{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T19:46:15Z","timestamp":1777837575887,"version":"3.51.4"},"reference-count":23,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Long-QT syndrome (LQTS) is characterized by QT prolongation and increased risk for syncope, seizures, and sudden cardiac death. The majority of LQTS stems from pathogenic mutations in\n              <jats:italic>KCNQ1<\/jats:italic>\n              ,\n              <jats:italic>KCNH2<\/jats:italic>\n              , or\n              <jats:italic>SCN5A<\/jats:italic>\n              . However, \u224810% of patients with LQTS remain genetically elusive. We utilized genome sequencing to identify a novel LQTS genetic substrate in a multigenerational genotype-negative LQTS pedigree.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Genome sequencing was performed on 5 affected family members. Only rare nonsynonymous variants present in all affected family members were considered. The candidate variant was characterized functionally in patient-derived induced pluripotent stem cell and gene-edited, variant corrected, isogenic control induced pluripotent stem cell\u2013derived cardiomyocytes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              A missense variant (p.G6S) was identified in\n              <jats:italic>ALG10B<\/jats:italic>\n              -encoded \u03b1-1,2-glucosyltransferase B protein. ALG10B (alpha-1,2-glucosyltransferase B protein) is a known interacting protein of\n              <jats:italic>KCNH2<\/jats:italic>\n              -encoded K\n              <jats:sub>v<\/jats:sub>\n              11.1 (HERG [human Ether-\u00e0-go-go\u2013related gene]). Compared with isogenic control, ALG10B-p.G6S induced pluripotent stem cell\u2013derived cardiomyocytes showed (1) decreased protein expression of ALG10B (p.G6S, 0.7\u00b10.18, n=8 versus control, 1.25\u00b10.16, n=9;\n              <jats:italic>P<\/jats:italic>\n              &lt;0.05), (2) significant retention of HERG in the endoplasmic reticulum (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.0005), and (3) a significantly prolonged action potential duration confirmed by both patch clamp (p.G6S, 531.1\u00b138.3 ms, n=15 versus control, 324.1\u00b121.8 ms, n=13;\n              <jats:italic>P<\/jats:italic>\n              &lt;0.001) and multielectrode assay (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.0001). Lumacaftor\u2014a compound known to rescue HERG trafficking\u2014shortened the pathologically prolonged action potential duration of ALG10B-p.G6S induced pluripotent stem cell\u2013derived cardiomyocytes by 10.6% (n=31 electrodes;\n              <jats:italic>P<\/jats:italic>\n              &lt;0.001).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Here, we demonstrate that ALG10B-p.G6S downregulates ALG10B, resulting in defective HERG trafficking and action potential duration prolongation. Therefore,\n              <jats:italic>ALG10B<\/jats:italic>\n              is a novel LQTS-susceptibility gene underlying the LQTS phenotype observed in a multigenerational pedigree. ALG10B mutation analysis may be warranted, especially in genotype-negative patients with an LQT2-like phenotype.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.122.003726","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T10:00:14Z","timestamp":1677060014000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Elucidation of\n            <i>ALG10B<\/i>\n            as a Novel Long-QT Syndrome\u2013Susceptibility Gene"],"prefix":"10.1161","volume":"16","author":[{"given":"Wei","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Division of Heart Rhythm Services (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."},{"name":"Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."},{"name":"Department of Molecular Pharmacology and Experimental Therapeutics (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0619-7070","authenticated-orcid":true,"given":"Dan","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Division of Heart Rhythm Services (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."},{"name":"Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."},{"name":"Department of Molecular Pharmacology and Experimental Therapeutics (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4554-2244","authenticated-orcid":true,"given":"David J.","family":"Tester","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Division of Heart Rhythm Services (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."},{"name":"Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."},{"name":"Department of Molecular Pharmacology and Experimental Therapeutics (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1357-7656","authenticated-orcid":true,"given":"Sahej","family":"Bains","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Division of Heart Rhythm Services (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."},{"name":"Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."},{"name":"Department of Molecular Pharmacology and Experimental Therapeutics (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5871-0265","authenticated-orcid":true,"given":"John R.","family":"Giudicessi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Division of Heart Rhythm Services (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."},{"name":"Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."},{"name":"Department of Molecular Pharmacology and Experimental Therapeutics (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."},{"name":"Department of Cardiovascular Medicine, Clinician-Investigator Training Program, Mayo Clinic, Rochester, MN (J.R.G.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5082-226X","authenticated-orcid":true,"given":"Carla M.","family":"Haglund-Turnquist","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Division of Heart Rhythm Services (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."},{"name":"Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."},{"name":"Department of Molecular Pharmacology and Experimental Therapeutics (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4510-448X","authenticated-orcid":true,"given":"Kate M.","family":"Orland","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Cellular and Molecular Arrhythmia Research Program and Inherited Arrhythmia Clinic, University of Wisconsin-Madison (K.M.O., C.T.J., L.L.E.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig T.","family":"January","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Cellular and Molecular Arrhythmia Research Program and Inherited Arrhythmia Clinic, University of Wisconsin-Madison (K.M.O., C.T.J., L.L.E.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5792-064X","authenticated-orcid":true,"given":"Lee L.","family":"Eckhardt","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Cellular and Molecular Arrhythmia Research Program and Inherited Arrhythmia Clinic, University of Wisconsin-Madison (K.M.O., C.T.J., L.L.E.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen R.","family":"Maginot","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Cellular and Molecular Arrhythmia Research Program and Inherited Arrhythmia Clinic, University of Wisconsin-Madison (K.M.O., C.T.J., L.L.E.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8011-3333","authenticated-orcid":true,"given":"Michael J.","family":"Ackerman","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Division of Heart Rhythm Services (W.Z., D.Y., D.J.T., S.B., J.R.G., C.M.H.-T., M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN."},{"name":"Department of 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