAGE). This paper has been possible thanks to the support of the the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2016-Early HFPEF, 2015-10, CVON She-PREDICTS, grant 2017-21. The views expressed in this work are those of the authors and not necessarily those of the funders.

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Authors

Contributions

Conceptualization: J.V., H.B., J.W. Data curation: J.V., D.H., G.C. Formal Analysis: J.V. Funding acquisition: S.H., H.B., A.v.d.W. Investigation: S.S., D.H., G.C., I.K., E.V., J.V. Methodology: J.V. Resources: H.B., A.v.d.W. Supervision: H.B. Visualization: S.S., J.V. Writing—original draft: S.S., J.V. Writing—review & editing: D.H., G.C., U.T., I.K., E.V., M.H., J.W.

Corresponding author

Correspondence to Job A. J. Verdonschot.

Ethics declarations

Ethics Declaration

The study was performed according to the declaration of Helsinki and was approved by the institutional Medical Ethics Committee of the Maastricht University Medical Center. All patients gave written informed consent.

Competing interests

The authors declare no competing interests.

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Supplementary information

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Stroeks, S.L.V.M., Hellebrekers, D.M.E.I., Claes, G.R.F. et al. Clinical impact of re-evaluating genes and variants implicated in dilated cardiomyopathy. Genet Med (2021). https://doi.org/10.1038/s41436-021-01255-1

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