Author + information
- Received February 13, 2018
- Revision received August 9, 2018
- Accepted August 12, 2018
- Published online October 29, 2018.
- Catalina Vasilescu, MSca,
- Tiina H. Ojala, MD, PhDb,
- Virginia Brilhante, PhDa,
- Simo Ojanen, MSca,
- Helena M. Hinterding, BSca,
- Eino Palin, MD, PhDa,
- Tero-Pekka Alastalo, MD, PhDc,
- Juha Koskenvuo, MD, PhDc,
- Anita Hiippala, MD, PhDb,
- Eero Jokinen, MD, PhDb,
- Timo Jahnukainen, MD, PhDd,
- Jouko Lohi, MD, PhDe,
- Jaana Pihkala, MD, PhDb,
- Tiina A. Tyni, MD, PhDa,f,
- Christopher J. Carroll, PhDa,g and
- Anu Suomalainen, MD, PhDa,h,i,∗ (, )@AWartiovaara
- aResearch Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland
- bDepartment of Pediatric Cardiology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- cBlueprint Genetics, Helsinki, Finland
- dDepartment of Pediatric Nephrology and Transplantation, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- eDepartment of Pathology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- fDepartment of Pediatric Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- gMolecular and Clinical Sciences, St. George’s, University of London, London, United Kingdom
- hDepartment of Neurology, Helsinki University Hospital and Clinical Neurosciences, University of Helsinki, Helsinki, Finland
- iNeuroscience Center, HiLife, University of Helsinki, Helsinki, Finland
- ↵∗Address for correspondence:
Dr. Anu Suomalainen, Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, r.C523B, Haartmaninkatu 8, 00290 Helsinki, Finland.
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.
- cardiac transplantation
- de novo mutations
- genotype-phenotype correlation
- heart failure
- next-generation sequencing
This study was supported by the Jane and Aatos Erkko Foundation, Sigrid Jusélius Foundation, Academy of Finland, University of Helsinki, Helsinki Doctoral Programme in Biomedicine, Finnish Cultural Foundation, and Foundation for Pediatric Research Finland. Drs. Alastalo and Koskenvuo are cofounders and directors of Blueprint Genetics, which offers genetic diagnostics for cardiomyopathies. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received February 13, 2018.
- Revision received August 9, 2018.
- Accepted August 12, 2018.
- 2018 American College of Cardiology Foundation
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