Pediatric Primary Cardiomyopathy Research Articles

Identification of Gene Mutations in Primary Pediatric Cardiomyopathy by Whole Exome Sequencing.

Pediatric primary cardiomyopathy is rare but serious, having high mortality; hypertrophic and dilated types are the most common. Its etiology has been mainly considered idiopathic; however, next generation sequencing techniques have revealed nearly half of idiopathic pediatric cases arose from specific genetic mutations. Therefore, our study aimed to identify the genetic causes of primary idiopathic cardiomyopathy. Newborns to 15-year old patients with this condition were recruited between March 2016 and May 2017 at Thammasat University Hospital. Complete patient history and physical examination data were collected by a geneticist with cardiac examinations and echocardiograms by pediatric cardiologists. Whole exome sequencing was performed for all. Of the 12 patients enrolled, 5 cases were dilated type and 7 hypertrophic. Two with dilated type were excluded during follow-up as cause was determined (hypocalcemia and pacemaker induced). A list of 118 genes for cardiomyopathy was analyzed in the remaining 10 cases. Pathogenic and likely pathogenic mutations were identified in 5 patients: HRAS, PTPN11, SOS1, FLNC and TXNRD2; half our patients were not actually idiopathic. Despite its high cost, genetic testing is useful for determining familial risk as well as predicting patient cardiomyopathy progress.

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3.

The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel-based next-generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation-not only in adult-but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP.

RIKADA Study Reveals Risk Factors in Pediatric Primary Cardiomyopathy.

BackgroundCardiomyopathies are heterogeneous diseases with clinical presentations varying from asymptomatic to life‐threatening events, including severe heart failure and sudden cardiac death. The role of underlying genetic and disease‐modulating factors in children and adolescents is relatively unknown. In this prospective study, in‐depth phenotypic and genetic characterization of pediatric patients with primary cardiomyopathy and their first‐degree family members (FMs) was performed. Outcome was assessed to identify clinical risk factors.Methods and ResultsSixty index patients with primary cardiomyopathy (median age: 7.8 years) and 124 FMs were enrolled in the RIKADA (Risk Stratification in Children and Adolescents with Primary Cardiomyopathy) study. Family screening included cardiac workup and genetic testing. Using cardiologic screening, we identified 17 FMs with cardiomyopathies and 30 FMs with suspected cardiomyopathies. Adverse events appeared in 32% of index patients and were more common in those with lower body surface area (P=0.019), increased NT‐proBNP (N‐terminal pro–brain natriuretic peptide; P<0.001), and left ventricular dysfunction (P<0.001) and dilatation (P=0.005). The worst prognosis was observed in dilated and restrictive cardiomyopathies. Genetic variants of interest were detected in patients (79%) and FMs (67%). In all 15 families with at least 1 FM with cardiomyopathy, we found a variant of interest in the index patient. Increased number of variants of interest per patient was associated with adverse events (P=0.021). Late gadolinium enhancement was related to positive genotypes in patients (P=0.041).ConclusionsLower body surface area, increased NT‐proBNP, left ventricular dysfunction or dilatation, late gadolinium enhancement, and increased number of variants of interest were associated with adverse outcome and should be considered for risk assessment in pediatric primary cardiomyopathies.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov/. Unique identifier: NCT03572569.