{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T08:23:00Z","timestamp":1793780580248,"version":"4.6.1"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2017,1]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Long QT syndrome confers susceptibility to ventricular arrhythmia, predisposing to syncope, seizures, and sudden death. While rare globally, long QT syndrome is \u224815\u00d7 more common in First Nations of Northern British Columbia largely because of a known mutation in\n              <jats:italic>KCNQ1<\/jats:italic>\n              . However, 2 large multigenerational families were affected, but negative for the known mutation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Long QT syndrome panel testing was carried out in the index case of each family, and clinical information was collected. Cascade genotyping was performed. Biochemical and myocyte-based assays were performed to evaluate the identified gene variant for loss-of-function activity. Index cases in these 2 families harbored a novel\n              <jats:italic>ANK2<\/jats:italic>\n              c.1937C&gt;T variant (p.S646F). An additional 16 carriers were identified, including 2 with structural heart disease: one with cardiomyopathy resulting in sudden death and the other with congenital heart disease. For all carriers of this variant, the average QTc was 475 ms (\u00b140). Although ankyrin-B p.S646F is appropriately folded and expressed in bacteria, the mutant polypeptide displays reduced expression in cultured H9c2 cells and aberrant localization in primary cardiomyocytes. Furthermore, myocytes expressing ankyrin-B p.S646F lack normal membrane targeting of the ankyrin-binding partner, the Na\/Ca exchanger. Thus, ankyrin-B p.S646F is a loss-of-function variant.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              We identify the first disease-causing\n              <jats:italic>ANK2<\/jats:italic>\n              variant localized to the membrane-binding domain resulting in reduced ankyrin-B expression and abnormal localization. Further study is warranted on the potential association of this variant with structural heart disease given the role of\n              <jats:italic>ANK2<\/jats:italic>\n              in targeting and stabilization of key structural and signaling molecules in cardiac cells.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.116.001537","type":"journal-article","created":{"date-parts":[[2017,2,15]],"date-time":"2017-02-15T02:00:24Z","timestamp":1487124024000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":43,"title":["Novel Variant in the\n            <i>ANK2<\/i>\n            Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome"],"prefix":"10.1161","volume":"10","author":[{"given":"Leigh Anne","family":"Swayne","sequence":"first","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel P.","family":"Murphy","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sirisha","family":"Asuri","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Chen","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxue","family":"Xu","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"McIntosh","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Lancione","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason D.","family":"Roberts","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Kerr","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubhayan","family":"Sanatani","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Sherwin","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal F.","family":"Kline","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Mohler","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura T.","family":"Arbour","sequence":"additional","affiliation":[{"name":"From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children\u2019s Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine,..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2008.05.008"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpcardiol.2013.08.001"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.07.038"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.88.2.782"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2008.02.068"},{"key":"e_1_3_4_7_2","volume-title":"GeneReviews\u00ae","author":"Alders M","year":"2003","unstructured":"Alders M, Christiaans I. 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