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

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

Synthetic vs. Real-World Continuous Landscapes: A Local Optima Networks View

Local optima networks (LONs) are a useful tool to analyse and visualise the global structure of fitness landscapes. The main goal of our study is to use LONs to contrast the global structure of synthetic benchmark functions against those of real-world continuous optimisation problems of similar dimensions. We selected two real-world problems, namely, an engineering design problem and a machine learning problem. Our results indicate striking differences in the global structure of synthetic vs real-world problems. The real-world problems studied were easier to solve than the synthetic ones, and our analysis reveals why; they have easier to traverse global structures with fewer nodes and edges, no sub-optimal funnels, higher neutrality and multiple global optima with shorter trajectories towards them

Deletions of specific exons of FHOD3 detected by next-generation-sequencing are associated with hypertrophic cardiomyopathy

Despite new strategies, such as evaluating deep intronic variants and new genes in whole-genome-sequencing studies, the diagnostic yield of genetic testing in hypertrophic cardiomyopathy (HCM) is still around 50%. FHOD3 has emerged as a novel disease-causing gene for this phenotype, but the relevance and clinical implication of copy-number-variations (CNVs) have not been determined. In this study, CNVs were evaluated using a comparative depth-of-coverage strategy by NGS in 5493 hypertrophic cardiomyopathy probands and 2973 disease-controls. We detected three symmetrical deletions in FHOD3 that involved exons 15 and 16 in three HCM families (no CNVs were detected in the control group). These exons are part of the diaphanous inhibitory domain of FHOD3 protein, considered a cluster of mutations for HCM. The clinical characteristics of the affected carriers were consistent with those reported in FHOD3 in previous studies. This study highlights the importance of performing CNV analysis systematically in NGS genetic testing panels for HCM, and reinforce the relevance of the FHOD3 gene in the disease. This article is protected by copyright. All rights reserved

Yield of Clinical Screening for Hypertrophic Cardiomyopathy in Child First-Degree Relatives: Evidence for a Change in Paradigm

Background: Hypertrophic Cardiomyopathy (HCM) is a heritable myocardial disease with age related penetrance. Current guidelines recommend clinical screening of relatives from the age of 10 years onwards but the clinical value of this approach has not been systematically evaluated. Methods: Anonymized, clinical data were collected from children referred for family screening between 1994-2017 following diagnosis of HCM in a first-degree relative. Results: 1198 consecutive children (aged ≤ 18 years) from 594 families underwent serial evaluation [median 3.5 years (IQR, 1.2-7)]; 32 individuals met diagnostic criteria at baseline (median maximal LV wall thickness (MLVWT) 13mm (IQR, 8-21mm)) and 25 additional patients developed HCM during follow up. Median age at diagnosis was 10 years (IQR 4-13); 44 (72%) were 12 years or younger. Median age of affected patients at last follow up was 14 years (IQR 9.5-18.2). A family history of childhood HCM was more common in those patients diagnosed with HCM (n=32, 56%, VS n=257, 23% P <0.001). 18 patients (32%) were started on medication for symptoms, 2 (4%) underwent a septal myectomy, 14 (25%) received an implantable cardioverter defibrillator, 1 underwent cardiac transplantation, 2 had a resuscitated cardiac arrest and 1 died following a cerebrovascular accident. Conclusions: Almost 5% of first-degree child relatives undergoing screening meet diagnostic criteria for HCM at first or subsequent evaluations, with the majority presenting as preadolescents; a diagnosis in a child first-degree relative is made in 8% of families screened. The phenotype of familial HCM in childhood is varied and includes severe disease, suggesting that clinical screening should commence at a younger ag