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Molecular Diagnosis of Inherited Cardiac Diseases in the Era of Next-Generation Sequencing: A Single Center’s Experience Over 5 Years

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Abstract

Background and objective

Molecular diagnosis in inherited cardiac diseases is challenging because of the significant genetic and clinical heterogeneity. We present a detailed molecular investigation of a cohort of 4185 patients with referrals for inherited cardiac diseases.

Methods

Patients suffering from cardiomyopathies (3235 probands), arrhythmia syndromes (760 probands), or unexplained sudden cardiac arrest (190 cases) were analyzed using a next-generation sequencing (NGS) workflow based on a panel of 105 genes involved in sudden cardiac death.

Results

(Likely) pathogenic variations were identified for approximately 30% of the cohort. Pathogenic copy number variations (CNVs) were detected in approximately 3.1% of patients for whom a (likely) pathogenic variation were identified. A (likely) pathogenic variation was also detected for 21.1% of patients who died from sudden cardiac death. Unexpected variants, including incidental findings, were present for 28 cases. Pathogenic variations were mainly observed in genes with definitive evidence of disease causation.

Conclusions

Our study, which comprises over than 4000 probands, is one of most important cohorts reported in inherited cardiac diseases. The global mutation detection rate would be significantly increased by determining the putative pathogenicity of the large number of variants of uncertain significance. Identification of "unexpected" variants also showed the clinical utility of genetic testing in inherited cardiac diseases as they can redirect clinical management and medical resources toward a meaningful precision medicine. In cases with negative result, a WGS approach could be considered, but would probably have a limited impact on mutation detection rate as (likely) pathogenic variations were essentially clustered in genes with strong evidence of disease causation.

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Acknowledgements

The authors are grateful to the patients and families involved, as well as to all their colleagues who provided them with biological samples and with invaluable clinical information.

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Authors and Affiliations

  1. Laboratoire de Cardiogénétique Moléculaire, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron Cedex, 69677, Lyon, France

    Alexandre Janin, Louis Januel, Cécile Cazeneuve & Gilles Millat

  2. Institut NeuroMyoGène, CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France

    Alexandre Janin & Gilles Millat

  3. Université de Lyon, 69003, Lyon, France

    Alexandre Janin, Antoine Delinière, Philippe Chevalier & Gilles Millat

  4. Hôpital Cardiologique Louis Pradel, Service de Rythmologie, Lyon, France

    Antoine Delinière & Philippe Chevalier

Authors
  1. Alexandre Janin
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  2. Louis Januel
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  3. Cécile Cazeneuve
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  4. Antoine Delinière
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  5. Philippe Chevalier
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  6. Gilles Millat
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Corresponding author

Correspondence to Gilles Millat.

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Funding

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Conflicts of interest

AJ, LJ, CC, AD, PC, and GM are employees of Hospices Civils de Lyon (France). None of the authors have potential conflicts of interest to declare.

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Not applicable.

Author contributions

AJ, LJ, CC, and GM are molecular biologists involved in all molecular diagnosis steps (from blood sample to clinical reports). AD and PC are cardiologists and coordinators of the National Reference Center of inherited cardiac diseases in Lyon.

Grant information

Molecular diagnosis was supported by Hospices Civils de Lyon (France).

Informed consent

The study was conducted in accordance with the principles of the Declaration of Helsinki and informed consent was obtained for all cases.

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Data availability statement

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

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Janin, A., Januel, L., Cazeneuve, C. et al. Molecular Diagnosis of Inherited Cardiac Diseases in the Era of Next-Generation Sequencing: A Single Center’s Experience Over 5 Years. Mol Diagn Ther 25, 373–385 (2021). https://doi.org/10.1007/s40291-021-00530-w

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