Jean A. Ballweg

BACKGROUND: Dilated cardiomyopathy (DCM) frequently presents with heart failure in children. Whether a genetic cause of DCM is associated with disease severity or eventual outcome in pediatric DCM is unclear. METHODS: A multiinstitutional prospective pediatric cohort study (0–18 years) with nonsyndromic DCM was undertaken from 2013 to 2016. A panel of 37 cardiomyopathy-associated genes was interrogated by exome sequencing with analysis for pathogenic or likely pathogenic (LP) variants. Clinical severity and outcomes of death, cardiac transplant, and continuing left ventricular dysfunction versus echocardiographic normalization were assessed. RESULTS: A total of 279 DCM probands (47% male) with a median (interquartile range) age at diagnosis of 1.6 (0.4–10.4) years were enrolled. Median follow-up was 1.1 (0.2–4.0) years. Gene variants designated as pathogenic/LP were identified in 18 of the 37 genes evaluated, and of all positive variants, TTN (17%), TNNT2 (15%), MYH7 (15%), RBM20 (9%), and LMNA (8%) were most frequently implicated. Only 19% of the overall cohort yielded an identifiable genetic cause, without any difference between ancestries. Children >12 years old had the highest genetic yield at 34% ( P P =0.09) toward greater echo normalization, was noted in those without a pathogenic/LP variant by 10 years after diagnosis. CONCLUSIONS: A genetic cause was detected in a minority of children and was not associated with the phenotypic severity of DCM at diagnosis. Echocardiographic normalization of left ventricular function over time was noted more frequently in patients who did not have an identified pathogenic/LP variant.

BACKGROUND: Studies have demonstrated that patients with myocarditis may have a higher burden of cardiomyopathy-associated genetic variants than the general population. However, data on children are limited. We compared the prevalence of rare predicted-damaging variants and clinically pathogenic variants in children with dilated cardiomyopathy (DCM) secondary to myocarditis with that in children with DCM alone and in heart-healthy controls. METHODS: Children with DCM secondary to myocarditis and children with DCM alone who underwent exome sequencing as part of a prior cross-sectional study were identified in the Pediatric Cardiomyopathy Registry, a large multicenter registry of children with cardiomyopathy. Controls from the Indiana University Biobank were matched 4:1 with myocarditis cases on genomic similarity. Rare predicted-damaging variants in cardiomyopathy-associated genes were identified using a bioinformatics approach. Clinical guidelines were used to determine clinical pathogenicity. The prevalence of variants was compared across the 3 groups. RESULTS: There were 32 patients with DCM secondary to myocarditis. The prevalence of rare predicted-damaging variants was 34.4% (11/32 [95% CI, 18.6%–53.2%]) in cases compared with 6.3% (8/128 [95% CI, 2.7%–11.9%]) in controls ( P P P =0.17 and P =1.00, respectively). CONCLUSIONS: Children with DCM secondary to myocarditis had a higher burden of variants in cardiomyopathy-associated genes than that of heart-healthy controls. Larger studies will be needed to determine the utility of routine genetic testing in this population.