Clinical impact of genetic testing in a large cohort of pediatric cardiomyopathies

Abstract

Background: There are limited data that can explain the earlier penetrance and the different expressivity of pediatric cardiomyopathy (pCM) compared to adult-onset cardiomyopathy (aCM). In addition, the relationship between genotype and pCM results is poorly described.

Objective: We compared the genotypes between a cohort of aCM and a cohort of pCM to propose hypotheses on the earlier penetrance and expressivity of pCM. Finally, we report how genetic testing was used to guide genetic counseling in pCM.

Methods: 253 pCM (<18 years old) and 1466 aCM patients were sequenced on a panel of 67 cardiomyopathy genes. Risk factors for death and heart transplantation were analyzed.

Results: In pCM, the variant of interest (VOI) yield was 53.7 % including 24.2 % carrying two VOI. De novo variants represented 11 % of VOI in pCM and 50 % in restrictive pCM. An age at diagnosis younger than 1 year (HR = 2.07, p = 0.029), restrictive phenotype (HR = 2.87, p = 0.03) and the presence of two VOI (HR = 2.97, p = 0.001) were independent risk factors for death or heart transplantation. In comparison with aCM, pCM patients harbored more frequently two VOI (p = 0.02), or de novo variants (p = 4.10^-13). In addition, the distribution of VOI was different in aCM and pCM. Genotyping of pCM improved genetic counseling in families and led to ten prenatal-diagnosis.

Conclusions: Genetic testing provides clues for earlier penetrance of pCM. The presence of two VOI in children with CM is a risk factor for severe and early cardiac events.

Keywords: Genetic landscape; Heart transplantation; Pediatric cardiomyopathy.