{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:31:02Z","timestamp":1790767862447,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T00:00:00Z","timestamp":1608681600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K08\u2010HL136839"],"award-info":[{"award-number":["K08\u2010HL136839"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UL1TR002553"],"award-info":[{"award-number":["UL1TR002553"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Long QT syndrome (LQTS) is a genetic disease resulting in a prolonged QT interval on a resting electrocardiogram, predisposing affected individuals to polymorphic ventricular tachycardia and sudden death. Although a number of genes have been implicated in this disease, nearly one in four individuals exhibiting the LQTS phenotype are genotype\u2010negative. Whole\u2010exome sequencing identified a missense T223M variant in <jats:italic>TBX5<\/jats:italic> that cosegregates with prolonged QT interval in a family with otherwise genotype\u2010negative LQTS and sudden death. The TBX5\u2010T223M variant was absent among large ostensibly healthy populations (gnomAD) and predicted to be pathogenic by <jats:italic>in silico<\/jats:italic> modeling based on Panther, PolyPhen\u20102, Provean, SIFT, SNAP2, and PredictSNP prediction tools. The variant was located in a highly conserved region of TBX5 predicted to be part of the DNA\u2010binding interface. A luciferase assay identified a 57.5% reduction in the ability of TBX5\u2010T223M to drive expression at the atrial natriuretic factor promotor compared to wildtype TBX5 <jats:italic>in vitro<\/jats:italic>. We conclude that the variant is pathogenic in this family, and we put <jats:italic>TBX5<\/jats:italic> forward as a disease susceptibility allele for genotype\u2010negative LQTS. The identification of this familial variant may serve as a basis for the identification of previously unknown mechanisms of LQTS with broader implications for cardiac electrophysiology.<\/jats:p>","DOI":"10.1002\/ajmg.a.62037","type":"journal-article","created":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T16:08:07Z","timestamp":1608826087000},"page":"923-929","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp><i>TBX5<\/i><\/scp>\u2010encoded T\u2010box transcription factor 5 variant <scp>T223M<\/scp> is associated with long <scp>QT<\/scp> syndrome and pediatric sudden cardiac death"],"prefix":"10.1002","volume":"185","author":[{"given":"Alexandra M.","family":"Markunas","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Cardiology Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perathu K. R.","family":"Manivannan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Cardiology Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan E.","family":"Ezekian","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Cardiology Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnim","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Department of Biology Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Eisner","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Cardiology Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherina","family":"Alsina","sequence":"additional","affiliation":[{"name":"Departments of Molecular Physiology &amp; Biophysics and Medicine (Cardiology) Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugh D.","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Section of Cardiology, Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory A.","family":"Wray","sequence":"additional","affiliation":[{"name":"Department of Biology Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey J.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Section of Cardiology, Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xander H. T.","family":"Wehrens","sequence":"additional","affiliation":[{"name":"Departments of Molecular Physiology &amp; Biophysics and Medicine (Cardiology) Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Landstrom","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Cardiology Duke University School of Medicine  Durham North Carolina USA"},{"name":"Department of Cell Biology Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,12,23]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2011.05.020"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.043132"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI62617"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199403313301302"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.6.2919"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003440"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1086\/376436"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00493-7"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv195"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M208120200"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.repc.2017.11.007"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2018.03.003"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21066"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9375"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40064-016-3275-1"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-5-59"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI124231"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0197-21"},{"issue":"1","key":"e_1_2_6_21_1","first-page":"67","article-title":"Holt\u2010Oram syndrome","volume":"48","author":"Lichiardopol C.","year":"2007","journal-title":"Romanian Journal of Morphology and Embryology"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9082"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000182593.95441.64"},{"key":"e_1_2_6_24_1","volume-title":"GeneReviews","author":"McDermott D. A.","year":"1993"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1038"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2015.74"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61635"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.863209"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks539"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcad.2019.05.006"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.14740\/cr767w"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ctdb.2016.08.008"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.14797\/mdcj-10-1-29"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI62613"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-018-0303-3"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2018.00137"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2016.01.009"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024242"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12872-019-1237-6"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2015.126"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0801779105"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.62037","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.62037","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.62037","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,2]],"date-time":"2023-09-02T07:39:36Z","timestamp":1693640376000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.62037"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,23]]},"references-count":40,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,3]]}},"alternative-id":["10.1002\/ajmg.a.62037"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.62037","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,23]]},"assertion":[{"value":"2020-08-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-01","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}