{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:45:13Z","timestamp":1790693113372,"version":"4.1.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2017,10]]},"abstract":"<jats:title\/>\n          <jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>Long-QT syndrome is a potentially fatal condition for which 30% of patients are without a genetically confirmed diagnosis. Rapid identification of causal mutations is thus a priority to avoid at-risk situations that can lead to fatal cardiac events. Massively parallel sequencing technologies are useful for the identification of sequence variants; however, electrophysiological testing of newly identified variants is crucial to demonstrate causality. Long-QT syndrome could, therefore, benefit from having a standardized platform for functional characterization of candidate variants in the physiological context of human cardiomyocytes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>Using a variant in Kir2.1 (Gly52Val) revealed by whole-exome sequencing in a patient presenting with symptoms of long-QT syndrome as a proof of principle, we demonstrated that commercially available human induced pluripotent stem cell\u2013derived cardiomyocytes are a powerful model for screening variants involved in genetic cardiac diseases. Immunohistochemistry experiments and whole-cell current recordings in human embryonic kidney cells expressing the wild-type or the mutant Kir2.1 demonstrated that Kir2.1-52V alters channel cellular trafficking and fails to form a functional channel. Using human induced pluripotent stem cell\u2013derived cardiomyocytes, we not only confirmed these results but also further demonstrated that Kir2.1-52V is associated with a dramatic prolongation of action potential duration with evidence of arrhythmic activity, parameters which could not have been studied using human embryonic kidney cells.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>Our study confirms the pathogenicity of Kir2.1-52V in 1 patient with long-QT syndrome and also supports the use of isogenic human induced pluripotent stem cell\u2013derived cardiomyocytes as a physiologically relevant model for the screening of variants of unknown function.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.117.001755","type":"journal-article","created":{"date-parts":[[2017,10,12]],"date-time":"2017-10-12T00:11:02Z","timestamp":1507767062000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Characterization of a Human Induced Pluripotent Stem Cell\u2013Derived Cardiomyocyte Model for the Study of Variant Pathogenicity"],"prefix":"10.1161","volume":"10","author":[{"given":"Roselle","family":"G\u00e9linas","sequence":"first","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabil","family":"El Khoury","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-A.","family":"Chaix","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudine","family":"Beauchamp","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azadeh","family":"Alikashani","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Ethier","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Boucher","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Villeneuve","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Robb","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Latour","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blandine","family":"Mondesert","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Rivard","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Goyette","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Talajic","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Fiset","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John David","family":"Rioux","sequence":"additional","affiliation":[{"name":"From the Research Center (R.G., N.E.K., M.-A.C., C.B., A.A., N.E., G.B., L.V., L.R., F.L., B.M., L.R., P.G., M.T., C.F., J.D.R.) and Cardiovascular Genetics Center (L. Robb, L. Rivard, M.T.), Montreal Heart Institute, Quebec, Canada; and Department of Medicine (R.G., M.-A.C., B.M., L.R., M.T., J.D.R.) and Faculty of Pharmacy (N.E.K., C.F.), Universit\u00e9 de Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2005.09.056"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.10.015"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2004.07.013"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.4065\/78.12.1479"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0908679"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201210899"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2013.08.015"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0083005"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2012.00346"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.88.2.782"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2013.10.010"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-010-0820-6"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.2174\/1573403X10666140514102528"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.111.962316"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature19057"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/mus.24293"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs206"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09747"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.008409"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.243139"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09855"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfs282"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00694.2011"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.066092"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.111.973420"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00819.2012"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncpcardio1130"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.98.22.2422"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M212243200"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2001.1344"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2001.t01-1-00697.x"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI17959"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(96)00191-5"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1109370109"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2015.00007"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00481.2015"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds556"}],"container-title":["Circulation: Cardiovascular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCGENETICS.117.001755","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T01:26:12Z","timestamp":1715563572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCGENETICS.117.001755"}},"subtitle":["Validation of a\n            <i>KCNJ2<\/i>\n            Mutation"],"short-title":[],"issued":{"date-parts":[[2017,10]]},"references-count":37,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2017,10]]}},"alternative-id":["10.1161\/CIRCGENETICS.117.001755"],"URL":"https:\/\/doi.org\/10.1161\/circgenetics.117.001755","relation":{},"ISSN":["1942-325X","1942-3268"],"issn-type":[{"value":"1942-325X","type":"print"},{"value":"1942-3268","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10]]},"article-number":"e001755"}}