{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T05:24:33Z","timestamp":1774329873184,"version":"3.50.1"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T00:00:00Z","timestamp":1606348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Ministerio de Econom\u00ed\u0131a y Competitividad-Instituto de Salud Carlos III and FondosEuropeos de Desarrollo Regional","award":["PI17\/00648"],"award-info":[{"award-number":["PI17\/00648"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Long QT syndrome (LQTS) is an inheritable arrhythmogenic disorder associated with life-threatening arrhythmic events (LAEs). In general, patients with LQTS2 (KCNH2) and LQTS3 (SCN5A) are considered to be a greater risk of LAEs than LQTS1 (KCNQ1) patients. Gender differences are also important. Series analyzing families with the same pathogenic variants may help in the progress of elaborating strong specific genotype-phenotype management strategies. In this manuscript, we describe the phenotype of seven unrelated families, carriers of the KCNQ1 G168R pathogenic variant. Methods: we identified all consecutive index cases referred for genetic testing with LQTS diagnosis carriers of KCNQ1 G168R variant. Genetic and clinical screening for all available relatives was performed. Results: we evaluated seven unrelated families, with a total 34 KCNQ1 G168R carriers (two obligated carriers died without available EKGs to evaluate the phenotype). All index cases but one were women and three of them presented with aborted sudden cardiac death (SCD) or syncope. The presence of sudden death in these families is notable, with a total of nine unexplained sudden deaths and four aborted SCD. Phenotype penetrance was 100% in women and 37.5% in men. Conclusions: KCNQ1 G168R is a pathogenic variant, with a high penetrance among women and mild penetrance among men. Risk for LAEs in this variant seems not negligible, especially among woman, and risk stratification should always be carefully evaluated.<\/jats:p>","DOI":"10.3390\/jcm9123846","type":"journal-article","created":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T22:00:33Z","timestamp":1606428033000},"page":"3846","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Clinical Implications and Gender Differences of KCNQ1 p.Gly168Arg Pathogenic Variant in Long QT Syndrome"],"prefix":"10.3390","volume":"9","author":[{"given":"Rebeca","family":"Lorca","sequence":"first","affiliation":[{"name":"\u00c1rea del Coraz\u00f3n y Departamento de Gen\u00e9tica Molecular, Hospital Universitario Central Asturias, Unidad de Referencia de Cardiopat\u00edas Familiares-HUCA, 33011 Oviedo, Spain"},{"name":"Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7003-3196","authenticated-orcid":false,"given":"Alejandro","family":"Junco-Vicente","sequence":"additional","affiliation":[{"name":"Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Martin-Fernandez","sequence":"additional","affiliation":[{"name":"Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5433-1364","authenticated-orcid":false,"given":"Isaac","family":"Pascual","sequence":"additional","affiliation":[{"name":"Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Aparicio","sequence":"additional","affiliation":[{"name":"Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0806-7827","authenticated-orcid":false,"given":"Noemi","family":"Barja","sequence":"additional","affiliation":[{"name":"Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elias","family":"Cuesta-LLavona","sequence":"additional","affiliation":[{"name":"\u00c1rea del Coraz\u00f3n y Departamento de Gen\u00e9tica Molecular, Hospital Universitario Central Asturias, Unidad de Referencia de Cardiopat\u00edas Familiares-HUCA, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis","family":"Roces","sequence":"additional","affiliation":[{"name":"Anestesiolog\u00eda, Reanimaci\u00f3n y terap\u00e9utica del dolor, Completo Asistencial Universitario de Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4958-6108","authenticated-orcid":false,"given":"Pablo","family":"Avanzas","sequence":"additional","affiliation":[{"name":"Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2871-190X","authenticated-orcid":false,"given":"Cesar","family":"Moris","sequence":"additional","affiliation":[{"name":"\u00c1rea del Coraz\u00f3n y Departamento de Gen\u00e9tica Molecular, Hospital Universitario Central Asturias, Unidad de Referencia de Cardiopat\u00edas Familiares-HUCA, 33011 Oviedo, Spain"},{"name":"Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eliecer","family":"Coto","sequence":"additional","affiliation":[{"name":"\u00c1rea del Coraz\u00f3n y Departamento de Gen\u00e9tica Molecular, Hospital Universitario Central Asturias, Unidad de Referencia de Cardiopat\u00edas