{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T02:06:32Z","timestamp":1775613992660,"version":"3.50.1"},"reference-count":47,"publisher":"Elsevier BV","issue":"12","license":[{"start":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T00:00:00Z","timestamp":1733011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T00:00:00Z","timestamp":1733011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"vor","delay-in-days":365,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["U01 HG011744"],"award-info":[{"award-number":["U01 HG011744"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["UM1 HG006493"],"award-info":[{"award-number":["UM1 HG006493"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["U24 HG011746"],"award-info":[{"award-number":["U24 HG011746"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015613","name":"Centre hospitalier r\u00e9gional universitaire de Lille","doi-asserted-by":"publisher","award":["DEC19-366"],"award-info":[{"award-number":["DEC19-366"]}],"id":[{"id":"10.13039\/501100015613","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["U614"],"award-info":[{"award-number":["U614"]}],"id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["gimjournal.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Genetics in Medicine"],"published-print":{"date-parts":[[2024,12]]},"DOI":"10.1016\/j.gim.2024.101267","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T12:51:42Z","timestamp":1725972702000},"page":"101267","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":2,"title":["Functional characterization vs in silico prediction for TBX5 missense and splice variants in Holt-Oram syndrome"],"prefix":"10.1016","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3884-2054","authenticated-orcid":false,"given":"Cl\u00e9mence","family":"Vanlerberghe","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne Sophie","family":"Jourdain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Frenois","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilie","family":"Ait-Yahya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mike","family":"Bamshad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Dieux","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Dufour","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fiona","family":"Leduc","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvie","family":"Manouvrier-Hanu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karynne","family":"Patterson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamal","family":"Ghoumid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabienne","family":"Escande","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Smol","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Perrine","family":"Brunelle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florence","family":"Petit","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"issue":"2","key":"10.1016\/j.gim.2024.101267_bib1","first-page":"73","article-title":"[Holt-Oram syndrome]","volume":"132","author":"Elek","year":"1991","journal-title":"Orv Hetil"},{"issue":"5","key":"10.1016\/j.gim.2024.101267_bib2","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1203\/01.PDR.0000182593.95441.64","article-title":"TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome","volume":"58","author":"McDermott","year":"2005","journal-title":"Pediatr Res"},{"issue":"1","key":"10.1016\/j.gim.2024.101267_bib3","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/ng0197-30","article-title":"Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome","volume":"15","author":"Basson","year":"1997","journal-title":"Nat Genet"},{"key":"10.1016\/j.gim.2024.101267_bib4","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1146\/annurev.genet.39.073003.105925","article-title":"T-box genes in vertebrate development","volume":"39","author":"Naiche","year":"2005","journal-title":"Annu Rev Genet"},{"issue":"11","key":"10.1016\/j.gim.2024.101267_bib5","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1242\/dev.124.11.2235","article-title":"The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor","volume":"124","author":"Ohuchi","year":"1997","journal-title":"Development"},{"issue":"3","key":"10.1016\/j.gim.2024.101267_bib6","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/90123","article-title":"Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation","volume":"28","author":"Hiroi","year":"2001","journal-title":"Nat Genet"},{"issue":"3","key":"10.1016\/j.gim.2024.101267_bib7","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.cardiores.2004.09.021","article-title":"Transcriptional regulation of the murine connexin40 promoter by cardiac factors Nkx2-5, GATA4 and Tbx5","volume":"64","author":"Linhares","year":"2004","journal-title":"Cardiovasc Res"},{"issue":"1","key":"10.1016\/j.gim.2024.101267_bib8","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1086\/376436","article-title":"Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype","volume":"73","author":"Brassington","year":"2003","journal-title":"Am J Hum Genet"},{"issue":"3","key":"10.1016\/j.gim.2024.101267_bib9","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1136\/hrt.2004.036855","article-title":"Identification of new mutations in the TBX5 gene in patients with Holt-Oram syndrome","volume":"91","author":"Heinritz","year":"2005","journal-title":"Heart"},{"issue":"9","key":"10.1016\/j.gim.2024.101267_bib10","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1002\/humu.9449","article-title":"Expanding the spectrum of TBX5 mutations in Holt-Oram syndrome: detection of two intragenic deletions by quantitative real time PCR, and report of eight novel point mutations","volume":"27","author":"Borozdin","year":"2006","journal-title":"Hum Mutat"},{"issue":"3","key":"10.1016\/j.gim.2024.101267_bib11","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/s41431-018-0303-3","article-title":"Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants","volume":"27","author":"Vanlerberghe","year":"2019","journal-title":"Eur