TTN variants in pediatric cardiomyopathy: a retrospective cohort study

Titin (TTN) variants have been implicated in various types of cardiomyopathy. Allelic variant heterogeneity results in variable clinical phenotypes, which remains a major barrier for effective disease management. We aim to investigate the relationship between TTN variants and their associated cardiomyopathies and clinical outcomes.

A retrospective observational study was performed to evaluate patients with cardiomyopathy and TTN variants confirmed by whole-exome sequencing (WES) from January 2015 to December 2024. Univariable Cox regression analysis was conducted to identify independent risk factors for major adverse cardiovascular events (MACEs), and receiver operating characteristic analysis was used to determine its capability. In addition, the contribution of combined pathogenic variants with the TTN gene was assessed.

A total of 53 patients were identified with TTN variants, with a median onset age of 42.3 months (IQR 18.5-76.1), while 48 of 53 (90.50%) individuals had other genetic variants. Among them, 47.17% of patients presented with recurrent heart failure, while late gadolinium enhancement (LGE) was identified in 56.67% of cases that underwent magnetic resonance imaging (MRI) assessment. The variants in the A-band of TTN were most frequently recorded among the patients. Notably, early age-onset disease (HR = 1.008; 95% CI = 1.000-1.016; p = 0.037) served as a predictor of MACE in pediatrics with TTN-associated cardiomyopathy, and the optimal cutoff value was calculated as 75.50 months (specificity 57.1% and sensitivity 75.0%). Unfortunately, the combined genetic disorders failed to establish an association with worse outcomes in the general cohort. However, the presence of multiple genetic variants was associated with more severe adverse outcomes specifically in patients with dilated cardiomyopathy (DCM), with a higher prevalence of MACE occurrence.

In our cohort, early age-onset disease was a predictor of MACE in pediatrics with TTN-associated cardiomyopathy. In addition, the early age of disease onset revealed a higher likelihood of MACE in the first year after diagnosis. Multiple genetic variants with TTN presented more severe adverse outcomes in DCM assessment.