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Original research
Cardiac myosin binding protein-C variants in paediatric-onset hypertrophic cardiomyopathy: natural history and clinical outcomes
  1. Ella Field1,2,
  2. Gabrielle Norrish1,2,
  3. Vanessa Acquaah2,
  4. Kathleen Dady1,2,
  5. Marcos Nicolas Cicerchia3,
  6. Juan Pablo Ochoa3,
  7. Petros Syrris2,
  8. Karen McLeod4,
  9. Ruth McGowan5,
  10. Hannah Fell1,
  11. Luis R Lopes2,6,
  12. Elena Cervi1,2,
  13. Juan Pablo Pablo Kaski1,2
  1. 1Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
  2. 2Institute of Cardiovascular Science, University College London, London, UK
  3. 3Health in Code, A Coruna, Galicia, Spain
  4. 4Department of Paediatric Cardiology, Royal Hospital for Children, Glasgow, UK
  5. 5West of Scotland Centre for Genomic Medicine, Glasgow, UK
  6. 6Inherited Cardiovascular Disease Unit, Saint Bartholomew's Hospital Barts Heart Centre, London, UK
  1. Correspondence to Dr Juan Pablo Pablo Kaski, Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital For Children NHS Trust, London, UK; j.kaski{at}ucl.ac.uk

Abstract

Background Variants in the cardiac myosin-binding protein C gene (MYBPC3) are a common cause of hypertrophic cardiomyopathy (HCM) in adults and have been associated with late-onset disease, but there are limited data on their role in paediatric-onset HCM. The objective of this study was to describe natural history and clinical outcomes in a large cohort of children with HCM and pathogenic/likely pathogenic (P/LP) MYBPC3 variants.

Methods and results Longitudinal data from 62 consecutive patients diagnosed with HCM under 18 years of age and carrying at least one P/LP MYBPC3 variant were collected from a single specialist referral centre. The primary patient outcome was a major adverse cardiac event (MACE). Median age at diagnosis was 10 (IQR: 2–14) years, with 12 patients (19.4%) diagnosed in infancy. Forty-seven (75%) were boy and 31 (50%) were probands. Median length of follow-up was 3.1 (IQR: 1.6–6.9) years. Nine patients (14.5%) experienced an MACE during follow-up and five (8%) died. Twenty patients (32.3%) had evidence of ventricular arrhythmia, including 6 patients (9.7%) presenting with out-of-hospital cardiac arrest. Five-year freedom from MACE for those with a single or two MYBPC3 variants was 95.2% (95% CI: 78.6% to 98.5%) and 68.4% (95% CI: 40.6% to 88.9%), respectively (HR 4.65, 95% CI: 1.16 to 18.66, p=0.03).

Conclusions MYBPC3 variants can cause childhood-onset disease, which is frequently associated with life-threatening ventricular arrhythmia. Clinical outcomes in this cohort vary substantially from aetiologically and genetically mixed paediatric HCM cohorts described previously, highlighting the importance of identifying specific genetic subtypes for clinical management of childhood HCM.

  • cardiomyopathies
  • pediatrics

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Footnotes

  • Twitter @MarcosCicerchia, @jpocardio

  • Contributors EF, GN and JPPK designed the study. EF, GN, VA, KD, MCC, JPO, PS, KM, RM, HF, LRL, EC and JPPK were involved in data acquisition, analysis and interpretation. EF, GN, VA, KD, MCC, JPO, PS, KM, RM, HF, LRL, EC and JPPK were involved in drafting, reviewing and revising of the manuscript and have approved the final version. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding This work was partly funded by a British Heart Foundation Alliance Learning and Development Grant and by Great Ormond Street Hospital NHS Foundation Trust. EF is funded by Max’s Foundation and the Great Ormond Street Hospital Children’s Charity. GN is supported by the British Heart Foundation. JPPK is supported by the British Heart Foundation, Medical Research Council Clinical Academic Partnership (CARP) award, Max’s Foundation and the Great Ormond Street Hospital Children’s Charity. LRL is funded by a Medical Research Council (MRC) Clinical Academic Research Partnership (CARP) award. This work is supported by the NIHR GOSH Biomedical Research Centre.

  • Disclaimer The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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