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