{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:44:02Z","timestamp":1792521842151,"version":"4.5.0"},"reference-count":25,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2023,10,28]],"date-time":"2023-10-28T00:00:00Z","timestamp":1698451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Rare variants in the KCNQ1 gene are found in the healthy population to a much greater extent than the prevalence of Long QT Syndrome type 1 (LQTS1). This observation creates challenges in the interpretation of KCNQ1 rare variants that may be identified as secondary findings in whole exome sequencing.<\/jats:p>\n                  <jats:p>This study sought to identify missense variants within sub-domains of the KCNQ1-encoded Kv7.1 potassium channel that would be highly predictive of disease in the context of secondary findings.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>We established a set of KCNQ1 variants reported in over 3700 patients with diagnosed or suspected LQTS sent for clinical genetic testing and compared the domain-specific location of identified variants to those observed in an unselected population of 140\u2005000 individuals. We identified three regions that showed a significant enrichment of KCNQ1 variants associated with LQTS at an odds ratio (OR) &amp;gt;2: the pore region, and the adjacent 5th (S5) and 6th (S6) transmembrane (TM) regions. An additional segment within the carboxyl terminus of Kv7.1, conserved region 2 (CR2), also showed an increased OR of disease association. Furthermore, the TM spanning S5\u2013Pore\u2013S6 region correlated with a significant increase in cardiac events.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Rare missense variants with a clear phenotype of LQTS have a high likelihood to be present within the pore and adjacent TM segments (S5\u2013Pore\u2013S6) and a greater tendency to be present within CR2. This data will enhance interpretation of secondary findings within the KCNQ1 gene. Further, our data support a more severe phenotype in LQTS patients with variants within the S5\u2013Pore\u2013S6 region.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/europace\/euad317","type":"journal-article","created":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T17:13:14Z","timestamp":1698426794000},"source":"Crossref","is-referenced-by-count":5,"title":["Enhancing the interpretation of genetic observations in KCNQ1 in unselected populations: relevance to secondary findings"],"prefix":"10.1093","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4859-0826","authenticated-orcid":false,"given":"Valeria","family":"Novelli","sequence":"first","affiliation":[{"name":"Centro Cardiologico Monzino, IRCCS , Via C. Parea 4 , Milano, 20138, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5172-3442","authenticated-orcid":false,"given":"Trent","family":"Faultless","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University of Toronto , Toronto , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6122-9939","authenticated-orcid":false,"given":"Marina","family":"Cerrone","sequence":"additional","affiliation":[{"name":"Inherited Arrhythmia Clinic and Heart Rhythm Center, \u2018Leon Charney\u2019 Division of Cardiology NYU Grossman School of Medicine , NewYork, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7651-5244","authenticated-orcid":false,"given":"Melanie","family":"Care","sequence":"additional","affiliation":[{"name":"Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, University of Toronto , 200 Elizabeth St.Rm 3GW-360 , Toronto M5G 2C4, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0861-9951","authenticated-orcid":false,"given":"Martina","family":"Manzoni","sequence":"additional","affiliation":[{"name":"Centro Cardiologico Monzino, IRCCS , Via C. Parea 4 , Milano, 20138, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4063-5935","authenticated-orcid":false,"given":"Sara L","family":"Bober","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University of Toronto , Toronto , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8142-4013","authenticated-orcid":false,"given":"Arnon","family":"Adler","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University of Toronto , Toronto , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"De-Giorgio","sequence":"additional","affiliation":[{"name":"Department of Health Care Surveillance and Bioethics, Section of Legal Medicine, Fondazione Policlinico A.Gemelli IRCCS,Universit\u00e0 Cattolica del Sacro Cuore , 00168, Rome , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2513-1627","authenticated-orcid":false,"given":"Danna","family":"Spears","sequence":"additional","affiliation":[{"name":"Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, University of Toronto , 200 Elizabeth St.Rm 3GW-360 , Toronto M5G 2C4, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0242-5208","authenticated-orcid":false,"given":"Michael H","family":"Gollob","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University of Toronto , Toronto , Canada"},{"name":"Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, University of Toronto , 200 Elizabeth St.Rm 3GW-360 , Toronto M5G 2C4, Ontario, Canada"},{"name":"Department of Physiology, University of Toronto , Toronto , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,10,28]]},"reference":[{"key":"2023111023550763300_euad317-B1","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1161\/CIRCULATIONAHA.118.035070","article-title":"Reappraisal of reported genes for sudden arrhythmic death: evidence-based evaluation of gene validity for Brugada syndrome","volume":"138","author":"Hosseini","year":"2018","journal-title":"Circulation"},{"key":"2023111023550763300_euad317-B2","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":"2023111023550763300_euad317-B3","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"2023111023550763300_euad317-B4","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/j.ajhg.2016.03.024","article-title":"Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the clinical sequencing exploratory research consortium","volume":"98","author":"Amendola","year":"2016","journal-title":"Am J Hum Genet"},{"key":"2023111023550763300_euad317-B5","doi-asserted-by":"crossref","first-page":"e200015","DOI":"10.1212\/NXG.0000000000200015","article-title":"Frequency and phenotype associations of rare variants in 5 monogenic cerebral small vessel disease genes in 200,000 UK biobank participants","volume":"8","author":"Ferguson","year":"2022","journal-title":"Neurol Genet"},{"key":"2023111023550763300_euad317-B6","doi-asserted-by":"crossref","first-page":"2523","DOI":"10.1093\/eurheartj\/ehv297","article-title":"Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval","volume":"36","author":"Ghouse","year":"2015","journal-title":"Eur Heart J"},{"key":"2023111023550763300_euad317-B7","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1016\/j.hrthm.2009.05.021","article-title":"Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test","volume":"6","author":"Kapplinger","year":"2009","journal-title":"Heart Rhythm"},{"key":"2023111023550763300_euad317-B8","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.1001\/jama.294.23.2975","article-title":"Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice","volume":"294","author":"Napolitano","year":"2005","journal-title":"JAMA"},{"key":"2023111023550763300_euad317-B9","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1161\/CIRCULATIONAHA.109.863076","article-title":"Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants","volume":"120","author":"Kapa","year":"2009","journal-title":"Circulation"},{"key":"2023111023550763300_euad317-B10","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1161\/01.CIR.102.10.1178","article-title":"Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2","volume":"102","author":"Splawski","year":"2000","journal-title":"Circulation"},{"key":"2023111023550763300_euad317-B11","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s12265-015-9622-8","article-title":"Enhancing the predictive power of mutations in the C-terminus of the KCNQ1-encoded Kv7.1 voltage-gated potassium channel","volume":"8","author":"Kapplinger","year":"2015","journal-title":"J Cardiovasc Transl Res"},{"key":"2023111023550763300_euad317-B12","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/s41436-020-00946-5","article-title":"Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls","volume":"23","author":"Walsh","year":"2021","journal-title":"Genet Med"},{"key":"2023111023550763300_euad317-B13","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1161\/CIRCULATIONAHA.106.665406","article-title":"Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene","volume":"115","author":"Moss","year":"2007","journal-title":"Circulation"},{"key":"2023111023550763300_euad317-B14","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/gim.2016.190","article-title":"Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics","volume":"19","author":"Kalia","year":"2017","journal-title":"Genet Med"},{"key":"2023111023550763300_euad317-B15","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1002\/humu.23996","article-title":"Critical