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Diagnostic and prognostic relevance of using large gene panels in the genetic testing of patients with dilated cardiomyopathy

European Journal of Human Genetics volume 31, pages 776–783 (2023)Cite this article

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Abstract

It was previously suggested that increasing the number of genes on diagnostic gene panels could increase the genetic yield in patient with dilated cardiomyopathy (DCM). We explored the diagnostic and prognostic relevance of testing DCM patients with an expanded gene panel. The current study included 225 consecutive DCM patients who had no genetic diagnosis after a 48-gene cardiomyopathy-panel. These were then evaluated using an expanded gene panel of 299 cardiac-associated genes. A likely pathogenic/pathogenic (P/LP) variant was detected in 13 patients. Five variants were reclassifications of variants found in genes which were already detected using the 48 gene panel. Only one of the other eight variants could explain the phenotype of the patient (KCNJ2). The panel detected 186 VUSs in 127 patients (of which 6 also had a P/LP variant). The presence of a VUS was significantly associated with the combined end-point of mortality, heart failure hospitalization, heart transplantation or life-threatening arrhythmias(HR, 2.04 [95% CI, 1.15 to 3.65]; p = 0.02). The association of a VUS with prognosis remained when we only included VUSs in robust DCM-associated genes (high suspicious VUSs), but disappeared when we only included VUSs in non-robust DCM-associated genes (low suspicious VUSs), highlighting the importance of weighing of VUSs. Overall, the use of large gene panels for genetic testing in DCM does not increase the diagnostic yield, although a VUS in a robust DCM-associated gene is associated with an adverse prognosis. Altogether, current diagnostic gene panels should be limited to the robust DCM-associated genes.

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Fig. 1: Flow chart of genetic testing in DCM patients.
Fig. 2: Genetic yield of the HEART panel.
Fig. 3: Survival curves show freedom from combined endpoint (cardiac death or transplantation, heart failure hospitalization or life-threatening arrhythmia) stratified on the number of detected variants of unknown significance (VUSs) in the HEART panel.
Fig. 4: Survival curves show freedom from combined endpoint (cardiac death or transplantation, heart failure hospitalization or life-threatening arrhythmia) stratified on the presence of at least one variant of unknown significance (VUS).

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Data availability

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

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Funding

JV is supported by a Dutch Heart Foundation Dekker – Clinical Scientist grant. The views expressed in this work are those of the authors and not necessarily those of the funders

Author information

Authors and Affiliations

  1. Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands

    Sophie L. V. M. Stroeks, Maurits Sikking & Job A. J. Verdonschot

  2. Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium

    Sophie L. V. M. Stroeks

  3. European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart, (ERN GUARD-Heart), Amsterdam, The Netherlands

    Sophie L. V. M. Stroeks, Debby Hellebrekers, Godelieve R. F. Claes, Ingrid P. C. Krapels, Maurits Sikking, Els K. Vanhoutte, Apollonia Helderman-van den Enden, Han G. Brunner, Arthur van den Wijngaard & Job A. J. Verdonschot

  4. Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands

    Debby Hellebrekers, Godelieve R. F. Claes, Ingrid P. C. Krapels, Els K. Vanhoutte, Apollonia Helderman-van den Enden, Han G. Brunner, Arthur van den Wijngaard & Job A. J. Verdonschot

  5. Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands

    Michiel H. T. M. Henkens

  6. Netherlands Heart Institute (NLHI), Utrecht, The Netherlands

    Michiel H. T. M. Henkens

  7. GROW Institute for Developmental Biology and Cancer, Maastricht University, Maastricht, The Netherlands

    Han G. Brunner

  8. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

    Han G. Brunner

Authors
  1. Sophie L. V. M. Stroeks
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  2. Debby Hellebrekers
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Contributions

Conceptualization: SS, DH, JV; Data curation: SS, DH, GC, MH, MS, JV; Formal Analysis: SS, JV; Funding acquisition: JV, HB, A-vdW; Investigation: SS, DH, GC, IK, EV, AH-vdE, JV; Methodology: JV, Resources: HB, A-vdW; Supervision: HB, JV; Visualization: SS, JV; Writing – original draft: SS, DH, JV; Writing – review & editing: GC, IK, MH, MS, EV, AH-vdE.

Corresponding author

Correspondence to Job A. J. Verdonschot.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

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.

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Stroeks, S.L.V.M., Hellebrekers, D., Claes, G.R.F. et al. Diagnostic and prognostic relevance of using large gene panels in the genetic testing of patients with dilated cardiomyopathy. Eur J Hum Genet 31, 776–783 (2023). https://doi.org/10.1038/s41431-023-01384-y

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