{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T09:40:30Z","timestamp":1792489230153,"version":"4.5.0"},"reference-count":101,"publisher":"Ovid Technologies (Wolters Kluwer Health)","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Variants in the ion channel gene\n                      <jats:italic toggle=\"yes\">KCNQ1<\/jats:italic>\n                      are the leading cause of congenital long QT syndrome (LQTS), a disorder characterized by QT prolongation and risk of fatal arrhythmias. The expanding use of genetic testing has led to the identification of numerous variants of uncertain significance, complicating clinical interpretation and risk stratification. Functional characterization of\n                      <jats:italic toggle=\"yes\">KCNQ1<\/jats:italic>\n                      variants is essential to define their role in long QT syndrome and advance precision medicine in cardiovascular care.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We generated a nearly comprehensive variant library of 13\u2009403 protein-coding variants in\n                      <jats:italic toggle=\"yes\">KCNQ1<\/jats:italic>\n                      . Using 4 pooled assays followed by high-throughput sequencing, we characterized the variants\u2019 effects on cell surface abundance and channel function in both the variant-only and heterozygous states. Case\u2013control analyses and data from large-scale biobanks were used to assess the clinical impact of loss-of-function variants on QT prolongation and long QT syndrome. Heterozygous assay results were used to determine dominant-negative effects, which were also evaluated for association with arrhythmia risk. Protein structural clustering of distinct classes of deleterious variants was analyzed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Across the 4 assays, we generated 49\u2009305 functional measurements of\n                      <jats:italic toggle=\"yes\">KCNQ1<\/jats:italic>\n                      variants. Of the 13\u2009403\n                      <jats:italic toggle=\"yes\">KCNQ1<\/jats:italic>\n                      studied variants, 1757 demonstrated strong pathogenic evidence, and 6660 showed moderate benign evidence. Loss-of-function variants were significantly associated with QT prolongation and long QT syndrome in case\u2013control and biobank analyses. Deleterious variants clustered within distinct structural domains based on their functional classification. A majority of pathogenic variants exhibited dominant-negative effects; these variants were linked to a higher risk of arrhythmia diagnoses than were haploinsufficient variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      This comprehensive\n                      <jats:italic toggle=\"yes\">KCNQ1<\/jats:italic>\n                      functional atlas provides novel functional evidence for most\n                      <jats:italic toggle=\"yes\">KCNQ1<\/jats:italic>\n                      variants of uncertain significance. It also reveals mechanistic principles linking genetic variation to ion channel biology and arrhythmia susceptibility, advancing cardiovascular precision medicine.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.126.080900","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T09:00:11Z","timestamp":1792486811000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Multimodal\n                    <i>KCNQ1<\/i>\n                    Variant-Effect Maps Define Ion Channel Mechanisms and Disease Risk"],"prefix":"10.1161","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4752-6081","authenticated-orcid":true,"given":"M. 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