Reduced kinase function in two ultra-rare TNNI3K variants in families with congenital junctional ectopic tachycardia

Caroline Pham, Tamara T. Koopmann, Jeffrey M. Vinocur, Nico A. Blom, Vivian Nogueira Silbiger, Kirti Mittal, Marianne Bootsma, Kaylin C. A. Palm, Sally-Ann B. Clur, Daniela Q. C. M. Barge-Schaapveld, Robert M. Hamilton, Elisabeth M. Lodder

Research output: Contribution to journalArticleAcademicpeer-review


Genetic missense variants in TNNI3K, encoding troponin-I interacting kinase, have been associated with dilated cardiomyopathy (DCM) and observed in families with supraventricular tachycardias (SVT). Previously, a family harboring the TNNI3K-c.1615A > G (p.Thr539Ala) variant presented with congenital junctional ectopic tachycardia (CJET), an arrhythmia that arises from the atrioventricular (AV) node and His bundle. However, this was a relatively small four-generational family with limited genetic testing (N = 3). We here describe a multigenerational family with CJET harboring a novel ultra-rare TNNI3K variant: TNNI3K-c.1729C > T (p.Leu577Phe). Of all 18 variant carriers, 13 individuals presented with CJET, resulting in a genetic penetrance of 72%. In addition, CJET is reported in another small family harboring TNNI3K-c.2225C > T (p.Pro742Leu). Similar to the previously published CJET family, both TNNI3K variants demonstrate a substantial reduction of kinase activity. Our study contributes novel evidence supporting the involvement of TNNI3K genetic variants as significant contributors to CJET, shedding light on potential mechanisms underlying this cardiac arrhythmia.
Original languageEnglish
Pages (from-to)37-46
Number of pages10
JournalClinical genetics
Issue number1
Early online date2024
Publication statusPublished - Jul 2024


  • TNNI3K
  • autophosphorylation
  • congenital junctional ectopic tachycardia
  • protein kinase
  • rare variants

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