Familiares-HUCA, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 Jul\u00edan","family":"Rodr\u00edguez Reguero","sequence":"additional","affiliation":[{"name":"\u00c1rea del Coraz\u00f3n y Departamento de Gen\u00e9tica Molecular, Hospital Universitario Central Asturias, Unidad de Referencia de Cardiopat\u00edas Familiares-HUCA, 33011 Oviedo, Spain"},{"name":"Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3318-4649","authenticated-orcid":false,"given":"Juan","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"\u00c1rea del Coraz\u00f3n y Departamento de Gen\u00e9tica Molecular, Hospital Universitario Central Asturias, Unidad de Referencia de Cardiopat\u00edas Familiares-HUCA, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1016\/j.jacc.2018.01.078","article-title":"Interplay Between Genetic Substrate, QTc Duration, and Arrhythmia Risk in Patients with Long QT Syndrome","volume":"71","author":"Mazzanti","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_2","first-page":"1297","article-title":"Spectrum and prevalence of mutations from the first 2500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test","volume":"6","author":"Kapplinger","year":"2009","journal-title":"HeartRhythm"},{"key":"ref_3","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":"ref_4","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/j.jacc.2006.06.034","article-title":"QT interval duration remains a major risk factor in long QT syndrome patients","volume":"48","author":"Locati","year":"2006","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.jacc.2010.07.038","article-title":"Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals","volume":"57","author":"Goldenberg","year":"2011","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_6","unstructured":"European Heart Rhythm Association, Heart Rhythm Society, Zipes, D.P., Camm, A.J., Borggrefe, M., Buxton, A.E., Chaitman, B., Fromer, M., Gregoratos, G., and Klein, G. (2006). ACC\/AHA\/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology\/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J. Am. Coll. Cardiol., 48, e247\u2013e346."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2793","DOI":"10.1093\/eurheartj\/ehv316","article-title":"2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC)","volume":"36","author":"Priori","year":"2015","journal-title":"Eur. Heart J."},{"key":"ref_8","first-page":"1932","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":"HeartRhythm"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1056\/NEJMoa022147","article-title":"Risk stratification in the long-QT syndrome","volume":"348","author":"Priori","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1161\/CIRCEP.111.962019","article-title":"Long-QT syndrome: From genetics to management","volume":"5","author":"Schwartz","year":"2012","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.1161\/CIRCULATIONAHA.105.572453","article-title":"Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population","volume":"112","author":"Brink","year":"2005","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1161\/CIRCULATIONAHA.107.726950","article-title":"The common long-QT syndrome mutation KCNQ1\/A341V causes unusually severe clinical manifestations in patients with different ethnic backgrounds: Toward a mutation-specific risk stratification","volume":"116","author":"Crotti","year":"2007","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1161\/01.CIR.103.1.89","article-title":"Genotype-phenotype correlation in the long-QT syndrome: Gene-specific triggers for life-threatening arrhythmias","volume":"103","author":"Schwartz","year":"2001","journal-title":"Circulation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.jacc.2008.12.014","article-title":"AHA\/ACCF\/HRS recommendations for the standardization and interpretation of the electrocardiogram: Part IV: The ST segment, T and U waves, and the QT interval: A scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology","volume":"53","author":"Rautaharju","year":"2009","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_15","first-page":"121","article-title":"Memoir of H. C. Bazett (1885\u20131950)","volume":"19","author":"Adler","year":"1952","journal-title":"Trans. Stud. Coll. Physicians Phila."},{"key":"ref_16","first-page":"2963","article-title":"Mutation analysis of the main hypertrophic cardiomyopathy genes using multiplex amplification and semiconductor next-generation sequencing","volume":"78","author":"Reguero","year":"2014","journal-title":"Circ. J. Off. J. Jpn. Circ. Soc."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"G\u00f3mez, J., Lorca, R., Reguero, J.R., Mor\u00eds, C., Mart\u00edn, M., Tranche, S., Alonso, B., Iglesias, S., Alvarez, V., and D\u00edaz-Molina, B. (2017). Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients. Circ. Cardiovasc. Genet., 10.","DOI":"10.1161\/CIRCGENETICS.116.001584"},{"key":"ref_18","first-page":"405","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. Off. J. Am. Coll. Med. Genet."},{"key":"ref_19","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":"ref_20","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.jacc.2004.03.043","article-title":"Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: Multicenter study in Japan","volume":"44","author":"Shimizu","year":"2004","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1161\/CIRCULATIONAHA.111.048041","article-title":"Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: Implications for mutation-specific response to \u03b2-blocker therapy in type 1 long-QT syndrome","volume":"125","author":"Barsheshet","year":"2012","journal-title":"Circulation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1046\/j.1540-8167.2003.03177.x","article-title":"Location of mutation in the KCNQ1 and phenotypic presentation of long QT syndrome","volume":"14","author":"Zareba","year":"2003","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_23","first-page":"1808","article-title":"Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith-Wiedemann locus","volume":"21","author":"Valente","year":"2019","journal-title":"Genet. Med. Off. J. Am. Coll. Med. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s13148-020-00856-y","article-title":"Frequency of KCNQ1 variants causing loss of methylation of Imprinting Centre 2 in Beckwith-Wiedemann syndrome","volume":"12","author":"Karch","year":"2020","journal-title":"Clin. Epigenet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1002\/ajmg.c.31363","article-title":"Molecular findings in Beckwith-Wiedemann syndrome","volume":"163","author":"Choufani","year":"2013","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2744","DOI":"10.1056\/NEJMoa042786","article-title":"Female predominance and transmission distortion in the long-QT syndrome","volume":"355","author":"Imboden","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1038\/ejhg.2015.257","article-title":"Asymmetry of parental origin in long QT syndrome: Preferential maternal transmission of KCNQ1 variants linked to channel dysfunction","volume":"24","author":"Itoh","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s00439-012-1257-0","article-title":"Transmission ratio distortion: Review of concept and implications for genetic association studies","volume":"132","author":"Huang","year":"2013","journal-title":"Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1161\/HYPERTENSIONAHA.111.173740","article-title":"Novel expression and regulation of voltage-dependent potassium channels in placentas from women with preeclampsia","volume":"58","author":"Mistry","year":"2011","journal-title":"Hypertension"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1210\/me.2013-1038","article-title":"Estrogen-related receptor \u03b3 (ERR\u03b3) regulates oxygen-dependent expression of voltage-gated potassium (K+) channels and tissue kallikrein during human trophoblast differentiation","volume":"27","author":"Luo","year":"2013","journal-title":"Mol. Endocrinol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"777","DOI":"10.2164\/jandrol.111.015552","article-title":"Ion channels in sperm physiology and male fertility and infertility","volume":"33","author":"Shukla","year":"2012","journal-title":"J. Androl."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1161\/01.CIR.97.22.2237","article-title":"Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: Findings from the International LQTS Registry","volume":"97","author":"Locati","year":"1998","journal-title":"Circulation"},{"key":"ref_33","first-page":"892","article-title":"Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome","volume":"9","author":"Costa","year":"2012","journal-title":"HeartRhythm"},{"key":"ref_34","first-page":"1068","article-title":"Effects of gonadal steroids on ventricular repolarization and on the response to E4031","volume":"285","author":"Hara","year":"1998","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_35","first-page":"395","article-title":"Modulation by testosterone of an endogenous hERG potassium channel current","volume":"59","author":"Ridley","year":"2008","journal-title":"J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/12\/3846\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:38:02Z","timestamp":1760179082000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/12\/3846"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,26]]},"references-count":35,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["jcm9123846"],"URL":"https:\/\/doi.org\/10.3390\/jcm9123846","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,26]]}}}