assessment of secondary findings in genes linked to primary arrhythmia syndromes","volume":"41","author":"Diebold","year":"2020","journal-title":"Hum Mutat"},{"key":"2023111023550763300_euad317-B16","doi-asserted-by":"crossref","first-page":"e96","DOI":"10.1212\/NXG.0000000000000096","article-title":"KCNQ2 Encephalopathy: features, mutational hot spots, and ezogabine treatment of 11 patients","volume":"2","author":"Millichap","year":"2016","journal-title":"Neurol Genet"},{"key":"2023111023550763300_euad317-B17","doi-asserted-by":"crossref","first-page":"4743","DOI":"10.1093\/eurheartj\/ehab582","article-title":"Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region","volume":"42","author":"Schwartz","year":"2021","journal-title":"Eur Heart J"},{"key":"2023111023550763300_euad317-B18","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1113\/jphysiol.2004.080887","article-title":"Mutation of colocalized residues of the pore helix and transmembrane segments S5 and S6 disrupt deactivation and modify inactivation of KCNQ1 K+ channels","volume":"563","author":"Seebohm","year":"2005","journal-title":"J Physiol"},{"key":"2023111023550763300_euad317-B19","doi-asserted-by":"crossref","first-page":"2584","DOI":"10.1016\/j.bpj.2018.04.023","article-title":"The structural basis of IKs ion-channel activation: mechanistic insights from molecular simulations","volume":"114","author":"Ramasubramanian","year":"2018","journal-title":"Biophys J"},{"key":"2023111023550763300_euad317-B20","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1093\/emboj\/19.3.332","article-title":"A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly","volume":"19","author":"Schmitt","year":"2000","journal-title":"EMBO J"},{"key":"2023111023550763300_euad317-B21","doi-asserted-by":"crossref","first-page":"28545","DOI":"10.1074\/jbc.M204130200","article-title":"The identification and characterization of a noncontinuous calmodulin-binding site in noninactivating voltage-dependent KCNQ potassium channels","volume":"277","author":"Yus-Najera","year":"2002","journal-title":"J Biol Chem"},{"key":"2023111023550763300_euad317-B22","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1161\/01.RES.0000218979.40770.69","article-title":"Calmodulin is essential for cardiac IKS channel gating and assembly: impaired function in long-QT mutations","volume":"98","author":"Ma","year":"2006","journal-title":"Circ Res"},{"key":"2023111023550763300_euad317-B23","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1161\/01.RES.0000218863.44140.f2","article-title":"KCNQ1 assembly and function is blocked by long-QT syndrome mutations that disrupt interaction with calmodulin","volume":"98","author":"Ghosh","year":"2006","journal-title":"Circ Res"},{"key":"2023111023550763300_euad317-B24","doi-asserted-by":"crossref","first-page":"e003672","DOI":"10.1161\/CIRCGEN.121.003672","article-title":"Variant location is a novel risk factor for individuals with arrhythmogenic cardiomyopathy due to a desmoplakin (DSP) truncating variant","volume":"16","author":"Hoorntje","year":"2023","journal-title":"Circ Genom Precis Med"},{"key":"2023111023550763300_euad317-B25","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1161\/CIRCGEN.120.002929","article-title":"Spatial and functional distribution of MYBPC3 pathogenic variants and clinical outcomes in patients with hypertrophic cardiomyopathy","volume":"13","author":"Helms","year":"2020","journal-title":"Circ Genom Precis Med"}],"container-title":["Europace"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/europace\/advance-article-pdf\/doi\/10.1093\/europace\/euad317\/52662343\/euad317.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/europace\/article-pdf\/25\/11\/euad317\/53119828\/euad317.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/europace\/article-pdf\/25\/11\/euad317\/53119828\/euad317.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,10]],"date-time":"2023-11-10T23:55:39Z","timestamp":1699660539000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/europace\/article\/doi\/10.1093\/europace\/euad317\/7332160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,28]]},"references-count":25,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2023,11,2]]}},"URL":"https:\/\/doi.org\/10.1093\/europace\/euad317","relation":{},"ISSN":["1099-5129","1532-2092"],"issn-type":[{"value":"1099-5129","type":"print"},{"value":"1532-2092","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,11]]},"published":{"date-parts":[[2023,10,28]]},"article-number":"euad317"}}