Genetic Evaluation of A Nation-Wide Dutch Pediatric DCM Cohort: The Use of Genetic Testing in Risk Stratification

Abstract

Background: This study aimed to describe the current practice and results of genetic evaluation in Dutch children with dilated cardiomyopathy and to evaluate genotype-phenotype correlations that may guide prognosis.

Methods: We performed a multicenter observational study in children diagnosed with dilated cardiomyopathy, from 2010 to 2017.

Results: One hundred forty-four children were included. Initial diagnostic categories were idiopathic dilated cardiomyopathy in 67 children (47%), myocarditis in 23 (16%), neuromuscular in 7 (5%), familial in 18 (13%), inborn error of metabolism in 4 (3%), malformation syndrome in 2 (1%), and "other" in 23 (16%). Median follow-up time was 2.1 years [IQR 1.0-4.3]. Hundred-seven patients (74%) underwent genetic testing. We found a likely pathogenic or pathogenic variant in 38 children (36%), most often in MYH7 (n = 8). In 1 patient initially diagnosed with myocarditis, a pathogenic LMNA variant was found. During the study, 39 patients (27%) reached study endpoint (SE: all-cause death or heart transplantation). Patients with a likely pathogenic or pathogenic variant were more likely to reach SE compared with those without (hazard ratio 2.8; 95% CI 1.3-5.8, P = 0.007), while transplant-free survival was significantly lower (P = 0.006). Clinical characteristics at diagnosis did not differ between the 2 groups.

Conclusions: Genetic testing is a valuable tool for predicting prognosis in children with dilated cardiomyopathy, with carriers of a likely pathogenic or pathogenic variant having a worse prognosis overall. Genetic testing should be incorporated in clinical work-up of all children with dilated cardiomyopathy regardless of presumed disease pathogenesis.

Keywords: cardiomyopathy, dilated; genetic testing; pediatric cardiology.

Figure 1.

Outcome genetic evaluation. The cases that were not genetically tested are explained by the underlying diagnosis, which was not an indication for a genetic test improbable at the time of initial evaluation: 16 cases of myocarditis, 6 cases of chemotherapy-related dilated cardiomyopathy (DCM), 2 cases of left ventricular-infarction, and 1 tachyarrhythmia-induced DCM. In the remaining 12 cases (11 idiopathic DCM and 1 DCM with features of non-compaction), genetic testing was declined by the parents for varying reasons. LP/P variant indicates likely pathogenic or pathogenic (class 4 or 5 variant according to the American College of Medical Genetics (ACMG) classification); and VUS, variant of unknown significance (class 3 variant according to the ACMG classification).

Figure 2.

Kaplan-Meier analysis of 107 genetically evaluated children with dilated cardiomyopathy, children with a likely pathogenic or pathogenic (LP/P) variant versus no variant or variant of unknown significance LP/P: class 4 or 5 variant according to the American College of Medical Genetics classification Transplant-free survival (%) since diagnosis in LP/P group versus variant negative group.