Genetic evaluation of a nation-wide Dutch pediatric DCM cohort: the use of genetic testing in risk stratification

Meulen, M.H. van der; Herkert, J.C.; Boer, S.L. den; Sarvaas, G.J.D.; Blom, N.A.; Harkel, A.D.J. ten; Breur, H.M.P.J.; Rammeloo, L.A.J.; Tanke, R.B.; Marcelis, C.; Laar, I.M.B.H. van de; Verhagen, J.M.A.; Deprez, R.H.L.D.; Barge-Schaapveld, D.Q.C.M.; Baas, A.F.; Sammani, A.; Christiaans, I.; Tintelen, J.P. van; Dalinghaus, M.

doi:doi:10.1161/CIRCGEN.120.002981

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...Show moreBackground: 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.Show less

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Genetic evaluation of a nation-wide Dutch pediatric DCM cohort: the use of genetic testing in risk stratification