{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T09:04:29Z","timestamp":1784106269072,"version":"3.55.0"},"reference-count":38,"publisher":"Elsevier BV","issue":"7","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007188","name":"Uniformed Services University of the Health Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009898","name":"Defense Health Agency Consortium","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009898","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","heartrhythmcasereports.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["HeartRhythm Case Reports"],"published-print":{"date-parts":[[2026,7]]},"DOI":"10.1016\/j.hrcr.2026.03.020","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T15:49:11Z","timestamp":1774885751000},"page":"802-809","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"title":["KCNQ1 D673N variant causes loss of adrenergic-induced cardiac action potential shortening"],"prefix":"10.1016","volume":"12","author":[{"given":"Naheed","family":"Fatima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0592-3552","authenticated-orcid":false,"given":"Lydia D.","family":"Hellwig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecelia C.","family":"Mangione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Princess","family":"Nwachukwu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Salzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clifton L.","family":"Dalgard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaquin","family":"Villar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark C.","family":"Haigney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3147-4060","authenticated-orcid":false,"given":"Thomas P.","family":"Flagg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.hrcr.2026.03.020_bib1","doi-asserted-by":"crossref","first-page":"e93","DOI":"10.1161\/CIR.0000000000001123","article-title":"Heart disease and stroke Statistics-2023 update: A report from the American Heart Association","volume":"147","author":"Tsao","year":"2023","journal-title":"Circulation"},{"key":"10.1016\/j.hrcr.2026.03.020_bib2","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1161\/CIRCRESAHA.116.304521","article-title":"The spectrum of epidemiology underlying sudden cardiac death","volume":"116","author":"Hayashi","year":"2015","journal-title":"Circ Res"},{"key":"10.1016\/j.hrcr.2026.03.020_bib3","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1001\/jama.2024.27916","article-title":"Out-of-hospital cardiac arrest in apparently healthy, young adults","volume":"333","author":"Tseng","year":"2025","journal-title":"JAMA"},{"key":"10.1016\/j.hrcr.2026.03.020_bib4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.14740\/jocmr4823","article-title":"Sudden cardiac death in young individuals: A current review of evaluation, screening and prevention","volume":"15","author":"Abbas","year":"2023","journal-title":"J Clin Med Res"},{"key":"10.1016\/j.hrcr.2026.03.020_bib5","first-page":"e210","volume":"138","author":"Al-Khatib","year":"2018","journal-title":"Circulation"},{"key":"10.1016\/j.hrcr.2026.03.020_bib6","doi-asserted-by":"crossref","first-page":"994","DOI":"10.7326\/M21-4109","article-title":"The challenge of genetic variants of uncertain clinical significance : A narrative review","volume":"175","author":"Burke","year":"2022","journal-title":"Ann Intern Med"},{"key":"10.1016\/j.hrcr.2026.03.020_bib7","doi-asserted-by":"crossref","DOI":"10.3389\/fcvm.2022.900431","article-title":"How functional genomics can keep pace with VUS identification","volume":"9","author":"Anderson","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"10.1016\/j.hrcr.2026.03.020_bib8","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":"10.1016\/j.hrcr.2026.03.020_bib9","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":"10.1016\/j.hrcr.2026.03.020_bib10","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.57680","article-title":"Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation","volume":"9","author":"Kuenze","year":"2020","journal-title":"Elife"},{"key":"10.1016\/j.hrcr.2026.03.020_bib11","doi-asserted-by":"crossref","DOI":"10.1161\/CIRCGEN.118.002345","article-title":"High-throughput functional evaluation of KCNQ1 decrypts variants of unknown significance","volume":"11","author":"Vanoye","year":"2018","journal-title":"Circ Genom Precis