{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:21:39Z","timestamp":1792524099513,"version":"4.5.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2020,2,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Utilizing an evidence-based framework, 3 gene curation teams blinded to each other\u2019s work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Of 17 genes reported as being causative for LQTS, 9 (\n                      <jats:italic>AKAP9, ANK2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1<\/jats:italic>\n                      ) were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes (\n                      <jats:italic>KCNQ1, KCNH2, SCN5A<\/jats:italic>\n                      ) were curated as definitive genes for typical LQTS. Another 4 genes (\n                      <jats:italic>CALM1, CALM2, CALM3, TRDN<\/jats:italic>\n                      ) were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene (\n                      <jats:italic>CACNA1C<\/jats:italic>\n                      ) had moderate level evidence for causing LQTS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.119.043132","type":"journal-article","created":{"date-parts":[[2020,1,27]],"date-time":"2020-01-27T05:00:22Z","timestamp":1580101222000},"page":"418-428","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":377,"title":["An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome"],"prefix":"10.1161","volume":"141","author":[{"given":"Arnon","family":"Adler","sequence":"first","affiliation":[{"name":"Division of Cardiology, Toronto General Hospital and University of Toronto, Canada (A.A, M.C., M.H.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Novelli","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, and Istituto di Medicina Genomica, Universit\u00e0 Cattolica del Sacro Cuore, Rome, Italy (V.N., E.A., S.A., D.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad S.","family":"Amin","sequence":"additional","affiliation":[{"name":"Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences (A.S.A., A.A.M.W.), Amsterdam University Medical Centers, University of Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Abiusi","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, and Istituto di Medicina Genomica, Universit\u00e0 Cattolica del Sacro Cuore, Rome, Italy (V.N., E.A., S.A., D.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Care","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Toronto General Hospital and University of Toronto, Canada (A.A, M.C., M.H.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eline A.","family":"Nannenberg","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (E.A.N., H.B.), Amsterdam University Medical Centers, University of Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harriet","family":"Feilotter","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, Queen\u2019s University, Kingston, Canada (H.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Amenta","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, and Istituto di Medicina Genomica, Universit\u00e0 Cattolica del Sacro Cuore, Rome, Italy (V.N., E.A., S.A., D.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Mazza","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, and Istituto di Medicina Genomica, Universit\u00e0 Cattolica del Sacro Cuore, Rome, Italy (V.N., E.A., S.A., D.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hennie","family":"Bikker","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (E.A.N., H.B.), Amsterdam University Medical Centers, University of Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy C.","family":"Sturm","sequence":"additional","affiliation":[{"name":"Geisinger Genomic Medicine Institute, Danville, PA (A.C.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Garcia","sequence":"additional","affiliation":[{"name":"Invitae Corporation, San Francisco, CA (J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Ackerman","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular Diseases, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Rochester, MN (M.J.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond E.","family":"Hershberger","sequence":"additional","affiliation":[{"name":"Divisions of Human Genetics and Cardiovascular Medicine in the Department of Internal Medicine, Ohio State University, Columbus (R.E.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco V.","family":"Perez","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Stanford University, CA (M.V.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"Zareba","sequence":"additional","affiliation":[{"name":"Cardiology Unit of the Department of Medicine, University of Rochester Medical Center, NY (W.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S.","family":"Ware","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute and Medical Research Council London Institute of Medical Sciences, Imperial College London, UK (J.S.W.)."},{"name":"Royal Brompton and Harefield Hospitals National Health Service Trust, London, UK (J.S.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur A.M.","family":"Wilde","sequence":"additional","affiliation":[{"name":"Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences (A.S.A., A.A.M.W.), Amsterdam University Medical Centers, University of Amsterdam, The Netherlands."},{"name":"Columbia University Irving Medical Center, New York (A.A.M.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Gollob","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Toronto General Hospital and University of Toronto, Canada (A.A, M.C., M.H.G.)."},{"name":"Department of Physiology, University of Toronto, and The Toronto General Hospital Research Institute, University Health Network, University of Toronto, Canada (M.H.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-8703(57)90079-0"},{"key":"e_1_3_4_3_2","first-page":"656","article-title":"[Rare cardiac arrythmias of the pediatric age. 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