| Title: | Genetic Burden of TNNI3K in Diagnostic Testing of Patients With Dilated Cardiomyopathy and Supraventricular Arrhythmias |
| Journal: | Circulation Genomic and Precision Medicine |
| Published: | 18 May 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37199186/ |
| DOI: | https://doi.org/10.1161/circgen.122.003975 |
| URL: | https://pure.eur.nl/files/98942683/Genetic_Burden_of_TNNI3K_in_Diagnostic_Testing_of_Patients_With_Dilated_Cardiomyopathy_and_Supraventricular_Arrhythmias.pdf |
| Citations: | 2 (2 in last 2 years) as of 8 Aug 2024 |
Publication 11459
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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.</p>
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.</p>
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.</p>
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.</p>
21 Authors
- 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. Bezzina
- Elisabeth M. Lodder
1 Application
| Application ID | Title |
|---|---|
| 17488 | Understanding the Genetic Basis of Cardiac Arrhythmias |
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