Abstract 4346181: The Impact of Genotype on Phenotypic Severity and Survival in Pediatric Dilated Cardiomyopathy: a report from the Pediatric Cardiomyopathy Registry

Introduction: Monogenic causes of dilated cardiomyopathy (DCM) are commonly identified in children. While DCM frequently presents with symptomatic heart failure (HF), whether an identified genetic cause of DCM implies disease severity or eventual outcome in children is unclear. Goals/Aims: To assess whether clinical or phenotypic disease severity is different in children with an identifiable pathogenic or likely pathogenic (P/LP) variant in a cardiomyopathy gene, using a multi-institutional cohort of children with DCM, and to determine the association of these variants with disease outcomes. Methods: Children (0-18 yrs) from 14 pediatric centers in North America with an echo diagnosis of non-syndromal DCM were studied: phenotypic features included ancestry, family history, presentation age, severity of LV dilation, ejection fraction (EF), and clinical HF. A panel of 37 known cardiomyopathy-associated genes was interrogated by exome sequencing with targeted analysis for P/LP variants. Outcomes of death, cardiac transplant, and continuing LV dysfunction vs echo normalization were assessed prospectively. Results: Between 2012-2016, 279 DCM probands (47% male) were enrolled with a median (IQR) age at diagnosis of 1.6 (0.4-10.4) yrs. Median follow-up time was 1.1 (0.2-4.0) yrs, Gene variants designated as P/LP were identified in 18 of the 37 genes evaluated, with TTN (17%), TNNT2 (15%), MYH7 (15%), RBM20 (9%), and LMNA (8%) being the most frequently implicated genes. Only 19% of the overall cohort yielded an identifiable genetic cause, without any difference between ancestries. Children >12 yrs old had the highest genetic yield at 34% (p<0.05). Symptoms of HF occurred in 62% of pts at or within 12 months of presentation who carried P/LP genetic variant, but presentation HF symptoms, LVEF, or LV dilation were not associated with an identifiable genetic cause. The rate of death or cardiac transplant did not differ with P/LP variant presence or absence and exceeded 60% at 10 yrs after diagnosis. On competing risks analysis (Figures 1 and 2), a trend (p=0.09) towards greater echo normalization, reaching 25% vs 10%, was noted in P/LP variant-negative pts by 10 yrs after diagnosis. Conclusions: A genetic etiology was not associated with the phenotypic severity of DCM at diagnosis. Echo normalization of LV function over time was noted more frequently in patients who did not have an identified P/LP variant.