Dataset Information

Cardiac myosin binding protein-C variants in paediatric-onset hypertrophic cardiomyopathy: natural history and clinical outcomes.

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.

SUBMITTER: Field E

PROVIDER: S-EPMC7613139 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AIMS:A 25-base pair deletion in the cardiac myosin binding protein-C (cMyBP-C) gene (MYBPC3), proposed to skip exon 33, modifies the C10 domain (cMyBP-C?C10mut) and is associated with hypertrophic cardiomyopathy (HCM) and heart failure, affecting approximately 100 million South Asians. However, the molecular mechanisms underlying the pathogenicity of cMyBP-C?C10mutin vivo are unknown. We hypothesized that expression of cMyBP-C?C10mut exerts a poison polypeptide effect leading to improper assembly of cardiac sarcomeres and the development of HCM. METHODS AND RESULTS:To determine whether expression of cMyBP-C?C10mut is sufficient to cause HCM and contractile dysfunction in vivo, we generated transgenic (TG) mice having cardiac-specific protein expression of cMyBP-C?C10mut at approximately half the level of endogenous cMyBP-C. At 12?weeks of age, significant hypertrophy was observed in TG mice expressing cMyBP-C?C10mut (heart weight/body weight ratio: 4.43?±?0.11?mg/g non-transgenic (NTG) vs. 5.34?±?0.25?mg/g cMyBP-C?C10mut, P?<?0.05). Furthermore, haematoxylin and eosin, Masson's trichrome staining, as well as second-harmonic generation imaging revealed the presence of significant fibrosis and a greater relative nuclear area in cMyBP-C?C10mut hearts compared with NTG controls. M-mode echocardiography analysis revealed hypercontractile hearts (EF: 53.4%±2.9% NTG vs. 66.4% ± 4.7% cMyBP-C?C10mut; P?<?0.05) and early diastolic dysfunction (E/E': 28.7?±?3.7 NTG vs. 46.3?±?8.4 cMyBP-C?C10mut; P?<?0.05), indicating the presence of an HCM phenotype. To assess whether these changes manifested at the myofilament level, contractile function of single skinned cardiomyocytes was measured. Preserved maximum force generation and increased Ca2+-sensitivity of force generation were observed in cardiomyocytes from cMyBP-C?C10mut mice compared with NTG controls (EC50: 3.6?±?0.02?µM NTG vs. 2.90?±?0.01?µM cMyBP-C?C10mut; P?<?0.0001). CONCLUSION:Expression of cMyBP-C protein with a modified C10 domain is sufficient to cause contractile dysfunction and HCM in vivo.