Genetic Burden of TNNI3K in Diagnostic Testing of Patients with Dilated Cardiomyopathy and Supraventricular Arrhythmias

Caroline Pham, Karolina Andrzejczyk, Sean J. Jurgens, Ronald Lekanne Deprez, Kaylin C.A. Palm, Alexa M.C. Vermeer, Janneke Nijman, Imke Christiaans, Daniela Q.C.M. Barge-Schaapveld, Pascal F.H.M. Van Dessel, Leander Beekman, Seung Hoan Choi, Steven A. Lubitz, Doris Skoric-Milosavljevic, Lisa Van Den Bersselaar, Philip R. Jansen, Jaël S. Copier, Patrick T. Ellinor, Arthur A.M. Wilde, Connie R. BezzinaElisabeth M. Lodder*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    3 Citations (Scopus)
    49 Downloads (Pure)

    Abstract

    BACKGROUND: Genetic variants in TNNI3K (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between TNNI3K variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function.

    METHODS: We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including TNNI3K. We further performed burden testing of TNNI3K in the UK Biobank. For 2 novel TNNI3K variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays.

    RESULTS: We demonstrate enrichment of rare coding TNNI3K variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between TNNI3K missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation.

    CONCLUSIONS: Our findings demonstrate an increased burden of rare coding TNNI3K variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic TNNI3K variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.

    Original languageEnglish
    Pages (from-to)328-336
    Number of pages9
    JournalCirculation: Genomic and Precision Medicine
    Volume16
    Issue number4
    DOIs
    Publication statusPublished - 1-Aug-2023

    Keywords

    • cardiac arrhythmias
    • dilated cardiomyopathy
    • genetics
    • phosphorylation

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