Sarcomeric variants in childhood-onset cardiomyopathy were associated with a nearly 7-fold higher odds of major cardiac events (OR = 6.7, 95% CI 1.83-24.55, p=0.004).
Are sarcomeric variants associated with an increased risk of major cardiac events in children with childhood-onset cardiomyopathy?
In childhood-onset cardiomyopathy, sarcomeric variants can manifest in infancy and are associated with a significantly increased risk of major cardiac events, underscoring the importance of early genetic testing.
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Abstract Background Childhood-onset cardiomyopathy (CMP) is a rare but life-threatening condition, with 25% of affected patients experiencing (sudden) cardiac death (SCD). Identifying the underlying aetiology is critical for optimal personalized treatment and prognosis management. Almost half of the children have a positive familial history of CMP or SCD and the current genetic yielding is 50-60% depending on the CMP phenotype. Purpose To investigate genotype-phenotype correlations, cardiac outcomes and prognostic factors in children with clinical diagnosis of CMP. Methods Children under 18yrs presenting at our institution between 1990-2025 with any type of CMP, were included in the study. Demographic, genetic, and outcome data were collected and analysed. Results A total of 166 children (63% male, mean age: 5±5.8yrs) were diagnosed with CMP. The most frequent subtypes were hypertrophic CMP (HCM, 48%) and dilated CMP (DCM, 47%) with limited cases of restrictive CMP (RCM, 6 patients) and arrhythmogenic right ventricle CMP (ARVC, 2 patients). Nearly half of the patients (47%) were diagnosed during infancy. 35.5% of patients had a positive family history for CMP or SCD, with 56% probands. Genetic sequencing was performed in 70.5% of patients, most frequently in HCM (75%). A causative variant was identified in 58.6% overall. But, genetic yield was higher in children with HCM in comparison to those with DCM (67.8% vs 47.1%, p=0.019). Variants of unknown significance were found in 3.4% and 19.6%, respectively. Higher genetic yield was seen with increasing age. Notably, sarcomeric variants, traditionally associated with adult-onset CMP, were present across all ages, with 38.2% of all variants found in the group diagnosed at infancy. Major cardiac events (MCE) occurred in 41.6%. Of all patients 24.1% died, 12.7% underwent a heart transplantation and 7.2% received an implantable cardioverter-defibrillator. In the general population, multivariate analysis revealed that consanguinity was associated with a 4.6-fold higher odds for MCE (OR = 4.6, 95%CI 1.45;14.52, p=0.009). Whereas the odds for MCE in patients with symptoms at diagnosis was 3.7 times higher (OR = 3.7, 95%CI 1.67;8.03, p=0.001) and 6.3 times higher (OR = 6.3, 95%CI 1.54;25.58, p=0.010) in the genotype positive population. In the latter, sarcomeric variants yielded an almost 7 times higher odds of having a MCE (OR = 6.7, 95%CI 1.83;24.55, p=0.004). Conclusions Genetic testing identified the underlying aetiology in almost 60% of patients with childhood-onset CMP. Sarcomeric variants – once thought to be limited to adult-onset CMP – starts manifesting at the youngest age. Symptoms at diagnosis and sarcomeric variants were associated with increased risk of MCE. These findings underscore the importance of early genetic testing to guide diagnosis and management.
Renders et al. (Sun,) reported a other. Sarcomeric variants in childhood-onset cardiomyopathy were associated with a nearly 7-fold higher odds of major cardiac events (OR = 6.7, 95% CI 1.83-24.55, p=0.004).