Key result
TTN truncating variants are found in ~7% of pediatric myocarditis-associated DCM but absent in primary DCM.
Why the study?
TTN truncating variants are a known genetic factor in adult-onset DCM, but their role in paediatric-onset DCM and relevance in myocarditis remained unclear.
Are TTN truncating variants more prevalent in pediatric myocarditis-associated DCM compared to primary pediatric DCM?
Observational (n=186)
Are TTN truncating variants more prevalent in pediatric myocarditis-associated DCM compared to primary pediatric DCM?
TTN truncating variants are significantly more prevalent in pediatric myocarditis-associated DCM than in primary pediatric DCM, suggesting a genetic susceptibility to inflammatory myocardial injury.
Supports genetic susceptibility to inflammatory myocardial injury in children; extends TTN-tvs role beyond primary pediatric DCM.
Background TTN truncating variants (TTN-tvs) are well-known as a genetic factor in adult-onset dilated cardiomyopathy (DCM); their role in paediatric-onset DCM is still unclear. Prior work suggested TTN-tvs are enriched in acute myocarditis (1), and reverse remodelling may be common in TTN-tvs carriers (2). Purpose and methods To investigate the role of TTN-tvs in paediatric DCM and their relevance in myocarditis, we assessed the frequency and characteristics of reported TTN-tvs in genotyped paediatric DCM (n=112) and paediatric DCM cases with myocarditis (n=74). Myocarditis was diagnosed by endomyocardial biopsy (EMB). Genotyping was performed through cardiomyopathy panel sequencing (n=61), whole-exome (n=120) or whole-genome sequencing (n=5). Results Variants were reported as potentially causative in 97/186 (52%), with 54 (29%) of them being pathogenic or likely pathogenic. TTN-tvs were identified as potentially causative in 5/74 myocarditis cases and in 0/112 primary paediatric DCM cases (Fisher’s exact p=0.009; 6.8% vs. 0%). Of the five potentially causative cases, three were female; the age of symptom onset ranged from 9 months to 8 years. All were genotyped through whole-exome sequencing. Three TTN-tvs variants localized to the I-band (PSI 66–100%), while two variants localized to the A-band. Four variants were PTC/frameshift (two inherited; two without segregation data); one was a de novo heterozygous deletion of exons 219–239. Three patients underwent heart transplantation (two I-band, one A-band); two (40%) showed sustained recovery (weaned off ventricular assist support). In two additional primary DCM cases (1.7%), heterozygous pathogenic TTN-tvs co-occurred with other causal variants (biallelic DST and NRAP); both were inherited. Both children required transplantation, and biopsies showed no inflammation. Conclusions TTN-tvs were more prevalent in paediatric myocarditis-associated DCM than in the primary paediatric DCM cohort, supporting a potential role in susceptibility to inflammatory myocardial injury. The pathogenicity of TTN-tvs is typically associated with the corresponding protein location; however, the percentage of spliced-in TTN exons in the adult heart may differ in the child’s heart. Follow-up studies are needed to elucidate the potential role of TTN truncating variants in both susceptibility to myocarditis with heart failure and treatment opportunities.
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Shcherbakova et al. (2026) conducted an observational in Paediatric dilated cardiomyopathy and myocarditis (n=186). TTN truncating variants (TTN-tvs) vs. Primary paediatric dilated cardiomyopathy was evaluated on Frequency of potentially causative TTN truncating variants (p=0.009). TTN truncating variants were significantly more prevalent in paediatric myocarditis-associated dilated cardiomyopathy (6.8%) than in primary paediatric dilated cardiomyopathy (0%; p=0.009).
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