{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T14:17:58Z","timestamp":1789222678586,"version":"build-2803163510"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T00:00:00Z","timestamp":1690848000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Genetic variants in\n              <jats:italic>TNNI3K<\/jats:italic>\n              (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between\n              <jats:italic>TNNI3K<\/jats:italic>\n              variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including\n              <jats:italic>TNNI3K<\/jats:italic>\n              . We further performed burden testing of\n              <jats:italic>TNNI3K<\/jats:italic>\n              in the UK Biobank. For 2 novel\n              <jats:italic>TNNI3K<\/jats:italic>\n              variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              We demonstrate enrichment of rare coding\n              <jats:italic>TNNI3K<\/jats:italic>\n              variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between\n              <jats:italic>TNNI3K<\/jats:italic>\n              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.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              Our findings demonstrate an increased burden of rare coding\n              <jats:italic>TNNI3K<\/jats:italic>\n              variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic\n              <jats:italic>TNNI3K<\/jats:italic>\n              variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.122.003975","type":"journal-article","created":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T09:01:02Z","timestamp":1684400462000},"page":"328-336","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Genetic Burden of\n            <i>TNNI3K<\/i>\n            in Diagnostic Testing of Patients With Dilated Cardiomyopathy and Supraventricular Arrhythmias"],"prefix":"10.1161","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8465-2978","authenticated-orcid":true,"given":"Caroline","family":"Pham","sequence":"first","affiliation":[{"name":"Department of Experimental Cardiology (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., C.R.B., E.M.L.), Heart Center, Amsterdam UMC location University of Amsterdam, the Netherlands."},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., A.A.M.W., C.R.B., E.M.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9305-9612","authenticated-orcid":true,"given":"Karolina","family":"Andrzejczyk","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., C.R.B., E.M.L.), Heart Center, Amsterdam UMC location University of Amsterdam, the Netherlands."},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., A.A.M.W., C.R.B., E.M.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1605-9782","authenticated-orcid":true,"given":"Sean J.","family":"Jurgens","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., C.R.B., E.M.L.), Heart Center, Amsterdam UMC location University of Amsterdam, the Netherlands."},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., A.A.M.W., C.R.B., E.M.L.)."},{"name":"Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.J.J., S.A.L., P.T.E.)."},{"name":"Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.J.J., S.A.L., P.T.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4687-0186","authenticated-orcid":true,"given":"Ronald","family":"Lekanne Deprez","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Amsterdam UMC location University of Amsterdam, the Netherlands (R.L.D., A.M.C.V., J.N., D.S.-M., 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