Supraventricular tachycardias, conduction disease, and cardiomyopathy in 3 families with the same rare variant in TNNI3K (p.Glu768Lys)

Svitlana Podliesna, Julian Delanne, Lindsey Miller, David J. Tester, Merujan Uzunyan, Shoji Yano, Mischa Klerk, Bryan C. Cannon, Apichai Khongphatthanayothin, Gabriel Laurent, Geraldine Bertaux, Sylvie Falcon-Eicher, Shengnan Wu, Hai Yun Yen, Hanlin Gao, Arthur A.M. Wilde, Laurence Faivre, Michael J. Ackerman, Elisabeth M. Lodder, Connie R. Bezzina

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Background: Rare genetic variants in TNNI3K encoding troponin-I interacting kinase have been linked to a distinct syndrome consisting primarily of supraventricular tachycardias and variably expressed conduction disturbance and dilated cardiomyopathy in 2 families. Objective: The purpose of this study was to identify new genetic variants associated with inherited supraventricular tachycardias, cardiac conduction disease, and cardiomyopathy. Methods: We conducted next generation sequencing in 3 independent multigenerational families with atrial/junctional tachycardia with or without conduction disturbance, dilated cardiomyopathy, and sudden death. We also assessed the effect of identified variant on protein autophosphorylation. Results: In this study, we uncovered the same ultra-rare genetic variant in TNNI3K (c.2302G>A, p.Glu768Lys), which co-segregated with disease features in all affected individuals (n = 23) from all 3 families. TNNI3K harboring the TNNI3K-p.Glu768Lys variant displayed enhanced kinase activity, in line with expectations from previous mouse studies that demonstrated increased conduction indices and procardiomyopathic effects with increased levels of Tnni3k. Conclusion: This study corroborates further the causal link between rare genetic variation in TNNI3K and this distinct complex phenotype, and points to enhanced kinase activity of TNNI3K as the underlying pathobiological mechanism.

Original languageEnglish (US)
Pages (from-to)98-105
Number of pages8
JournalHeart rhythm
Issue number1
StatePublished - Jan 2019


  • Conduction disease
  • Dilated cardiomyopathy
  • Genetics
  • Kinase
  • Rare variant
  • Supraventricular tachycardia
  • TNNI3K

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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