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Genetic Basis of Childhood-Onset Cardiomyopathies Identified

By Labmedica International staff writers
Posted on 21 Nov 2018
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Image: A diagram of the KidCMP cohort of children with severe cardiomyopathies from the past 21 years who were analyzed genetically (Photo courtesy of Catalina Vasilescu/University of Helsinki).
Image: A diagram of the KidCMP cohort of children with severe cardiomyopathies from the past 21 years who were analyzed genetically (Photo courtesy of Catalina Vasilescu/University of Helsinki).
Personalized medicine is one of the goals of the current medical studies, where the understanding of the genetic cause and disease mechanism in each individual will promote tailored forms of treatment. Investigators make an important step in this direction by deciphering genetic causes in children and their implications for treatment decisions.

Cardiac muscle degeneration (cardiomyopathy) is the most common cause of severe cardiac dysfunction and life-threatening cardiac arrhythmias in children. These severe disorders often lead to consideration of heart transplant. However, their actual cause, the genetic basis, has been poorly characterized.

A collaborative effort of pediatric cardiologists of the Helsinki University Hospital (Helsinki, Finland) and the University of Helsinki (Helsinki, Finland) succeeded to collect a globally unique KidCMP cohort of 66 children with severe cardiomyopathies from the past 21 years, and analyzed them genetically. 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. For genetic diagnosis, next-generation sequencing and subsequent validation using genetic, cell biology, and computational approaches were used.

The team identified the pathogenic variants in 39% of patients: 46% de novo, 34% recessive, and 20% dominantly inherited. They reported 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).

The authors concluded that 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.

Tiina Ojala, MD, PhD, a pediatric cardiologist and a senior author of the study, said, “All children had life-threatening diseases early on, and some genetic defects predicted a primarily progressive disorder requiring cardiac transplant. However, if intensively treated, some gene defects predicted a recuperative course, without a transplant.” The study was published in the November 2018 issue of the Journal of the American College of Cardiology.

Related Links:
Helsinki University
University of Helsinki


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