Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy

Abstract

Background Pediatric dilated cardiomyopathy (DCM) is a well-known clinical entity; however, phenotype-genotype correlations are inadequately described. Our objective was to provide genotype associations with life-threatening cardiac outcomes in pediatric DCM probands. Methods and Results We performed a retrospective review of children with DCM at a large pediatric referral center (2007-2016), excluding syndromic, chemotherapy-induced, and congenital heart disease causes. Genetic variants were adjudicated by an expert panel and an independent clinical laboratory. In a cohort of 109 pediatric DCM cases with a mean age at diagnosis of 4.2 years (SD 5.9), life-threatening cardiac outcomes occurred in 47% (42% heart transplant, 5% death). One or more pathogenic/likely pathogenic variants were present in 40/109 (37%), and 36/44 (82%) of pathogenic/likely pathogenic variants occurred in sarcomeric genes. The frequency of pathogenic/likely pathogenic variants was not different in patients with familial cardiomyopathy (15/33 with family history versus 25/76 with no family history, P=0.21). TTN truncating variants occurred in a higher percentage of children diagnosed as teenagers (26% teenagers versus 6% younger children, P=0.01), but life-threatening cardiac outcomes occurred in both infants and teenagers with these TTN variants. DCM with left ventricular noncompaction features occurred in 6/6 patients with MYH7 variants between amino acids 1 and 600. Conclusions Sarcomeric variants were common in pediatric DCM. We demonstrated genotype-specific associations with age of diagnosis and cardiac outcomes. In particular, MYH7 had domain-specific association with DCM with left ventricular noncompaction features. Family history did not predict pathogenic/likely pathogenic variants, reinforcing that genetic testing should be considered in all children with idiopathic DCM.

Keywords: dilated cardiomyopathy; genotype; pediatrics; transplant.

Figure 1. Kaplan–Meier analysis, time from diagnosis to life‐threatening cardiac outcome (years).

A life‐threatening cardiac outcome (LTCO) was 1 or more of the following: resuscitated cardiac arrest, mechanical circulatory support, heart transplant, or death secondary to a cardiac cause.

Figure 2. Distribution of genes for pathogenic and likely pathogenic variants.

Pie chart displaying the distribution of all genes containing pathogenic or likely pathogenic (P/LP) variants, weighted by the number of P/LP variants in each gene.

Figure 3. Domain‐specific association with DCM‐LVNC in MYH7.

Schematic illustration of each variant positioned in the 1935 amino‐acid β‐myosin heavy chain protein. Pediatric DCM cases with variants mapping to the head region of the protein (blue) had a phenotypic presentation of DCM and DCM‐LVNC, whereas those with variants in the neck (orange) and rod (green) regions presented with DCM alone. DCM indicates dilated cardiomyopathy; DCM‐LVNC, dilated cardiomyopathy with left ventricular noncompaction; and β‐MyHC, β‐myosin heavy chain protein.