Submission Details

TNNI3K was evaluated for autosomal dominant dilated cardiomyopathy (DCM). TNNI3K was originally evaluated for DCM by the ClinGen DCM GCEP on August 12, 2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v11 on November 1, 2024. As a result, the association was increased from limited to moderate. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein.

Genetic data published supports an association with DCM presenting with or without cardiac conduction disease, including several studies of families showing TNNI3K variants segregating in individuals with conduction disease. Affected individuals may or may not also have DCM. Conduction disease may present years before cardiomyopathy. (PMID: 37199186; 30010057; 24925317). At least 4 missense variants have been reported in individuals with both cardiac conduction disease and DCM, one of which was reported in three families, the other in six. One intronic variant was reported in a family with conduction disease and DCM and was identified in one person with only DCM noted. This family was not scored, however, since the authors asserted a loss of function (LoF) mechanism, which does not appear to be a mechanism of disease at this time (PMID: 29355681). The mechanism of disease has not been established, though LoF is debated given the lack of experimental evidence and the presence of homozygous LoF variants in the general population. Gene-based burden testing found that rare missense variants in TNNI3K were significantly associated with DCM whereas LoF variants were not (PMID: 37199186).

TNNI3K has cardiac-specific expression in the fetal and adult heart and interacts with cardiac troponin I (PMID: 12721663). Experimental evidence for this gene included model systems using transgenic mouse lines expressing WT human TNNI3K (PMID: 19763165). TNNI3K expression alone did not result in overt cardiomyopathy or decreased survival. Transgenic mice showed greater diastolic and systolic dysfunction and significantly reduced fractional shortening compared to the control mice after undergoing transthoracic aortic constriction (TAC). Double transgenic mice were created (Calsequestrin (Csq) and TNNI3K WT). In the CSQ mouse, cardiac-specific overexpression of the CSQ protein leads to DCM, recapitulating many of the hallmarks of human DCM. The double transgenic mice had profoundly premature death, significantly decreased fractional shortening, larger heart size and histological staining showing obvious chamber dilation, suggesting that TNNI3K modifies disease progression. TNNI3K overexpression increased heart weight, cardiomyocyte diameter, cardiac fibrosis and reduced fractional shortening in transgenic mice and TNNI3K phosphorylation was significantly induced by transverse aortic constriction (PMID: 23085512). In summary, there is moderate evidence to support this gene-disease relationship. More evidence is needed to establish the relationship of TNNI3K with autosomal dominant DCM definitively. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 11/1/2024 (SOP Version 10).