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.
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.).
Circ Genom Precis Med. 2023 Aug;16(4):328-336. doi: 10.1161/CIRCGEN.122.003975. Epub 2023 May 18.
Genetic variants in (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function.
We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including . We further performed burden testing of in the UK Biobank. For 2 novel variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays.
We demonstrate enrichment of rare coding variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between 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.
Our findings demonstrate an increased burden of rare coding variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.
（肌钙蛋白 I 相互作用激酶）中的遗传变异先前与扩张型心肌病（DCM）、心脏传导疾病和室上性心动过速有关。然而， 变异体与这些心脏表型之间的联系在表型和蛋白功能方面缺乏共识。
我们描述了一项对接受心律失常和心肌病基因检测的患者队列进行系统回顾性研究，其中包括 。我们进一步对英国生物库中的 进行了负担测试。对于 2 个新的 变异体，我们测试了共分离。通过 TNNI3K 自身磷酸化测定来估计 TNNI3K 激酶功能。
我们证明了在阿姆斯特丹队列中 DCM 患者中罕见编码 变异体的富集。在英国生物库中，我们观察到 错义（而非功能丧失）变异体与 DCM 和房颤之间存在关联。此外，我们证明了 2 个罕见变异体 TNNI3K-p.Ile512Thr 和 TNNI3K-p.His592Tyr 的遗传分离，其表型包括 DCM、心脏传导疾病和室上性心动过速，并伴有自身磷酸化增加。相比之下，TNNI3K-p.Arg556_Asn590del，一种可能良性的变异体，表现出耗尽的自身磷酸化。
我们的研究结果表明 DCM 心脏患者中罕见编码 变异体的负担增加。此外，我们提出了 2 个具有增加自身磷酸化的新的可能致病性 变异体，这表明增强的自身磷酸化可能导致致病性。
