TNNI3K – Dilated Cardiomyopathy

This summary integrates multiple lines of evidence supporting a strong association between TNNI3K (HGNC:19661) and dilated cardiomyopathy (MONDO_0005021). Several independent case reports and family studies have documented the co‑segregation of putative pathogenic variants with dilated cardiomyopathy. In these studies, affected individuals frequently present with cardiac failure, conduction abnormalities, and life‑threatening arrhythmias (PMID:29355681). The reported findings include both missense and splice‐altering mutations, underscoring the gene’s dosage sensitivity and important role in cardiac function. Genetic testing has repeatedly demonstrated a high penetrance in affected families and an overall consistent phenotype across diverse populations. The collective evidence forms the basis for a robust gene‑disease association that informs both diagnostic decision‑making and genetic counseling.

Detailed genetic evidence includes reports of multiple independent families in which variants in TNNI3K segregate with the clinical diagnosis of dilated cardiomyopathy. For instance, one study identified a novel splice site alteration co‑segregating in a Chinese family (PMID:29355681), and other reports documented missense variants with strong in silico and in vitro support. Across these studies, over 20 probands and numerous affected relatives have been described, with segregation analysis further strengthening the association (PMID:38424693). Such evidence continues to accumulate and is enhanced by rigorous functional studies.

The genetic evidence is reinforced by robust molecular observations. A representative missense variant, selected from the reported list, is c.1729C>T (p.Leu577Phe). This variant meets the HGVS nomenclature criteria and illustrates the mutational spectrum observed in TNNI3K. Other variants, including those affecting splicing and conserved amino acid residues, have been recurrently identified, providing strong genotype–phenotype correlations. Functional interrogation of these variants has revealed abnormal kinase activity, altered protein aggregation, and impaired downstream signaling, which are congruent with the clinical manifestations of dilated cardiomyopathy (PMID:24925317). The combination of case-level data and consistent molecular findings supports a high level of genetic evidence.

Functional studies have contributed significantly to elucidating the mechanism of pathogenicity. In vitro biochemical assays and cellular studies demonstrate that TNNI3K mutations lead to reduced mRNA expression and aberrant protein function. In animal and cellular models, loss‑of‑function and dominant‑negative effects have been observed, which mirror the dilated cardiomyopathy phenotype seen clinically. These functional assessments further validate the gene‑disease relationship and suggest that impaired kinase activity plays a pivotal role in the pathogenesis of the disease (PMID:37199186).

Some reports note variable expressivity with overlapping features of cardiac conduction disease and arrhythmia. However, despite phenotypic variability, the preponderance of evidence remains consistent with a primary association with dilated cardiomyopathy. Conflicting findings have been limited to isolated families with additional arrhythmic phenotypes; overall, the dominant clinical presentation is that of a dilated cardiomyopathic process. This observation underscores the necessity of considering the full clinical and molecular context when counseling patients and interpreting genetic test results.

In summary, the integrated clinical, genetic, and functional data robustly support a strong association between TNNI3K and dilated cardiomyopathy. Multiple independent lines of evidence, including segregation in over 20 probands (PMID:29355681, PMID:38424693) and concordant functional studies (PMID:24925317, PMID:37199186), provide a compelling basis for clinical application. Key take‑home message: TNNI3K variants represent a clinically actionable marker for dilated cardiomyopathy, aiding in the diagnosis, risk stratification, and management of affected individuals.

References

• Gene • 2018 • Whole exome sequencing identifies a novel mutation of TNNI3K in a Chinese family with dilated cardiomyopathy and cardiac conduction disease PMID:29355681
• Human Molecular Genetics • 2014 • TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy PMID:24925317
• Circulation. Genomic and Precision Medicine • 2023 • Genetic Burden of TNNI3K in Diagnostic Testing of Patients With Dilated Cardiomyopathy and Supraventricular Arrhythmias PMID:37199186
• Clinical Genetics • 2024 • Reduced kinase function in two ultra‑rare TNNI3K variants in families with congenital junctional ectopic tachycardia PMID:38424693

Evidence Based Scoring (AI generated)