Purpose Dilated cardiomyopathy (DCM) is characterized by ventricular dilation and systolic dysfunction, with 25-50% familial inheritance and up to 40% transplant rate within 5 years of diagnosis. Genotype-phenotype correlation for pediatric DCM is poorly described. The objective was to identify genetic characteristics associated with earlier onset or severe phenotype. Methods Retrospective chart review of genotyped children with DCM at a tertiary pediatric center from 2007-2016. Variants were reclassified with updated population/ancestry frequency information and literature reports. Results We reviewed 111 children (55% male) with a mean age of 4.4 ± 6.1 years (range 0 to 17.6 years) at time of diagnosis of DCM. A family history of DCM was present in 30%. Cardiac death (defined as transplant or patient death) occurred in 48/111 (43%); 46 were transplanted, 2 died prior to transplant, and 6 died post-transplant. Forty children (36%) had at least one likely pathogenic/pathogenic (LP/P) variant; 45 (41%) had variants of uncertain significance (VUS), but no LP/P variants; and 26 (23%) had only benign variants or no variants identified. Sarcomeric/cytoskeletal genes accounted for 131/171 VUS/LP/P variants (77%). The average number of VUS/LP/P variants per patient was 1.5 ± 1.6. VUS/LP/P variants in TPM1, MYBPC3, and LAMA4 were more prevalent in patients who presented before age one year (13/61 vs. 1/50 p=0.003). Truncating and frameshift LP/P variants in TTN were all seen after the age of 13 (3/21 vs. 0/90, p=0.01). All children with MYH7 variants occurring between amino acid residues 1 and 600 presented with dilated cardiomyopathy with left ventricular non-compaction (LVNC), accounting for 6/12 cases with MYH7 variants. With respect to outcome, DSP and MYBPC3 variants occurred more frequently in patients with transplant or death (12/51 vs. 4/60, p=0.01). Conclusion Pediatric DCM is associated with a different pattern of genetic variation than described in adult studies. Sarcomeric/cytoskeletal gene variants were more common in this population, especially MYH7 missense variants. We provide four candidate genes that may be associated with early onset of disease and cardiac death (TPM1, MYBPC3, LAMA4, and DSP) and provide support for the association between domain-specific MYH7 variants and LVNC. We plan to expand to a multi-center study for further exploration of genotype-phenotype relationships in DCM.
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