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Published on: November 3, 2010
Genetic Basis of Severe Childhood-Onset Cardiomyopathies
Catalina Vasilescu1, Tiina H Ojala2, Virginia Brilhante1
1Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
Insights
Genetic analysis of severe childhood cardiomyopathies identified pathogenic variants in 39% of patients. This research highlights the importance of next-generation sequencing for diagnosing these rare heart conditions and guiding treatment.
Area of Science:
- Pediatric Cardiology
- Genetics
- Molecular Biology
Background:
- Childhood cardiomyopathies are a leading cause of heart failure in children, often resulting in severe outcomes.
- The genetic underpinnings of these progressive heart disorders remain largely uncharacterized.
Purpose of the Study:
- To genetically characterize a nationwide cohort of children with severe cardiomyopathies.
- To identify the genetic basis of early-onset and severe heart conditions in pediatric patients.
Main Methods:
- Collected a cohort of 66 severe childhood cardiomyopathy cases from Finland's sole cardiac transplant center.
- Employed next-generation sequencing (NGS) for genetic diagnosis, followed by validation using genetic, cell biology, and computational methods.
Main Results:
- Identified pathogenic variants in 39% of patients, with 46% being de novo, 34% recessive, and 20% dominant.
- Reported NRAP as a cause of childhood dilated cardiomyopathy and identified novel phenotypes for known heart disease genes.
- Highlighted immediate treatment implications for variants in CALM1 (arrhythmias) and TAZ (cardiac prognosis).
- Found disease gene convergence on metabolic pathways, MAPK signaling, development, calcium signaling, and sarcomeric function.
Conclusions:
- Childhood cardiomyopathies are frequently caused by rare, often de novo mutations, making trio-based NGS a preferred diagnostic approach.
- Genetic diagnoses are crucial for guiding treatment strategies, predicting prognosis, and prioritizing patients for cardiac transplantation.
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.
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