{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:39:06Z","timestamp":1790811546077,"version":"4.1.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T00:00:00Z","timestamp":1677715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Ministry of Health"},{"name":"Labor and Welfare of Japan"},{"name":"for Clinical Research on Intractable Disease"},{"name":"MEXT KAKENHI","award":["15H04818"],"award-info":[{"award-number":["15H04818"]}]},{"name":"MEXT KAKENHI","award":["19K08538"],"award-info":[{"award-number":["19K08538"]}]},{"name":"MEXT KAKENHI","award":["18K07875"],"award-info":[{"award-number":["18K07875"]}]},{"DOI":"10.13039\/100005859","name":"Heart Rhythm Society","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100005859","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["830951"],"award-info":[{"award-number":["830951"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>More than one-third of type 2 long QT syndrome (LQT2) patients carry KCNH2 non-missense variants that can result in haploinsufficiency (HI), leading to mechanistic loss-of-function. However, their clinical phenotypes have not been fully investigated. The remaining two-thirds of patients harbour missense variants, and past studies uncovered that most of these variants cause trafficking deficiency, resulting in different functional changes: either HI or dominant-negative (DN) effects. In this study, we examined the impact of altered molecular mechanisms on clinical outcomes in LQT2 patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>We included 429 LQT2 patients (234 probands) carrying a rare KCNH2 variant from our patient cohort undergoing genetic testing. Non-missense variants showed shorter corrected QT (QTc) and less arrhythmic events (AEs) than missense variants. We found that 40% of missense variants in this study were previously reported as HI or DN. Non-missense and HI-groups had similar phenotypes, while both exhibited shorter QTc and less AEs than the DN-group. Based on previous work, we predicted the functional change of the unreported variants\u2014whether they cause HI or DN via altered functional domains\u2014and stratified them as predicted HI (pHI)- or pDN-group. The pHI-group including non-missense variants exhibited milder phenotypes compared to the pDN-group. Multivariable Cox model showed that the functional change was an independent risk of AEs (P = 0.005).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Stratification based on molecular biological studies enables us to better predict clinical outcomes in the patients with LQT2.<\/jats:p><\/jats:sec>","DOI":"10.1093\/europace\/euac269","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T13:20:39Z","timestamp":1677763239000},"page":"1491-1499","source":"Crossref","is-referenced-by-count":23,"title":["Non-missense variants of<i>KCNH2<\/i>show better outcomes in type 2 long QT syndrome"],"prefix":"10.1093","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5192-3962","authenticated-orcid":false,"given":"Takanori","family":"Aizawa","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine , Kyoto , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8533-8040","authenticated-orcid":false,"given":"Yuko","family":"Wada","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shiga University of Medical Science , Setatsukinowacho, Otsu, Shiga 520-2192 , Japan"},{"name":"Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1275 MRBIV, Nashville, TN 37232 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0517-0255","authenticated-orcid":false,"given":"Kanae","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1275 MRBIV, Nashville, TN 37232 , USA"},{"name":"Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui , Fukui , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2693-6993","authenticated-orcid":false,"given":"Hai","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine , Kyoto , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0197-0597","authenticated-orcid":false,"given":"Tomohiko","family":"Imamura","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine , Kyoto , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1599-7803","authenticated-orcid":false,"given":"Jingshan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine , Kyoto , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9562-8981","authenticated-orcid":false,"given":"Asami","family":"Kashiwa","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine , Kyoto , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8281-8396","authenticated-orcid":false,"given":"Hirohiko","family":"Kohjitani","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine , Kyoto , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3990-4053","authenticated-orcid":false,"given":"Megumi","family":"Fukuyama","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shiga University of Medical Science , Setatsukinowacho, Otsu, Shiga 520-2192 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6125-0789","authenticated-orcid":false,"given":"Koichi","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shiga University of Medical Science , Setatsukinowacho, Otsu, Shiga 520-2192 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6484-7743","authenticated-orcid":false,"given":"Eri Toda","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine , Kyoto , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6244-1763","authenticated-orcid":false,"given":"Takashi","family":"Hisamatsu","sequence":"additional","affiliation":[{"name":"Department of Public Health, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science , Okayama , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1209-8896","authenticated-orcid":false,"given":"Seiko","family":"Ohno","sequence":"additional","affiliation":[{"name":"Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center , Osaka , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeru","family":"Makiyama","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine , Kyoto , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5665-4076","authenticated-orcid":false,"given":"Takeshi","family":"Kimura","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Hirakata Kohsai Hospital , Osaka , 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