TY - JOUR
T1 - Genetic Burden of TNNI3K in Diagnostic Testing of Patients with Dilated Cardiomyopathy and Supraventricular Arrhythmias
AU - Pham, Caroline
AU - Andrzejczyk, Karolina
AU - Jurgens, Sean J.
AU - Lekanne Deprez, Ronald
AU - Palm, Kaylin C.A.
AU - Vermeer, Alexa M.C.
AU - Nijman, Janneke
AU - Christiaans, Imke
AU - Barge-Schaapveld, Daniela Q.C.M.
AU - Van Dessel, Pascal F.H.M.
AU - Beekman, Leander
AU - Choi, Seung Hoan
AU - Lubitz, Steven A.
AU - Skoric-Milosavljevic, Doris
AU - Van Den Bersselaar, Lisa
AU - Jansen, Philip R.
AU - Copier, Jaël S.
AU - Ellinor, Patrick T.
AU - Wilde, Arthur A.M.
AU - Bezzina, Connie R.
AU - Lodder, Elisabeth M.
N1 - Publisher Copyright:
© 2021 Society of Trauma Nurses. Unauthorized reproduction of this article is prohibited.
PY - 2023/8/1
Y1 - 2023/8/1
N2 - 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.
AB - 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.
KW - cardiac arrhythmias
KW - dilated cardiomyopathy
KW - genetics
KW - phosphorylation
UR - http://www.scopus.com/inward/record.url?scp=85168222844&partnerID=8YFLogxK
U2 - 10.1161/CIRCGEN.122.003975
DO - 10.1161/CIRCGEN.122.003975
M3 - Article
C2 - 37199186
AN - SCOPUS:85168222844
SN - 2574-8300
VL - 16
SP - 328
EP - 336
JO - Circulation: Genomic and Precision Medicine
JF - Circulation: Genomic and Precision Medicine
IS - 4
ER -