{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T11:29:59Z","timestamp":1782818999821,"version":"3.54.5"},"reference-count":42,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,4,8]],"date-time":"2022-04-08T00:00:00Z","timestamp":1649376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Long QT syndrome (LQTS) is an inherited (autosomal dominant) channelopathy associated with susceptibility to ventricular arrhythmias due to malfunction of ion channels in cardiomyocytes, that could lead to sudden death (SD). Most pathogenic variants are in the main 3 genes: KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3). Efforts to improve the understanding of the genotype-phenotype relationship are essential to improve the medical clinical practice. In this study, we identified all index patients referred for NGS genetic sequencing due to LQTS, in a Spanish cohort, who were carriers of a new pathogenic variant (KCNH2 p.Gly262AlafsTer98). Genetic and clinical family screening was performed in order to describe its phenotypic characteristics. We identified 22 relatives of Romani ethnicity, who were carriers of the variant. Penetrance reached a 100% and adherence to medical treatment was low. There was a high rate of clinical events, particularly arrhythmic events and SD (1 in every 4 patients presented syncope, 1 presented an aborted SD, 2 obligated carriers suffered SD before the age of 40 and 4 out of 6 carriers of an implantable cardioverter-defibrillator (ICD) had appropriate ICD therapies. Correct adherence to medical treatment in all carriers should be specially encouraged in this population. ICD implantation decision in non-compliant patients, and refusing left cardiac sympathetic denervation, should be carefully outweighed.<\/jats:p>","DOI":"10.3390\/life12040556","type":"journal-article","created":{"date-parts":[[2022,4,9]],"date-time":"2022-04-09T05:13:08Z","timestamp":1649481188000},"page":"556","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["KCNH2 p.Gly262AlafsTer98: A New Threatening Variant Associated with Long QT Syndrome in a Spanish Cohort"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7803-4011","authenticated-orcid":false,"given":"Rebeca","family":"Lorca","sequence":"first","affiliation":[{"name":"Unidad de Referencia de Cardiopat\u00edas Familiares-HUCA, \u00c1rea del Coraz\u00f3n y Departamento de Gen\u00e9tica Molecular, Hospital Universitario Central de Asturias, 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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7948-528X","authenticated-orcid":false,"given":"Alicia","family":"P\u00e9rez-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Pediatric Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvan Rafael","family":"Persia-Paulino","sequence":"additional","affiliation":[{"name":"Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Gonz\u00e1lez-Urbistondo","sequence":"additional","affiliation":[{"name":"Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"El\u00edas","family":"Cuesta-Llavona","sequence":"additional","affiliation":[{"name":"Unidad de Referencia de Cardiopat\u00edas Familiares-HUCA, \u00c1rea del Coraz\u00f3n y Departamento de Gen\u00e9tica Molecular, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e1rbara C.","family":"Fern\u00e1ndez-Barrio","sequence":"additional","affiliation":[{"name":"Pediatric Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9sar","family":"Mor\u00eds","sequence":"additional","affiliation":[{"name":"Unidad de Referencia de Cardiopat\u00edas Familiares-HUCA, \u00c1rea del Coraz\u00f3n y Departamento de Gen\u00e9tica Molecular, Hospital Universitario Central de Asturias, 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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Manuel","family":"Rub\u00edn","sequence":"additional","affiliation":[{"name":"Unidad de Referencia de Cardiopat\u00edas Familiares-HUCA, \u00c1rea del Coraz\u00f3n y Departamento de Gen\u00e9tica Molecular, Hospital Universitario Central de Asturias, 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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliecer","family":"Coto","sequence":"additional","affiliation":[{"name":"Unidad de Referencia de Cardiopat\u00edas Familiares-HUCA, \u00c1rea del Coraz\u00f3n y Departamento de Gen\u00e9tica Molecular, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3318-4649","authenticated-orcid":false,"given":"Juan","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Unidad de Referencia de Cardiopat\u00edas Familiares-HUCA, \u00c1rea del Coraz\u00f3n y Departamento de Gen\u00e9tica Molecular, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain"},{"name":"CIBER-Enfermedades Respiratorias, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Juli\u00e1n Rodr\u00edguez","family":"Reguero","sequence":"additional","affiliation":[{"name":"Unidad de Referencia de Cardiopat\u00edas Familiares-HUCA, \u00c1rea del Coraz\u00f3n y Departamento de Gen\u00e9tica Molecular, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"},{"name":"Heart Area, Hospital Universitario 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Rev. Dis. Primer"},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"3068","DOI":"10.1111\/jce.14227","article-title":"Update on long QT syndrome","volume":"30","author":"Neira","year":"2019","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1161\/CIRCULATIONAHA.109.863209","article-title":"Prevalence of the congenital long-QT syndrome","volume":"120","author":"Schwartz","year":"2009","journal-title":"Circulation"},{"key":"ref_5","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 2500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test","volume":"6","author":"Kapplinger","year":"2009","journal-title":"Heart Rhythm"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/ng0196-17","article-title":"Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias","volume":"12","author":"Wang","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1016\/j.hrthm.2011.05.020","article-title":"HRS\/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA)","volume":"8","author":"Ackerman","year":"2011","journal-title":"Heart Rhythm"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/0092-8674(95)90358-5","article-title":"A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome","volume":"80","author":"Curran","year":"1995","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/0092-8674(95)90340-2","article-title":"A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel","volume":"81","author":"Sanguinetti","year":"1995","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ono, M., Burgess, D.E., Schroder, E.A., Elayi, C.S., Anderson, C.L., January, C.T., Sun, B., Immadisetty, K., Kekenes-Huskey, P.M., and Delisle, B.P. (2020). Long QT Syndrome Type 2: Emerging Strategies for Correcting Class 2 KCNH2 (hERG) Mutations and Identifying New Patients. Biomolecules, 10.","DOI":"10.3390\/biom10081144"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1161\/CIRCULATIONAHA.120.045956","article-title":"Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome","volume":"142","author":"Lahrouchi","year":"2020","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1161\/01.CIR.99.4.529","article-title":"Low penetrance in the long-QT syndrome: Clinical impact","volume":"99","author":"Priori","year":"1999","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/j.jelectrocard.2018.08.013","article-title":"QT interval: Bazett\u2019s Correction corrected","volume":"51","author":"Smulyan","year":"2018","journal-title":"J. Electrocardiol."