{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T08:27:03Z","timestamp":1771921623492,"version":"3.50.1"},"reference-count":87,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Long QT Syndrome (LQTS) is characterized by prolonged QT intervals on electrocardiogram, which may progress into life-threatening polymorphic ventricular tachycardia and sudden cardiac death. Variants in the\n                      <jats:italic>KCNH2<\/jats:italic>\n                      gene have been associated with congenital LQTS, with thousands identified to date but very few clinically characterized.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      To describe the rare single nucleotide variant\n                      <jats:italic>KCNH2<\/jats:italic>\n                      (NM_000238.4):c.1066C&amp;gt;T (p.Arg356Cys) associated with drug-induced QT prolongation and to assess its pathogenicity risk using\n                      <jats:italic>in silico<\/jats:italic>\n                      tools and protein structural modeling in accordance with American College of Medical Genetics and Genomics (ACMG) guidelines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Next-generation sequencing was performed for a patient presenting with drug-induced QT prolongation who was found to carry the rare\n                      <jats:italic>KCNH2<\/jats:italic>\n                      1066C&amp;gt;T variant. Thirteen established gene discovery computational tools were employed to analyze the variant\n                      <jats:italic>in silico<\/jats:italic>\n                      . Additionally, structural modeling of the variant\u2019s region within the wild-type protein was performed utilizing AlphaFold.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The clinical phenotype associated with the\n                      <jats:italic>KCNH2<\/jats:italic>\n                      1066C&amp;gt;T variant has not been previously described in literature, except in combination with a variant in the\n                      <jats:italic>KCNQ1<\/jats:italic>\n                      gene. Computational analysis with a meta-predictor, REVEL, supported variant pathogenicity, while predictive modeling and AlphaMissense illustrated the uncertainty of structural impacts in a disordered region. Risk analysis of the variant performed utilizing ACMG guidelines and ClinGen criteria-specific recommendations resulted in an overall classification of \u201cuncertain significance\u201d.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      To our knowledge, this is the first study reporting a direct phenotype-to-genotype association between the\n                      <jats:italic>KCNH2<\/jats:italic>\n                      1066C&amp;gt;T variant and drug-induced QT prolongation, supplemented by\n                      <jats:italic>in silico<\/jats:italic>\n                      analyses and ACMG-based variant risk stratification. Our study underscores the importance of recognizing genetic predisposition in drug-induced QT prolongation and motivate further investigation of\n                      <jats:italic>KCNH2<\/jats:italic>\n                      variants within the N-linker region.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1715155","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T06:47:44Z","timestamp":1771915664000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Association of a rare single nucleotide variant in the KCNH2 gene with drug-induced QT prolongation"],"prefix":"10.3389","volume":"17","author":[{"given":"Tianci","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medicine, Sathyamoorthy Laboratory, Burnett School of Medicine at TCU","place":["Fort Worth, TX, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlene R.","family":"Norgan Radler","sequence":"additional","affiliation":[{"name":"Department of Medicine, Sathyamoorthy Laboratory, Burnett School of Medicine at TCU","place":["Fort Worth, TX, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohanakrishnan","family":"Sathyamoorthy","sequence":"additional","affiliation":[{"name":"Department of Medicine, Sathyamoorthy Laboratory, Burnett School of Medicine at TCU","place":["Fort Worth, TX, United States"]},{"name":"Consultants in Cardiovascular Medicine and Science","place":["Fort Worth, TX, United States"]},{"name":"Fort Worth Institute for Molecular Medicine and Genomics Research","place":["Fort Worth, TX, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. 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