{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:07:53Z","timestamp":1792670873286,"version":"4.5.0"},"reference-count":44,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T00:00:00Z","timestamp":1738800000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82030018"],"award-info":[{"award-number":["82030018"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC3601304"],"award-info":[{"award-number":["2022YFC3601304"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pacing Clinical Electrophis"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>The aim of this study was to investigate the topological distribution of single nucleotide variants (SNVs) in the <jats:italic>KCNH2<\/jats:italic> gene from patients with type 2 long QT syndrome (LQT2) and to explore the genotype\u2010phenotype relationships.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Information on <jats:italic>KCNH2<\/jats:italic> variants in LQT2 patients was retrospectively obtained from the HGMD, ClinVar, and PubMed databases through October 2022. Pathogenicity of SNV was classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Unpaired <jats:italic>t<\/jats:italic>\u2010tests and Fisher's exacts were used to analyze the SNV distributions across structural and functional domains, and their correlation with clinical phenotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 2826 variants were obtained; 2152 were SNVs, 1328 of which were nonsynonymous SNVs (nsSNVs) associated with LQT2. Enrichment analysis revealed that 602 pathogenic (P) and likely pathogenic (LP) nsSNVs were significantly enriched at S5, H5, S6, Extra3, and Extra4. In addition, 759 nsSNVs and 289 P\/LP nsSNVs within function domain were enriched at the per\u2010arnt\u2010sim (PAS) and selectivity filter (SF) functional domain. Clinical data revealed that patients with nsSNVs enriched at the N\u2010terminal, S5\u2010H5\u2010S6 region and PAS domain were associated with an increased risk of syncope. Moreover, nsSNVs located at the N\u2010terminal, S5\u2010H5\u2010S6 region, and PAS, SF domains were associated with an increased risk of life\u2010threatening cardiac events, including Torsade de Pointes (TdP) and sudden cardiac death (SCD), and were predominantly female.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>KCNH2<\/jats:italic> nsSNVs located at the N\u2010terminal, S5\u2010H5\u2010S6 region, and the PAS and SF functional domains are associated with an increased risk of life\u2010threatening cardiac events in LQT2 patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/pace.15145","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T16:18:21Z","timestamp":1738858701000},"page":"351-362","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Topological Distribution of <i>KCNH2<\/i> Variants and Genotype\u2010Phenotype Relationship in Patients With Long QT Syndrome"],"prefix":"10.1111","volume":"48","author":[{"given":"Hongyu","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Medical Genetics The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Molecular Medicine of Jiangxi Key Laboratory The Second Affiliated Hospital, Nanchang University  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University  Nanchang Jiangxi China"},{"name":"Molecular Medicine of Jiangxi Key Laboratory The Second Affiliated Hospital, Nanchang University  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Shao","sequence":"additional","affiliation":[{"name":"Nanchang University Queen Mary School, Jiangxi Medical College, Nanchang University  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhao","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daowu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Brugada","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center Institut 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