Med"},{"key":"10.1016\/j.hrcr.2026.03.020_bib12","doi-asserted-by":"crossref","first-page":"527","DOI":"10.5966\/sctm.2015-0428","article-title":"Heparin promotes cardiac differentiation of human pluripotent stem cells in chemically defined albumin-free medium, enabling consistent manufacture of cardiomyocytes","volume":"6","author":"Lin","year":"2017","journal-title":"Stem Cells Transl Med"},{"key":"10.1016\/j.hrcr.2026.03.020_bib13","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/384080a0","article-title":"Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel","volume":"384","author":"Sanguinetti","year":"1996","journal-title":"Nature"},{"key":"10.1016\/j.hrcr.2026.03.020_bib14","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/384078a0","article-title":"K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current","volume":"384","author":"Barhanin","year":"1996","journal-title":"Nature"},{"key":"10.1016\/j.hrcr.2026.03.020_bib15","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"REVEL: an ensemble method for predicting the pathogenicity of rare missense variants","volume":"99","author":"Ioannidis","year":"2016","journal-title":"Am J Hum Genet"},{"issue":"May Suppl.","key":"10.1016\/j.hrcr.2026.03.020_bib16","first-page":"S42","article-title":"Long QT syndrome-associated mutations in hypertrophic cardiomyopathy: a cause of sudden death?","volume":"8","author":"Bos","year":"2011","journal-title":"Heart Rhythm"},{"key":"10.1016\/j.hrcr.2026.03.020_bib17","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"10.1016\/j.hrcr.2026.03.020_bib18","doi-asserted-by":"crossref","DOI":"10.1002\/jcla.24967","article-title":"The challenges in the interpretation of genetic variants detected by genomics techniques in patients with congenital anomalies","volume":"37","author":"Vaseghi","year":"2023","journal-title":"J Clin Lab Anal"},{"key":"10.1016\/j.hrcr.2026.03.020_bib19","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":"10.1016\/j.hrcr.2026.03.020_bib20","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1097\/HCO.0b013e32835b0a41","article-title":"Genetic testing in heritable cardiac arrhythmia syndromes: differentiating pathogenic mutations from background genetic noise","volume":"28","author":"Giudicessi","year":"2013","journal-title":"Curr Opin Cardiol"},{"key":"10.1016\/j.hrcr.2026.03.020_bib21","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":"10.1016\/j.hrcr.2026.03.020_bib22","doi-asserted-by":"crossref","DOI":"10.1161\/CIRCGENETICS.117.001754","article-title":"Predicting the functional impact of KCNQ1 variants of unknown significance","volume":"10","author":"Li","year":"2017","journal-title":"Circ Cardiovasc Genet"},{"key":"10.1016\/j.hrcr.2026.03.020_bib23","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.aar2631","article-title":"Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations","volume":"4","author":"Huang","year":"2018","journal-title":"Sci Adv"},{"key":"10.1016\/j.hrcr.2026.03.020_bib24","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2412971122","article-title":"Integrative analysis of KCNQ1 variants reveals molecular mechanisms of type 1 long QT syndrome pathogenesis","volume":"122","author":"Brewer","year":"2025","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.hrcr.2026.03.020_bib25","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/S0735-1097(00)01124-4","article-title":"A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics","volume":"37","author":"Piippo","year":"2001","journal-title":"J Am Coll Cardiol"},{"key":"10.1016\/j.hrcr.2026.03.020_bib26","doi-asserted-by":"crossref","first-page":"6561","DOI":"10.3390\/ijms26146561","article-title":"Predicting the damaging potential of uncharacterized KCNQ1 and KCNE1 variants","volume":"26","author":"Tarnovskaya","year":"2025","journal-title":"Int J Mol Sci"},{"key":"10.1016\/j.hrcr.2026.03.020_bib27","doi-asserted-by":"crossref","first-page":"7389","DOI":"10.3390\/ijms23137389","article-title":"Mutation-specific differences in Kv7.1 (KCNQ1) and Kv11.1 (KCNH2) channel dysfunction and long QT syndrome phenotypes","volume":"23","author":"Kekenes-Huskey","year":"2022","journal-title":"Int J Mol Sci"},{"key":"10.1016\/j.hrcr.2026.03.020_bib28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.trsl.2012.08.005","article-title":"Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes","volume":"161","author":"Giudicessi","year":"2013","journal-title":"Transl