{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T21:03:44Z","timestamp":1789506224584,"version":"build-2803163510"},"reference-count":178,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,7,2]],"date-time":"2022-07-02T00:00:00Z","timestamp":1656720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gary and Marie Weiner Professorship in Cardiovascular Medicine Research","award":["R01 HL139738-01"],"award-info":[{"award-number":["R01 HL139738-01"]}]},{"name":"Gary and Marie Weiner Professorship in Cardiovascular Medicine Research","award":["R01HL141342-01"],"award-info":[{"award-number":["R01HL141342-01"]}]},{"name":"Gary and Marie Weiner Professorship in Cardiovascular Medicine Research","award":["20IPA35320141"],"award-info":[{"award-number":["20IPA35320141"]}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"publisher","award":["R01 HL139738-01"],"award-info":[{"award-number":["R01 HL139738-01"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"publisher","award":["R01HL141342-01"],"award-info":[{"award-number":["R01HL141342-01"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"publisher","award":["20IPA35320141"],"award-info":[{"award-number":["20IPA35320141"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"publisher","award":["R01 HL139738-01"],"award-info":[{"award-number":["R01 HL139738-01"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"publisher","award":["R01HL141342-01"],"award-info":[{"award-number":["R01HL141342-01"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"publisher","award":["20IPA35320141"],"award-info":[{"award-number":["20IPA35320141"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["R01 HL139738-01"],"award-info":[{"award-number":["R01 HL139738-01"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["R01HL141342-01"],"award-info":[{"award-number":["R01HL141342-01"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["20IPA35320141"],"award-info":[{"award-number":["20IPA35320141"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The electrocardiogram (ECG) empowered clinician scientists to measure the electrical activity of the heart noninvasively to identify arrhythmias and heart disease. Shortly after the standardization of the 12-lead ECG for the diagnosis of heart disease, several families with autosomal recessive (Jervell and Lange-Nielsen Syndrome) and dominant (Romano\u2013Ward Syndrome) forms of long QT syndrome (LQTS) were identified. An abnormally long heart rate-corrected QT-interval was established as a biomarker for the risk of sudden cardiac death. Since then, the International LQTS Registry was established; a phenotypic scoring system to identify LQTS patients was developed; the major genes that associate with typical forms of LQTS were identified; and guidelines for the successful management of patients advanced. In this review, we discuss the molecular and cellular mechanisms for LQTS associated with missense variants in KCNQ1 (LQT1) and KCNH2 (LQT2). We move beyond the \u201cbenign\u201d to a \u201cpathogenic\u201d binary classification scheme for different KCNQ1 and KCNH2 missense variants and discuss gene- and mutation-specific differences in K+ channel dysfunction, which can predispose people to distinct clinical phenotypes (e.g., concealed, pleiotropic, severe, etc.). We conclude by discussing the emerging computational structural modeling strategies that will distinguish between dysfunctional subtypes of KCNQ1 and KCNH2 variants, with the goal of realizing a layered precision medicine approach focused on individuals.<\/jats:p>","DOI":"10.3390\/ijms23137389","type":"journal-article","created":{"date-parts":[[2022,7,3]],"date-time":"2022-07-03T22:50:46Z","timestamp":1656888646000},"page":"7389","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Mutation-Specific Differences in Kv7.1 (KCNQ1) and Kv11.1 (KCNH2) Channel Dysfunction and Long QT Syndrome Phenotypes"],"prefix":"10.3390","volume":"23","author":[{"given":"Peter M.","family":"Kekenes-Huskey","sequence":"first","affiliation":[{"name":"Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don E.","family":"Burgess","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8273-8057","authenticated-orcid":false,"given":"Daniel C.","family":"Bartos","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezekiel R.","family":"Rozmus","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6898-8479","authenticated-orcid":false,"given":"Corey L.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Arrythmias Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig T.","family":"January","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Arrythmias Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee L.","family":"Eckhardt","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Arrythmias Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2146-327X","authenticated-orcid":false,"given":"Brian P.","family":"Delisle","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1001\/jama.289.16.2041","article-title":"Long QT Syndrome","volume":"289","author":"Moss","year":"2003","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1016\/j.hrthm.2013.05.014","article-title":"HRS\/EHRA\/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013","volume":"10","author":"Priori","year":"2013","journal-title":"Heart Rhythm"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1161\/CIRCULATIONAHA.119.043132","article-title":"An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome","volume":"141","author":"Adler","year":"2020","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"579525","DOI":"10.3389\/fphar.2020.579525","article-title":"The Efficacy of Beta-Blockers in Patients with Long QT Syndrome 1-3 According to Individuals\u2019 Gender, Age, and QTc Intervals: A Network Meta-analysis","volume":"11","author":"Han","year":"2020","journal-title":"Front. 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