Phenotypic heterogeneity, inheritance patterns, and clinical outcomes in children with cardiomyopathy carrying TNNI3 variants: a single-centre retrospective cohort study

Background Pediatric cardiomyopathy is clinically and genetically heterogeneous, and variants in TNNI3, which affect the gene encoding cardiac troponin I, have been associated with diverse cardiomyopathy phenotypes. This study aimed to characterize the phenotypic spectrum, inheritance patterns, variant distribution, longitudinal cardiac function, and clinical outcomes of children with cardiomyopathy carrying TNNI3 variants. Methods This single-centre retrospective cohort study included children with cardiomyopathy carrying TNNI3 variants who had available baseline and follow-up data. Clinical manifestations, electrocardiography, cardiac imaging, biomarkers, genetic findings, mode of inheritance, treatment, and outcomes were reviewed. Variant classifications were extracted from source clinical laboratory reports that applied American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria. Continuous variables were summarized as median and range, and categorical variables as counts. Genotype-phenotype associations and longitudinal trajectories were assessed descriptively without formal hypothesis testing. Results Seven children were included, comprising four males and three females, with a median age at diagnosis of 7.0 years (range, 1.1–13.2). The phenotypic spectrum included hypertrophic cardiomyopathy in one patient, restrictive cardiomyopathy in three, dilated cardiomyopathy in two, and left ventricular noncompaction in one. Seven distinct heterozygous TNNI3 variants were identified: five missense variants, one splice-site variant, and one stop-gain variant. Two variants were classified as pathogenic, four as likely pathogenic, and one as a variant of uncertain significance. Among the six pathogenic/likely pathogenic variants, the four missense variants observed in hypertrophic or restrictive cardiomyopathy clustered in the flexible C-terminal tail, and the three restrictive cardiomyopathy-associated variants were de novo. During follow-up, the two included patients with dilated cardiomyopathy showed substantial recovery of left ventricular ejection fraction after optimized medical therapy, whereas the restrictive cardiomyopathy subgroup experienced severe clinical courses despite relatively preserved systolic function, including two patients listed for heart transplantation and one death. Conclusions In this small, descriptive cohort, children with cardiomyopathy carrying TNNI3 variants showed heterogeneous phenotypes and clinical courses. The three de novo pathogenic/likely pathogenic variants observed in restrictive cardiomyopathy clustered in the flexible C-terminal tail and were accompanied by severe clinical events despite relatively preserved LVEF. These observations are hypothesis-generating; the remaining variant of uncertain significance does not establish causality, and larger multicentre studies are needed before genotype-based prognostic or management strategies can be proposed.