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Here, we investigated the influence of an <jats:italic>SCN5A<\/jats:italic> gene variant on tachycardia phenotype by deriving patient\u2010specific iPSCs and cardiomyocytes (iPSC\u2010CM). Two tachycardia patients were genetically analyzed and revealed to inherit a heterozygous p.F1465L variant in the <jats:italic>SCN5A<\/jats:italic> gene. Gene expression and immunocytochemical analysis in iPSC\u2010CMs generated from patients did not show any significant changes in mRNA levels of <jats:italic>SCN5A<\/jats:italic> or gross NaV1.5 cellular mislocalization, compared to healthy\u2010derived iPSC\u2010CMs. Electrophysiological and contraction imaging analysis in patient iPSC\u2010CMs revealed intermittent fibrillation\u2010like states, occasional arrhythmic events, and sustained high\u2010paced contractions that could be selectively reduced by flecainide treatment. The patch\u2010clamp analysis demonstrated a negative shift in the voltage\u2010dependent activation at the patient\u2010derived iPSC\u2010CMs compared to the healthy control line, suggestive of a gain\u2010of\u2010function activity associated with the <jats:italic>SCN5A<\/jats:italic><jats:sup><jats:italic>+\/p.F1465L<\/jats:italic><\/jats:sup> variant. Our patient\u2010derived iPSC\u2010CM model recapitulated the clinically relevant characteristics of tachycardia associated with a novel pathogenic <jats:italic>SCN5A<\/jats:italic><jats:sup><jats:italic>+\/p.F1465L<\/jats:italic><\/jats:sup> variant leading to altered Na<jats:sup>+<\/jats:sup> channel kinetics as the likely mechanism underlying high excitability and tachycardia phenotype.<\/jats:p>","DOI":"10.1002\/jcp.30843","type":"journal-article","created":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T07:56:32Z","timestamp":1660290992000},"page":"3900-3911","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Functional evaluation of the tachycardia patient\u2010derived iPSC cardiomyocytes carrying a novel pathogenic SCN5A variant"],"prefix":"10.1002","volume":"237","author":[{"given":"Sevilay","family":"Goktas Sahoglu","sequence":"first","affiliation":[{"name":"Research Institute for Health Sciences and Technologies (SABITA) Istanbul Medipol University  Istanbul Turkey"},{"name":"Institute of Health Sciences, Neuroscience Program Istanbul Medipol University  Istanbul Turkey"},{"name":"Department of Medical Biology, School of Medicine Istanbul Medipol University  Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuf Enes","family":"Kazci","sequence":"additional","affiliation":[{"name":"Research Institute for Health Sciences and Technologies (SABITA) Istanbul Medipol University  Istanbul Turkey"},{"name":"Institute of Health Sciences, Neuroscience Program Istanbul Medipol University  Istanbul Turkey"},{"name":"Deparment of Medical Biology, International School of Medicine Istanbul Medipol University  Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erkan","family":"Tuncay","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Faculty of Medicine Ankara University  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tugce","family":"Torun","sequence":"additional","affiliation":[{"name":"Research Institute for Health Sciences and Technologies (SABITA) Istanbul Medipol University  Istanbul Turkey"},{"name":"Medical Biology and Genetics Program, Institute of Health Sciences Istanbul Medipol University  Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celal","family":"Akdeniz","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, School of Medicine Istanbul Medipol University  Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Volkan","family":"Tuzcu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, School of Medicine Istanbul Medipol University  Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7199-583X","authenticated-orcid":false,"given":"Esra","family":"Cagavi","sequence":"additional","affiliation":[{"name":"Research Institute for Health Sciences and Technologies (SABITA) Istanbul Medipol University  Istanbul Turkey"},{"name":"Department of Medical Biology, School of Medicine Istanbul Medipol University  Istanbul Turkey"},{"name":"Deparment of Medical Biology, International School of Medicine Istanbul Medipol University  Istanbul Turkey"},{"name":"Medical Biology and Genetics Program, Institute of Health Sciences Istanbul Medipol University  Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,8,12]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1201\/9781420005615.ax4"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.4330\/wjc.v7.i2.76"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cnc.2016.04.004"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2020.05.002"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvz217"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2016.36"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2019.05.017"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.310355"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-018-0790-0"},{"key":"e_1_2_10_11_1","unstructured":"FFmpeg Developers. 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