},{"key":"ref_14","first-page":"353","article-title":"An analysis of the time-relations of the electrocardiogram","volume":"7","author":"Bazett","year":"1920","journal-title":"Heart"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/nar\/16.3.1215","article-title":"A simple salting out procedure for extracting DNA from human nucleated cells","volume":"16","author":"Miller","year":"1988","journal-title":"Nucleic Acids Res."},{"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","first-page":"e001584","DOI":"10.1161\/CIRCGENETICS.116.001584","article-title":"Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients","volume":"10","author":"Lorca","year":"2017","journal-title":"Circ. Cardiovasc. Genet."},{"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":"1661","DOI":"10.1093\/eurheartj\/ehab007","article-title":"Precision Medicine and cardiac channelopathies: When dreams meet reality","volume":"42","author":"Gnecchi","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.joa.2015.11.009","article-title":"Molecular pathogenesis of long QT syndrome type 2","volume":"32","author":"Smith","year":"2016","journal-title":"J. Arrhythmia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1161\/CIRCULATIONAHA.107.708818","article-title":"Nonsense mutations in hERG cause a decrease in mutant mRNA transcripts by nonsense-mediated mRNA decay in human long-QT syndrome","volume":"116","author":"Gong","year":"2007","journal-title":"Circulation"},{"key":"ref_22","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_23","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_24","doi-asserted-by":"crossref","first-page":"e190","DOI":"10.1016\/j.hrthm.2017.10.035","article-title":"2017 AHA\/ACC\/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary: A Report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society","volume":"15","author":"Stevenson","year":"2018","journal-title":"Heart Rhythm"},{"key":"ref_25","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_26","doi-asserted-by":"crossref","unstructured":"Writing Committee Members, Shah, M.J., Silka, M.J., Silva, J.N.A., Balaji, S., Beach, C.M., Benjamin, M.N., Berul, C.I., Cannon, B., and Cecchin, F. (2021). 2021 PACES Expert Consensus Statement on the Indications and Management of Cardiovascular Implantable Electronic Devices in Pediatric Patients. Heart Rhythm, 18, 1888\u20131924.","DOI":"10.1016\/j.hrthm.2021.07.038"},{"key":"ref_27","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_28","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1016\/j.jacc.2009.08.028","article-title":"Genotype-phenotype aspects of type 2 long QT syndrome","volume":"54","author":"Shimizu","year":"2009","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1161\/hc0702.105124","article-title":"Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel","volume":"105","author":"Moss","year":"2002","journal-title":"Circulation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.hrthm.2005.01.020","article-title":"Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing","volume":"2","author":"Tester","year":"2005","journal-title":"Heart Rhythm"},{"key":"ref_31","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":"ref_32","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":"ref_33","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1161\/01.CIR.97.5.451","article-title":"Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome. LQTS Investigators","volume":"97","author":"Rashba","year":"1998","journal-title":"Circulation"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1016\/j.jacc.2006.09.054","article-title":"Long QT syndrome and pregnancy","volume":"49","author":"Seth","year":"2007","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_35","first-page":"1374","article-title":"Arrhythmia risk and \u03b2-blocker therapy in pregnant women with long QT syndrome","volume":"103","author":"Ishibashi","year":"2017","journal-title":"Heart Br. Card. Soc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1097\/CRD.0000000000000108","article-title":"Influence of Pregnancy in Patients With Congenital Long QT Syndrome","volume":"25","author":"Garg","year":"2017","journal-title":"Cardiol. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1111\/j.1540-8167.2010.01737.x","article-title":"International LQTS Registry Investigators Beta-blocker efficacy in high-risk patients with the congenital long-QT syndrome types 1 and 2: Implications for patient management","volume":"21","author":"Goldenberg","year":"2010","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1161\/01.CIR.92.12.3381","article-title":"Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy","volume":"92","author":"Schwartz","year":"1995","journal-title":"Circulation"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e007280","DOI":"10.1161\/CIRCEP.118.007280","article-title":"Mexiletine Shortens the QT Interval in Patients With Potassium Channel-Mediated Type 2 Long QT Syndrome","volume":"12","author":"Bos","year":"2019","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.jacep.2021.09.002","article-title":"Left Cardiac Sympathetic Denervation for Long QT Syndrome","volume":"8","author":"Dusi","year":"2022","journal-title":"JACC Clin. Electrophysiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1161\/01.CIR.0000125523.14403.1E","article-title":"Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome","volume":"109","author":"Schwartz","year":"2004","journal-title":"Circulation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1161\/CIRCULATIONAHA.110.950147","article-title":"Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them? Data from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator (LQTS ICD) Registry","volume":"122","author":"Schwartz","year":"2010","journal-title":"Circulation"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/12\/4\/556\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:50:17Z","timestamp":1760136617000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/12\/4\/556"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,8]]},"references-count":42,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["life12040556"],"URL":"https:\/\/doi.org\/10.3390\/life12040556","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,8]]}}}