Key result
Rare coding TNNI3K variants are linked to DCM and AF, likely driven by enhanced autophosphorylation.
Why the study?
Genetic variants in TNNI3K have been associated with DCM, cardiac conduction disease, and supraventricular tachycardias, but consensus on phenotype and protein function has been lacking.
Are rare coding TNNI3K variants associated with dilated cardiomyopathy and supraventricular arrhythmias?
Cohort
Yes
Are rare coding TNNI3K variants associated with dilated cardiomyopathy and supraventricular arrhythmias?
Rare coding TNNI3K variants, particularly those enhancing autophosphorylation, are associated with an increased burden of dilated cardiomyopathy and supraventricular arrhythmias.
May support TNNI3K inclusion in DCM panels; leaves open therapeutic targeting and prospective validation.
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.
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Pham et al. (2023) conducted a cohort in Dilated cardiomyopathy and supraventricular arrhythmias. Rare coding TNNI3K variants was evaluated on Dilated cardiomyopathy and atrial fibrillation. Rare coding TNNI3K variants are enriched in patients with dilated cardiomyopathy and associated with DCM and atrial fibrillation, with enhanced autophosphorylation likely driving pathogenicity.
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