Res"},{"key":"10.1016\/j.hrcr.2026.03.020_bib29","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.hrthm.2011.08.020","article-title":"Trigger-specific ion-channel mechanisms, risk factors, and response to therapy in type 1 long QT syndrome","volume":"9","author":"Goldenberg","year":"2012","journal-title":"Heart Rhythm"},{"key":"10.1016\/j.hrcr.2026.03.020_bib30","doi-asserted-by":"crossref","first-page":"29815","DOI":"10.1074\/jbc.M112.380568","article-title":"The A-kinase anchoring protein Yotiao facilitates complex formation between adenylyl cyclase type 9 and the IKs potassium channel in heart","volume":"287","author":"Li","year":"2012","journal-title":"J Biol Chem"},{"key":"10.1016\/j.hrcr.2026.03.020_bib31","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1126\/science.1066843","article-title":"Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel","volume":"295","author":"Marx","year":"2002","journal-title":"Science"},{"key":"10.1016\/j.hrcr.2026.03.020_bib32","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1161\/01.RES.0000150055.06226.4e","article-title":"Proarrhythmic consequences of a KCNQ1 AKAP-binding domain mutation: computational models of whole cells and heterogeneous tissue","volume":"95","author":"Saucerman","year":"2004","journal-title":"Circ Res"},{"key":"10.1016\/j.hrcr.2026.03.020_bib33","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1161\/CIRCRESAHA.118.311209","article-title":"Human induced pluripotent stem cell-derived cardiomyocytes as models for cardiac Channelopathies: A primer for non-electrophysiologists","volume":"123","author":"Garg","year":"2018","journal-title":"Circ Res"},{"key":"10.1016\/j.hrcr.2026.03.020_bib34","doi-asserted-by":"crossref","first-page":"2983","DOI":"10.1016\/j.hrthm.2025.03.2005","article-title":"The role of iPSC research for insight into inherited arrhythmia conditions","volume":"22","author":"Josvai","year":"2025","journal-title":"Heart Rhythm"},{"key":"10.1016\/j.hrcr.2026.03.020_bib35","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1016\/j.stem.2024.08.008","article-title":"Modeling the atrioventricular conduction axis using human pluripotent stem cell-derived cardiac assembloids","volume":"31","author":"Li","year":"2024","journal-title":"Cell Stem Cell"},{"key":"10.1016\/j.hrcr.2026.03.020_bib36","doi-asserted-by":"crossref","first-page":"261.e1","DOI":"10.5694\/mja14.01674","article-title":"The Cardiac Genetics Clinic: a model for multidisciplinary genomic medicine","volume":"203","author":"Zentner","year":"2015","journal-title":"Med J Aust"},{"key":"10.1016\/j.hrcr.2026.03.020_bib37","doi-asserted-by":"crossref","DOI":"10.1161\/HCG.0000000000000054","article-title":"Establishment of specialized clinical cardiovascular genetics programs: recognizing the need and meeting standards: A scientific statement from the American Heart Association","volume":"12","author":"Ahmad","year":"2019","journal-title":"Circ Genom Precis Med"},{"key":"10.1016\/j.hrcr.2026.03.020_bib38","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2024.1475152","article-title":"Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) for modeling cardiac arrhythmias: strengths, challenges and potential solutions","volume":"15","author":"Joshi","year":"2024","journal-title":"Front Physiol"}],"container-title":["HeartRhythm Case Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S221402712600117X?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S221402712600117X?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T08:13:43Z","timestamp":1784103223000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S221402712600117X"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7]]},"references-count":38,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["S221402712600117X"],"URL":"https:\/\/doi.org\/10.1016\/j.hrcr.2026.03.020","relation":{},"ISSN":["2214-0271"],"issn-type":[{"value":"2214-0271","type":"print"}],"subject":[],"published":{"date-parts":[[2026,7]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"KCNQ1 D673N variant causes loss of adrenergic-induced cardiac action potential shortening","name":"articletitle","label":"Article Title"},{"value":"HeartRhythm Case Reports","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.hrcr.2026.03.020","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"Published by Elsevier Inc. on behalf of Heart Rhythm Society.","name":"copyright","label":"Copyright"}]}}