Next-generation sequencing identified pathogenic variants in 39% of patients with severe childhood cardiomyopathies, with 46% of these being de novo mutations.
Cohort (n=66)
No
Does next-generation sequencing identify pathogenic variants in children with severe childhood cardiomyopathies?
Next-generation sequencing identified pathogenic variants in 39% of severe childhood cardiomyopathy cases, mostly de novo, highlighting its utility for diagnosis, prognosis, and treatment guidance.
BACKGROUND Childhood cardiomyopathies are progressive and often lethal disorders, forming the most common cause of heart failure in children. Despite severe outcomes, their genetic background is still poorly characterized. OBJECTIVES The purpose of this study was to characterize the genetics of severe childhood cardiomyopathies in a countrywide cohort. METHODS The authors collected a countrywide cohort, KidCMP, of 66 severe childhood cardiomyopathies from the sole center in Finland performing cardiac transplantation. For genetic diagnosis, next-generation sequencing and subsequent validation using genetic, cell biology, and computational approaches were used. RESULTS The KidCMP cohort presents remarkable early-onset and severe disorders: the median age of diagnosis was 0.33 years, and 17 patients underwent cardiac transplantation. The authors identified the pathogenic variants in 39% of patients: 46% de novo, 34% recessive, and 20% dominantly-inherited. The authors report NRAP underlying childhood dilated cardiomyopathy, as well as novel phenotypes for known heart disease genes. Some genetic diagnoses have immediate implications for treatment: CALM1 with life-threatening arrhythmias, and TAZ with good cardiac prognosis. The disease genes converge on metabolic causes (PRKAG2, MRPL44, AARS2, HADHB, DNAJC19, PPA2, TAZ, BAG3), MAPK pathways (HRAS, PTPN11, RAF1, TAB2), development (NEK8 and TBX20), calcium signaling (JPH2, CALM1, CACNA1C), and the sarcomeric contraction cycle (TNNC1, TNNI3, ACTC1, MYH7, NRAP). CONCLUSIONS Childhood cardiomyopathies are typically caused by rare, family-specific mutations, most commonly de novo, indicating that next-generation sequencing of trios is the approach of choice in their diagnosis. Genetic diagnoses may suggest intervention strategies and predict prognosis, offering valuable tools for prioritization of patients for transplantation versus conservative treatment.
“The results highlighted an extremely variable genetic background, each family presenting a different pathogenic variant that often arose during the patient's own embryonal development”
Vasilescu et al. (Thu,) conducted a cohort in Severe childhood cardiomyopathies (n=66). Next-generation sequencing was evaluated on Identification of pathogenic variants. Next-generation sequencing identified pathogenic variants in 39% of patients with severe childhood cardiomyopathies, with 46% of these being de novo mutations.