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Molecular Diagnosis of Primary Cardiomyopathy in 231 Unrelated Pediatric Cases by Panel-Based Next-Generation Sequencing: A Major Focus on Five Carriers of Biallelic TNNI3 Pathogenic Variants

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Abstract

Background and Objective

Pediatric cardiomyopathies are clinically heterogeneous heart muscle disorders associated with significant morbidity and mortality for which substantial evidence for a genetic contribution was previously reported. We present a detailed molecular investigation of a cohort of 231 patients presenting with primary cardiomyopathy below the age of 18 years.

Methods

Cases with pediatric cardiomyopathies were analyzed using a next-generation sequencing (NGS) workflow based on a virtual panel including 57 cardiomyopathy-related genes.

Results

This molecular approach led to the identification of 69 cases (29.9% of the cohort) genotyped as a carrier of at least one pathogenic or likely pathogenic variant. Fourteen patients were carriers of two mutated alleles (homozygous or compound heterozygous) on the same cardiomyopathy-related gene, explaining the severe clinical disease with early-onset cardiomyopathy. Homozygous TNNI3 pathogenic variants were detected for five unrelated neonates (2.2% of the cohort), with four of them carrying the same truncating variant, i.e. p.Arg69Alafs*8.

Conclusions

Our study confirmed the importance of genetic testing in pediatric cardiomyopathies. Discovery of novel pathogenic variations is crucial for clinical management of affected families, as a positive genetic result might be used by a prospective parent for prenatal genetic testing or in the process of pre-implantation genetic diagnosis.

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Acknowledgements

The authors are grateful to the patients and families, as well as to all colleagues who, over many years, 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, 69677, Bron, Cedex, France

    Alexandre Janin, Cécile Cazeneuve, Rajae El-Malti & Gilles Millat

  2. Université de Lyon 1, Lyon, France

    Alexandre Janin, Cécile Cazeneuve, Rajae El-Malti & Gilles Millat

  3. Unité médico-chirurgicale des cardiopathies congénitales, Hôpital Cardiologique Louis Pradel, Hospices Civils de Lyon, Bron, France

    Thomas Perouse de Montclos

  4. Département de Génétique, APHM, Hôpital Timone Adultes, Marseille, France

    Karine Nguyen & Emilie Consolino

  5. Genetics Department, Metropole Savoie Hospital Center, Chambéry, France

    Gwenael Nadeau & Gaelle Rey

  6. Service de Cardiologie, Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France

    Océane Bouchot

  7. Département de Génétique Médicale, CHU de Montpellier, Montpellier, France

    Patricia Blanchet & Quentin Sabbagh

  8. Service de Rythmologie, Hôpital Cardiologique Louis Pradel, Hospices Civils de Lyon, Bron, France

    Elodie Morel, Antoine Delinière & Philippe Chevalier

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  1. Alexandre Janin
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  2. Thomas Perouse de Montclos
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  3. Karine Nguyen
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  10. Cécile Cazeneuve
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  15. Gilles Millat
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Corresponding author

Correspondence to Gilles Millat.

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Funding

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

Conflict of interest

Alexandre Janin, Thomas Perouse de Montclos, Cécile Cazeneuve, Rajae El-Malti, Elodie Morel, Antoine Delinière, Philippe Chevalier, and Gilles Millat are employees of Hospices Civils de Lyon (HCL), France. Karine Nguyen and Emilie Consolino are employees of Assistance Publique Hôpitaux Marseille (APHM), France. Gwenael Nadeau and Gaelle Rey are employees of Metropole Savoie Hospital Center at Chambéry, France. Océane Bouchot is employee of Centre Hospitalier Annecy, Genevois, France. Patricia Blanchet is employee of CHU de Montpellier, France. Quentin Sabbagh is an employee of Département de Génétique Médicale, CHU de Montpellier, Montpellier, France. None of the authors have any potential conflicts of interest to declare.

Informed consent and ethical approval

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

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Data availability statement

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

Code availability

Not applicable.

Authors’ contributions

AJ, CC, and GM are Molecular Biologists involved in all molecular diagnosis steps (from blood sample to clinical reports). TPM, AD, PC and OB are Cardiologists involved in the clinical follow-up of the different families reported in this study. REM and EM are Clinical Research Assistants at the National Reference Center of Inherited Cardiac Diseases in Lyon. KN, EC, GN, GR, QS and PB are medical geneticists involved in genetic follow-up of the different families reported in this study (genetic counseling).

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Janin, A., Perouse de Montclos, T., Nguyen, K. et al. Molecular Diagnosis of Primary Cardiomyopathy in 231 Unrelated Pediatric Cases by Panel-Based Next-Generation Sequencing: A Major Focus on Five Carriers of Biallelic TNNI3 Pathogenic Variants. Mol Diagn Ther 26, 551–560 (2022). https://doi.org/10.1007/s40291-022-00604-3

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