{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T22:14:07Z","timestamp":1785363247496,"version":"3.55.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2022,10,21]],"date-time":"2022-10-21T00:00:00Z","timestamp":1666310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Netherlands CardioVascular Research Initiative","award":["CVON2017-15"],"award-info":[{"award-number":["CVON2017-15"]}]},{"DOI":"10.13039\/501100003246","name":"Dutch Research Council","doi-asserted-by":"publisher","award":["VIDI-91718361"],"award-info":[{"award-number":["VIDI-91718361"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Australian Genomics Cardiovascular Genetic Disorders Flagship"},{"name":"NSW Cardiovascular Disease Senior Scientist","award":["40-46300-98-19009"],"award-info":[{"award-number":["40-46300-98-19009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Background: Variants in KCNH2, encoding the human ether a-go-go (hERG) channel that is responsible for the rapid component of the cardiac delayed rectifier K+ current (IKr), are causal to long QT syndrome type 2 (LQTS2). We identified eight index patients with a new variant of unknown significance (VUS), KCNH2:c.2717C\u2009&amp;gt;\u2009T:p.(Ser906Leu). We aimed to elucidate the biophysiological effect of this variant, to enable reclassification and consequent clinical decision-making. Methods: A genotype\u2013phenotype overview of the patients and relatives was created. The biophysiological effects were assessed independently by manual-, and automated calibrated patch clamp. HEK293a cells expressing (i) wild-type (WT) KCNH2, (ii) KCNH2-p.S906L alone (homozygous, Hm) or (iii) KCNH2-p.S906L in combination with WT (1:1) (heterozygous, Hz) were used for manual patching. Automated patch clamp measured the variants function against known benign and pathogenic variants, using Flp-In T-rex HEK293 KCNH2-variant cell lines. Results: Incomplete penetrance of LQTS2 in KCNH2:p.(Ser906Leu) carriers was observed. In addition, some patients were heterozygous for other VUSs in CACNA1C, PKP2, RYR2 or AKAP9. The phenotype of carriers of KCNH2:p.(Ser906Leu) ranged from asymptomatic to life-threatening arrhythmic events. Manual patch clamp showed a reduced current density by 69.8 and 60.4% in KCNH2-p.S906L-Hm and KCNH2-p.S906L-Hz, respectively. The time constant of activation was significantly increased with 80.1% in KCNH2-p.S906L-Hm compared with KCNH2-WT. Assessment of KCNH2-p.S906L-Hz by calibrated automatic patch clamp assay showed a reduction in current density by 35.6%. Conclusion: The reduced current density in the KCNH2-p.S906L-Hz indicates a moderate loss-of-function. Combined with the reduced penetrance and variable phenotype, we conclude that KCNH2:p.(Ser906Leu) is a low penetrant likely pathogenic variant for LQTS2.<\/jats:p>","DOI":"10.1093\/hmg\/ddac261","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T16:39:43Z","timestamp":1666197583000},"page":"1072-1082","source":"Crossref","is-referenced-by-count":5,"title":["Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8421-9346","authenticated-orcid":false,"given":"Ja\u00ebl S","family":"Copier","sequence":"first","affiliation":[{"name":"Experimental Cardiology, Amsterdam UMC location University of Amsterdam , Meibergdreef 9, Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Amsterdam , The Netherlands"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart\u2019"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Bootsma","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Leiden University Medical Center , Albinusdreef 2, 2300 Leiden , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chai A","family":"Ng","sequence":"additional","affiliation":[{"name":"Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute , Darlinghurst, New South Wales , Australia"},{"name":"School of Clinical Medicine, UNSW Sydney , Darlinghurst, New South Wales , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur A M","family":"Wilde","sequence":"additional","affiliation":[{"name":"Experimental Cardiology, Amsterdam UMC location University of Amsterdam , Meibergdreef 9, Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Amsterdam , The Netherlands"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart\u2019"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin A","family":"Bertels","sequence":"additional","affiliation":[{"name":"Department of Paediatric Cardiology, Leiden University Medical Center, Willem-Alexander Children's Hospital , Albinusdreef 2, 2333 Leiden , Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hennie","family":"Bikker","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart\u2019"},{"name":"Human Genetics, Amsterdam UMC location University of Amsterdam , Meibergdreef 9, Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imke","family":"Christiaans","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, University Medical Centre Groningen , 9713GZ Groningen , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia N","family":"van der Crabben","sequence":"additional","affiliation":[{"name":"Human Genetics, Amsterdam UMC location University of Amsterdam , Meibergdreef 9, Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janna A","family":"Hol","sequence":"additional","affiliation":[{"name":"Erasmus MC, Clinical Genetics , Doctor Molewaterplein 40, 3015 Rotterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara T","family":"Koopmann","sequence":"additional","affiliation":[{"name":"Clinical Genetics, Leiden University Medical Center , Albinusdreef 2, 2333 Leiden , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen","family":"Knijnenburg","sequence":"additional","affiliation":[{"name":"Clinical Genetics, Leiden University Medical Center , Albinusdreef 2, 2333 Leiden , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aafke A J","family":"Lommerse","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Leiden University Medical Center , Albinusdreef 2, 2300 Leiden , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper J","family":"van der Smagt","sequence":"additional","affiliation":[{"name":"Clinical Genetics, University Medical Center Utrecht , Lundlaan 6, Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connie R","family":"Bezzina","sequence":"additional","affiliation":[{"name":"Experimental Cardiology, Amsterdam UMC location University of Amsterdam , Meibergdreef 9, Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Amsterdam , The Netherlands"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart\u2019"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie I","family":"Vandenberg","sequence":"additional","affiliation":[{"name":"Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute , Darlinghurst, New South Wales , Australia"},{"name":"School of Clinical Medicine, UNSW Sydney , Darlinghurst, New South Wales , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arie O","family":"Verkerk","sequence":"additional","affiliation":[{"name":"Experimental Cardiology, Amsterdam UMC location University of Amsterdam , Meibergdreef 9, Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Amsterdam , The Netherlands"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart\u2019"},{"name":"Medical Biology, Amsterdam UMC location University of Amsterdam , Meibergdreef 9, Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela Q C M","family":"Barge-Schaapveld","sequence":"additional","affiliation":[{"name":"Clinical Genetics, Leiden University Medical Center , Albinusdreef 2, 2333 Leiden , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6017-3796","authenticated-orcid":false,"given":"Elisabeth M","family":"Lodder","sequence":"additional","affiliation":[{"name":"Experimental Cardiology, Amsterdam UMC location University of Amsterdam , Meibergdreef 9, Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Amsterdam , The Netherlands"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN 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