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

Abstract

BackgroundVariants 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 resultsLongitudinal 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).ConclusionsMYBPC3 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.

Genetic Basis of Childhood Cardiomyopathy

“…2 While variants in MYBPC3 were predominantly loss-of-function, there were 5 unique P/LP missense variants, and all but one were located between amino acid residues 495 to 531 within a previously reported cluster of the C3 domain. 20,21 Variants in TNNT2 and TNNI3 accounted for almost one-third of DCM and half of RCM, and while rare overall in HCM, were more likely to be associated with symptomatic presentation (P<0.01) and heart transplant or sudden cardiac death (P<0.01) when compared to P/LP variants in MYH7 and MYBPC3.…”

Clinical and Genetic Screening for Hypertrophic Cardiomyopathy in Paediatric Relatives: Changing Paradigms in Clinical Practice

“…In addition, patients with disease-causing variants in MYH7 and MYBC3 were at the highest risk for developing HCM in childhood and experiencing an adverse event or requiring intervention. Indeed, while previous data had suggested that MYBPC3 variants in particular were associated with late-onset disease [38], more recent studies have shown that MYBPC3 variants in heterozygosis can cause severe phenotypic expression of disease in childhood, with a high prevalence of malignant ventricular arrhythmia [39]. Furthermore, there are data to show that, in the context of a multidisciplinary expert setting and with adequate psychological support, clinical screening of paediatric first-degree relatives does not result in psychological harm [40].…”

Childhood Hypertrophic Cardiomyopathy Caused by Beta-Myosin Heavy Chain Variants Is Associated With a More Obstructive but Less Arrhythmogenic Phenotype Than Myosin-Binding Protein C Disease

“…1,2 We have recently described the clinical presentation and outcomes of children with HCM caused by MYBPC3 variants and showed that these can cause early-onset disease with a high incidence of lifethreatening arrhythmias, 3 contrasting with previous suggestions that they cause late-onset disease. 4 Using the same methods, 3 we established a retrospective, longitudinal cohort of children diagnosed with HCM aged <18 years with a disease-causing variant in MYH7 at our center. Variant pathogenicity was reassessed according to the American College of Medical Genetics and Genomics criteria.…”

“…Hypertrophic cardiomyopathy (HCM) presenting in childhood is most commonly caused by sarcomeric variants, with the β-myosin heavy chain ( MYH7 ) or myosin-binding protein C ( MYBPC3 ) genes most frequently implicated. 1,2 We have recently described the clinical presentation and outcomes of children with HCM caused by MYBPC3 variants and showed that these can cause early-onset disease with a high incidence of life-threatening arrhythmias, 3 contrasting with previous suggestions that they cause late-onset disease. 4…”

“…Using the same methods, 3 we established a retrospective, longitudinal cohort of children diagnosed with HCM aged <18 years with a disease-causing variant in MYH7 at our center. Variant pathogenicity was reassessed according to the American College of Medical Genetics and Genomics criteria.…”