Pediatric cardiomyopathies: Assessment of genetic causes by next generation sequencing of cardiomyopathy genes and genotype-phenotype correlation

Cardiomyopathies (CM) are cardiac muscle diseases of the young adults. In 30–60% of cases, a genetic origin is observed with most often an autosomal dominant transmission. Except for syndromic and metabolic diseases, pediatric forms of primary cardiomyopathies remains poorly known regarding their genetic etiology, and frequently present a severe evolution. The aim of the work is to determine the genetic causes of a primary cardiomyopathy in a cohort of 57 children diagnosed under 15 years, sequenced on a custom panel of 52 cardiomyopathy genes and attempt to correlate the disease causing gene with the severity of the phenotype. This cohort was composed of 57 patients (31 males and 26 females) including 24 HCM, 20 DCM and 13 other sub-types (RCM, LVNC). The overall mutation rate was 61%. Age of onset was significantly earlier in the patients ( P  = 0.02) with DCM (4 ± 3.5 years) and with others CM (3 ± 3.5 years) than in HCM patients (7 ± 5 years). In patients with DCM and other CMs, the mutation rate was higher (14/20, 70% and 8/13, 62%, respectively) than in patients with HCM (13/24, 54%). Similarly, the proportion of patients carrying 2 pathogenic variants was higher in patients with DCM (35%) and other CMs (62%) than in HCM patients (23%). The mutated genes were predominantly sarcomeric genes (13/21) (MYH7, MYCPB3, TNNC1 etc). A significant rate of de novo mutations (5/49, 10%) was observed in the cohort. We report a cohort of genotyped pediatric cardiomyopathies analyzed on a large panel of genes. We observed a molecular cause in 61% of patients including more than 23% of patients were carrier of two disease causing variants, suggesting that the early and severe phenotype could be explained by the cumulative effect of several pathogenic dominant variants. The predominance of sarcomeric gene supported the hypothesis of a common genetic origin between adult and pediatric cardiomyopathy cases. Our results support genetic testing in pediatric cardiomyopathies.