Pediatric genetic cardiomyopathies: Genetic profile and genotype–phenotype correlations

Abstract

Genetic cardiomyopathies (CM) affect 1–1.5 children per 100,000 each year. Five subtypes of cardiomyopathy exist, dilated CM (DCM) and hypertrophic CM (HCM) being the most common. This study aimed to establish the genetic profile of CM in children in the French South-East Region and describe the genotype–phenotype correlations. Retrospective analysis of children with CM diagnosed < 18 years in the French South-East Region, after exclusion of mitochondrial and other secondary causes. Retrospective study of genotype–phenotype correlations and genetic analyses performed. Completion of the gene panel according to current scientific data was performed for incomplete panels. Exome sequencing was proposed for patients without identified mutation. Eighty-three children were included from 2005 to 2019. Thirty-one (31%) patients had HCM, 22 (27%) had CMD, 10 (12%) had left ventricular non-compaction, 5 (6%) had restrictive CM and 13 (16%) had “mixed” CM. The mean age at diagnosis was 4.9 years (0–16.6). CM was discovered because of presence of a murmur in 29% of cases, signs of heart failure in 19% and cardiogenic shock in 8.5%. Thirty percent of the children required a heart transplant. 9(11%) patients died during the course of the study at a mean age of 8.4 years (±7). Genetic investigations had been performed in 66 (80%) patients, with a mutation found in 61% of them. MYH7 (35% of cases, often associated with HCM), MYBPC3 (10%) and TTNT2 (7.5%) were the genes most frequently found as involved with the CM. Further analysis (64 genes) is underway in 13 patients, with negative or incomplete panel or in those not yet tested. Genotype–phenotype correlations are in progress. Exome sequencing analysis is in progress for 3 patients with a negative complete panel, and their parents. Our preliminary data show a pathogenic mutation in 60% of the tested CM, in our pediatric population. Additional genetic analyses and genotype–phenotype correlations are currently in progress.