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

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.

Novel Insights Into the Prevalence of TNNI3K -Mediated Dilated Cardiomyopathy and Putative Disease Mechanisms

“…Second, they validated their findings by burden testing of TNNI3K variants in the UK biobank and finally, they performed functional analyses of TNNI3K kinase activity for various variants using a TNNI3K autophosphorylation assay. 5 They demonstrate an enrichment of rare coding TNNI3K variants in patients with DCM in the Amsterdam cohort and a significant association between TNNI3K missense variants and DCM in the UK biobank. While their Amsterdam DCM cohort consisted of 2467 patients, 5 the UK biobank is a population-based cohort with whole exome sequencing data available from several hundred thousand subjects.…”

“…5 They demonstrate an enrichment of rare coding TNNI3K variants in patients with DCM in the Amsterdam cohort and a significant association between TNNI3K missense variants and DCM in the UK biobank. While their Amsterdam DCM cohort consisted of 2467 patients, 5 the UK biobank is a population-based cohort with whole exome sequencing data available from several hundred thousand subjects. 11 Furthermore, many phenotypic information is available on UK biobank participants including imaging data, information on biomarkers and even follow-up data.…”

“…In their article "Genetic burden of TNNI3K in diagnostic testing of patients with dilated cardiomyopathy and supraventricular arrhythmias, " Caroline Pham, Elisabeth Lodder, and colleagues investigated the role of pathogenic variants in the TNNI3K gene in patients with DCM. 5 TNNI3K is localized on chromosome 1 and encodes for the TNNI3K (troponin I interacting kinase) that was first discovered 20 years ago by Zhao et al 6 It is a dual-specific (tyrosine and serine/threonine) kinase predominantly expressed in the heart, where it plays an important role in cardiac growth and contractility. 7 TNNI3K was described to be involved in cardiac hypertrophy, ischemic cardiomyopathy, ischemia/ reperfusion injury, cardiac maturation, and cardiac conduction in mice.…”

“…10 However, such family reports were so far the only evidence for an association of TNNIK3 variants with DCM, conduction system disorders, and supraventricular arrhythmias in humans. 5 Moreover, thus far, the exact mechanism by which pathogenic variants in TNNI3K cause DCM (and/or atrial/supraventricular arrhythmias), underlying pathways, and whether an increased or reduced kinase activity (or both) is contributing to the pathomechanism remained unclear. 5 In their article, Caroline Pham, Elisabeth Lodder, and colleagues now provide strong evidence for the role of TNNIK3 variants in DCM by using a triple approach: first, they reviewed genetic testing results of their large Amsterdam DCM cohort.…”

“…5 Moreover, thus far, the exact mechanism by which pathogenic variants in TNNI3K cause DCM (and/or atrial/supraventricular arrhythmias), underlying pathways, and whether an increased or reduced kinase activity (or both) is contributing to the pathomechanism remained unclear. 5 In their article, Caroline Pham, Elisabeth Lodder, and colleagues now provide strong evidence for the role of TNNIK3 variants in DCM by using a triple approach: first, they reviewed genetic testing results of their large Amsterdam DCM cohort. Second, they validated their findings by burden testing of TNNI3K variants in the UK biobank and finally, they performed functional analyses of TNNI3K kinase activity for various variants using a TNNI3K autophosphorylation assay.…”