{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T21:03:43Z","timestamp":1789506223300,"version":"build-2803163510"},"reference-count":44,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,10]],"date-time":"2023-01-10T00:00:00Z","timestamp":1673308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["DE1482-9\/2"],"award-info":[{"award-number":["DE1482-9\/2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["LO2093\/9-1"],"award-info":[{"award-number":["LO2093\/9-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["S413635475"],"award-info":[{"award-number":["S413635475"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"DGerman Research Foundation, Clinician Scientist Program","award":["DE1482-9\/2"],"award-info":[{"award-number":["DE1482-9\/2"]}]},{"name":"DGerman Research Foundation, Clinician Scientist Program","award":["LO2093\/9-1"],"award-info":[{"award-number":["LO2093\/9-1"]}]},{"name":"DGerman Research Foundation, Clinician Scientist Program","award":["S413635475"],"award-info":[{"award-number":["S413635475"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The KCNQ1 gene encodes the \u03b1-subunit of the cardiac voltage-gated potassium (Kv) channel KCNQ1, also denoted as Kv7.1 or KvLQT1. The channel assembles with the \u00df-subunit KCNE1, also known as minK, to generate the slowly activating cardiac delayed rectifier current IKs, a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function variants in KCNQ1 cause the congenital Long QT1 (LQT1) syndrome, characterized by delayed cardiac repolarization and a QT interval prolongation in the surface electrocardiogram (ECG). Autosomal dominant loss-of-function variants in KCNQ1 result in the LQT syndrome called Romano-Ward syndrome (RWS), while autosomal recessive variants affecting function, lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. The aim of this study was the characterization of novel KCNQ1 variants identified in patients with RWS to widen the spectrum of known LQT1 variants, and improve the interpretation of the clinical relevance of variants in the KCNQ1 gene. We functionally characterized nine human KCNQ1 variants using the voltage-clamp technique in Xenopus laevis oocytes, from which we report seven novel variants. The functional data was taken as input to model surface ECGs, to subsequently compare the functional changes with the clinically observed QTc times, allowing a further interpretation of the severity of the different LQTS variants. We found that the electrophysiological properties of the variants correlate with the severity of the clinically diagnosed phenotype in most cases, however, not in all. Electrophysiological studies combined with in silico modelling approaches are valuable components for the interpretation of the pathogenicity of KCNQ1 variants, but assessing the clinical severity demands the consideration of other factors that are included, for example in the Schwartz score.<\/jats:p>","DOI":"10.3390\/ijms24021350","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T01:33:12Z","timestamp":1673400792000},"page":"1350","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome KCNQ1 Variants"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2326-7069","authenticated-orcid":false,"given":"Susanne","family":"Rinn\u00e9","sequence":"first","affiliation":[{"name":"Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, 35037 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemarie","family":"Oertli","sequence":"additional","affiliation":[{"name":"Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, 35037 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4193-7257","authenticated-orcid":false,"given":"Claudia","family":"Nagel","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Tomsits","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University Hospital, LMU Munich, 80802 Munich, Germany"},{"name":"Deutsches Zentrum f\u00fcr Herz-Kreislauferkrankungen (DZHK), Partner Site Munich, 80636 Munich, Germany"},{"name":"Member of the European Reference Network for Rare, Low Prevalance and Complex Diseases of the Heart (ERN GUARD-Heart), 81377 Munich, Germany"},{"name":"Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, Marchioninistrasse 27, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Jenewein","sequence":"additional","affiliation":[{"name":"Institute of Legal Medicine, Goethe University, University Hospital Frankfurt, 60590 Frankfurt, Germany"},{"name":"Institute for Transfusion Medicine and Immunohematology, German Red Cross Blood Service Baden-W\u00fcrttemberg-Hessen, Goethe University Frankfurt, 60528 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"K\u00e4\u00e4b","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University Hospital, LMU Munich, 80802 Munich, Germany"},{"name":"Deutsches Zentrum f\u00fcr Herz-Kreislauferkrankungen (DZHK), Partner Site Munich, 80636 Munich, Germany"},{"name":"Member of the European Reference Network for Rare, Low Prevalance and Complex Diseases of the Heart (ERN GUARD-Heart), 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Kauferstein","sequence":"additional","affiliation":[{"name":"Institute of Legal Medicine, Goethe University, University Hospital Frankfurt, 60590 Frankfurt, Germany"},{"name":"Deutsches Zentrum f\u00fcr Herz-Kreislauferkrankungen (DZHK), Partner Site Frankfurt, 60596 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2487-4744","authenticated-orcid":false,"given":"Axel","family":"Loewe","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britt Maria","family":"Beckmann","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University Hospital, LMU Munich, 80802 Munich, Germany"},{"name":"Institute of Legal Medicine, Goethe University, University Hospital Frankfurt, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9433-687X","authenticated-orcid":false,"given":"Niels","family":"Decher","sequence":"additional","affiliation":[{"name":"Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, 35037 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/384078a0","article-title":"KVLQT1 and lsK (minK) proteins associate to form the IKs cardiac potassium 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