Key result
Children with cardiomyopathy and de novo variants were more likely to have a history of arrhythmia (p=0.049), sudden cardiac arrest (p=0.024), hospitalization (p=0.041), and transplant (p=0.030).
Why the study?
De novo variants have been reported in pediatric cardiomyopathies, but their overall frequency is largely unknown.
Does the presence of de novo pathogenic variants worsen clinical outcomes in pediatric cardiomyopathy?
Observational (n=126)
Does the presence of de novo pathogenic variants worsen clinical outcomes in pediatric cardiomyopathy?
De novo pathogenic variants are present in a significant proportion of pediatric cardiomyopathy cases, particularly restrictive cardiomyopathy, and are associated with worse clinical outcomes including sudden cardiac arrest and transplantation.
Findings should not yet change practice in pediatric cardiomyopathy; leaves open whether de novo variants independently predict outcomes.
Pediatric cardiomyopathies can be caused by variants in genes encoding the sarcomere and cytoskeleton in cardiomyocytes. Variants are typically inherited in an autosomal dominant manner with variable expressivity. De novo variants have been reported, however their overall frequency is largely unknown. We sought to determine the rate of de novo, pathogenic and likely pathogenic (P/LP) variants in children with a diagnosis of hypertrophic, dilated, or restrictive cardiomyopathy (HCM, DCM, or RCM), and to compare disease outcomes between individuals with and without a de novo variant. A retrospective record review identified 126 individuals with HCM (55%), DCM (37%), or RCM (8%) ≤18 years of age who had genetic testing. Overall, 50 (40%) had positive genetic testing and 18% of P/LP variants occurred de novo. The rate of de novo variation in those with RCM (80%) was higher than in those with HCM (9%) or DCM (20%). There was evidence of germline mosaicism in one family with RCM. Individuals with de novo variants were more likely than those without to have a history of arrhythmia (p = .049), sudden cardiac arrest (p = .024), hospitalization (p = .041), and cardiac transplantation (p = .030). The likelihood of de novo variation and impact on family risk and screening should be integrated into genetic counseling.
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Parrott et al. (2020) conducted an observational in Pediatric cardiomyopathy (HCM, DCM, or RCM) (n=126). De novo pathogenic/likely pathogenic variants vs. Without a de novo variant was evaluated on Disease outcomes including arrhythmia, sudden cardiac arrest, hospitalization, and cardiac transplantation. Children with cardiomyopathy and de novo variants were more likely to have a history of arrhythmia (p=0.049), sudden cardiac arrest (p=0.024), hospitalization (p=0.041), and transplant (p=0.030).
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