Backgound
Severe heart failure in children commonly results from dilated cardiomyopathy (DCM) or myocarditis. Although regarded as distinct entities, myocarditis can mimic or evolve into a dilated phenotype (MycDCM). In primary DCM, likely pathogenic or pathogenic (LP/P) variants are identified in approximately one third of patients, but the genetic landscape of MycDCM remains less defined. This study aimed to compare the genetic spectrum and outcomes in paediatric DCM with and without biopsy-proven myocarditis.
Methods
We retrospectively analysed 138 children diagnosed with DCM between 2013 and 2023. Genetic testing included cardiomyopathy gene panels, whole-exome sequencing (WES) or whole-genome sequencing (WGS). Variants were classified according to ACMG guidelines; only LP/P variants were included. Syndromic cases were excluded. Myocarditis was confirmed by endomyocardial biopsy.
Results
Among 138 patients, 81 (59%) had primary DCM and 57 (41%) MycDCM. Patients with DCM were younger with median age at disease onset of 0.4 years (IQR 0.0–10.3). MycDCM patients were 3.1 years (IQR 0.5–8.4) old. LP/P variants were found in 34 children overall (DCM: 21/86, 26%; MycDCM: 13/57, 23%). In DCM, sarcomere genes predominated (71%, 15/21), including TNNT2 (n=4), TNNI3 (n=3), TPM1 (n=3), MYBPC3 (n=2), MYH7 (n=1), ACTC1 (n=1), and ACTN2 (n=1). In 54% (7/13) of MycDCM patients, sarcomere variants were detected: TNNT2, TNNI3, TTN (n=2, each), MYH7 (n=1). Of note, MycDCM patients were more likely to carry variants in genes related to cytoskeletal stability or inflammatory stress compared to primary DCM (BAG3 n=2, LMNA n=2; FLNC n=1, DES n=1). Heart transplantation was required in 52% of DCM and 69% of MycDCM cases. Deaths occurred in three patients, and only among primary DCM patients.
Conclusion
The overall genetic yield was comparable between DCM and myocarditis-associated DCM, but the affected gene patterns differed. Though we do see a relevant overlap in involvement of sarcomeric genes in both entities, MycDCM frequently involves genes implicated in cytoskeletal integrity and inflammatory pathways. These findings highlight the need for integrated phenotypic and molecular diagnostics to improve classification and management of paediatric heart failure.
