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J Am Coll Cardiol. 2018 Nov 6;72(19):2324-2338. doi: 10.1016/j.jacc.2018.08.2171.

Genetic Basis of Severe Childhood-Onset Cardiomyopathies.

Author information

1
Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
2
Department of Pediatric Cardiology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
3
Blueprint Genetics, Helsinki, Finland.
4
Department of Pediatric Nephrology and Transplantation, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
5
Department of Pathology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
6
Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Department of Pediatric Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
7
Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Molecular and Clinical Sciences, St. George's, University of London, London, United Kingdom.
8
Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Department of Neurology, Helsinki University Hospital and Clinical Neurosciences, University of Helsinki, Helsinki, Finland; Neuroscience Center, HiLife, University of Helsinki, Helsinki, Finland. Electronic address: anu.wartiovaara@helsinki.fi.

Abstract

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.

KEYWORDS:

cardiac transplantation; de novo mutations; genotype-phenotype correlation; heart failure; next-generation sequencing; pediatric

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