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<p>Troponin I–interacting kinase (<i>TNNI3K</i>) is a crucial regulator of cardiac conduction and structure, with both gain- and loss-of-function variants implicated in conduction disturbances and cardiomyopathies. We describe a 35-year-old male who presented with complete heart block (CHB) and a prior history of atrioventricular nodal reentrant tachycardia ablation. Diagnostic imaging and laboratory evaluations revealed no structural or metabolic causes for CHB. Cardiac MRI demonstrated subendocardial late gadolinium enhancement confined to the apical region with concordant perfusion abnormality and akinesia, an ischemic-type pattern despite preserved ejection fraction and absent traditional risk factors. Genetic workup was performed which identified a novel <i>TNNI3K</i> variant (NM_015978.3:c.1722G &gt; C, p.Met574Ile). This mutation, previously unreported, expands the spectrum of <i>TNNI3K</i>-associated phenotypes and highlights the gene’s role in idiopathic conduction disease. Given the patient’s young age and concern for long-term lead complications, a leadless ventricular pacemaker was implanted, resulting in rapid clinical improvement and significant symptom reduction. This case underscores the importance of genetic evaluation in younger individuals presenting with unexplained conduction disease, as identification of a pathogenic mutation may guide both clinical management and familial screening. By delineating the molecular etiology of CHB, clinicians can tailor treatments that minimize procedural risks while optimizing long-term outcomes. The implications of this report extend to broadening the genetic understanding of <i>TNNI3K</i>-related cardiac disorders and underscore the evolving role of leadless pacemaker technology as a viable therapeutic option. Ultimately, our findings emphasize the need to integrate genetic insights into routine clinical care for patients with CCD, fostering personalized therapeutic strategies that can improve quality of life and potentially alter disease trajectories. Further investigations into <i>TNNI3K’s</i> pathogenic mechanisms will yield targeted therapies for inherited conduction disorders and expand available treatment paradigms.</p>

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Identification of a Novel TNNI3K Variant in a Young Patient with Complete Heart Block: Implications for Genetic Evaluation and Leadless Pacemaker Therapy

  • 期刊论文

  • 发表日期：

    2026年1月7日

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  • Ariadna Robledo,
  • Sean O’Leary,
  • Chaitra Mohan

摘要

Troponin I–interacting kinase (TNNI3K) is a crucial regulator of cardiac conduction and structure, with both gain- and loss-of-function variants implicated in conduction disturbances and cardiomyopathies. We describe a 35-year-old male who presented with complete heart block (CHB) and a prior history of atrioventricular nodal reentrant tachycardia ablation. Diagnostic imaging and laboratory evaluations revealed no structural or metabolic causes for CHB. Cardiac MRI demonstrated subendocardial late gadolinium enhancement confined to the apical region with concordant perfusion abnormality and akinesia, an ischemic-type pattern despite preserved ejection fraction and absent traditional risk factors. Genetic workup was performed which identified a novel TNNI3K variant (NM_015978.3:c.1722G > C, p.Met574Ile). This mutation, previously unreported, expands the spectrum of TNNI3K-associated phenotypes and highlights the gene’s role in idiopathic conduction disease. Given the patient’s young age and concern for long-term lead complications, a leadless ventricular pacemaker was implanted, resulting in rapid clinical improvement and significant symptom reduction. This case underscores the importance of genetic evaluation in younger individuals presenting with unexplained conduction disease, as identification of a pathogenic mutation may guide both clinical management and familial screening. By delineating the molecular etiology of CHB, clinicians can tailor treatments that minimize procedural risks while optimizing long-term outcomes. The implications of this report extend to broadening the genetic understanding of TNNI3K-related cardiac disorders and underscore the evolving role of leadless pacemaker technology as a viable therapeutic option. Ultimately, our findings emphasize the need to integrate genetic insights into routine clinical care for patients with CCD, fostering personalized therapeutic strategies that can improve quality of life and potentially alter disease trajectories. Further investigations into TNNI3K’s pathogenic mechanisms will yield targeted therapies for inherited conduction disorders and expand available treatment paradigms.