J Hum Genet"},{"key":"10.1016\/j.gim.2024.101267_bib12","author":"Barnett"},{"issue":"10","key":"10.1016\/j.gim.2024.101267_bib13","doi-asserted-by":"crossref","first-page":"8780","DOI":"10.1074\/jbc.M208120200","article-title":"Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome","volume":"278","author":"Fan","year":"2003","journal-title":"J\u00a0Biol Chem"},{"issue":"1","key":"10.1016\/j.gim.2024.101267_bib14","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1093\/cvr\/cvq178","article-title":"Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome","volume":"88","author":"Boogerd","year":"2010","journal-title":"Cardiovasc Res"},{"issue":"1","key":"10.1016\/j.gim.2024.101267_bib15","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jmb.2010.04.052","article-title":"Structural basis of TBX5-DNA recognition: the T-box domain in its DNA-bound and -unbound form","volume":"400","author":"Stirnimann","year":"2010","journal-title":"J\u00a0Mol Biol"},{"issue":"6664","key":"10.1016\/j.gim.2024.101267_bib16","doi-asserted-by":"crossref","DOI":"10.1126\/science.adg7492","article-title":"Accurate proteome-wide missense variant effect prediction with AlphaMissense","volume":"381","author":"Cheng","year":"2023","journal-title":"Science"},{"issue":"5","key":"10.1016\/j.gim.2024.101267_bib17","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"issue":"4","key":"10.1016\/j.gim.2024.101267_bib18","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/j.gim.2021.11.018","article-title":"Evaluating the impact of in silico predictors on clinical variant classification","volume":"24","author":"Wilcox","year":"2022","journal-title":"Genet Med"},{"issue":"1","key":"10.1016\/j.gim.2024.101267_bib19","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1093\/nar\/26.1.285","article-title":"The human gene mutation database","volume":"26","author":"Cooper","year":"1998","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"10.1016\/j.gim.2024.101267_bib20","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.hrcr.2017.12.002","article-title":"Holt-Oram syndrome in two families diagnosed with left ventricular noncompaction and conduction disease","volume":"4","author":"Ross","year":"2018","journal-title":"HeartRhythm Case Rep"},{"key":"10.1016\/j.gim.2024.101267_bib21","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1097\/BLO.0b013e3181123ffe","article-title":"Novel TBX5 mutations in patients with Holt-Oram syndrome","volume":"462","author":"Debeer","year":"2007","journal-title":"Clin Orthop Relat Res"},{"issue":"1","key":"10.1016\/j.gim.2024.101267_bib22","doi-asserted-by":"crossref","first-page":"55","DOI":"10.5152\/jtgga.2015.15233","article-title":"A\u00a0novel mutated sequence in the T-box transcription factor-5 (TBX-5) gene (c.241A>T) in Holt-Oram syndrome","volume":"17","author":"Ersoy","year":"2016","journal-title":"J\u00a0Turk Ger Gynecol Assoc"},{"issue":"11","key":"10.1016\/j.gim.2024.101267_bib23","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1136\/jmg.2009.066027","article-title":"Genetic screening of 202 individuals with congenital limb malformations and requiring reconstructive surgery","volume":"46","author":"Furniss","year":"2009","journal-title":"J\u00a0Med Genet"},{"issue":"2","key":"10.1016\/j.gim.2024.101267_bib24","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1590\/S1415-47572010005000051","article-title":"Novel mutations in the TBX5 gene in patients with Holt-Oram syndrome","volume":"33","author":"Porto","year":"2010","journal-title":"Genet Mol Biol"},{"issue":"8","key":"10.1016\/j.gim.2024.101267_bib25","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1134\/S1022795421070061","article-title":"New missense mutation Gly238Ala in the TBX5 gene and its phenotypical characteristics","volume":"57","author":"Chakova","year":"2021","journal-title":"Russ J Genet"},{"issue":"2","key":"10.1016\/j.gim.2024.101267_bib26","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s41431-020-00755-z","article-title":"MobiDetails: online DNA variants interpretation","volume":"29","author":"Baux","year":"2021","journal-title":"Eur J Hum Genet"},{"issue":"7873","key":"10.1016\/j.gim.2024.101267_bib27","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/s41586-021-03828-1","article-title":"Highly accurate protein structure prediction for the human proteome","volume":"596","author":"Tunyasuvunakool","year":"2021","journal-title":"Nature"},{"issue":"3","key":"10.1016\/j.gim.2024.101267_bib28","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting splicing from primary sequence with deep learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"issue":"18","key":"10.1016\/j.gim.2024.101267_bib29","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1093\/hmg\/10.18.1983","article-title":"Characterization of the TBX5 binding site and analysis of mutations that cause Holt-Oram syndrome","volume":"10","author":"Ghosh","year":"2001","journal-title":"Hum Mol Genet"},{"key":"10.1016\/j.gim.2024.101267_bib30","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/978-1-60761-759-4_15","article-title":"Use of splicing reporter minigene assay to evaluate the effect on splicing of unclassified genetic variants","volume":"653","author":"Gaildrat","year":"2010","journal-title":"Methods Mol Biol"},{"issue":"1","key":"10.1016\/j.gim.2024.101267_bib31","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13073-019-0690-2","article-title":"Recommendations for application of the functional evidence PS3\/BS3 criterion using the ACMG\/AMP sequence variant interpretation framework","volume":"12","author":"Brnich","year":"2019","journal-title":"Genome Med"},{"issue":"7","key":"10.1016\/j.gim.2024.101267_bib47","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.ajhg.2023.06.002","article-title":"Using the ACMG\/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup","volume":"110","author":"Walker","year":"2023","journal-title":"Am J Hum Genet"},{"issue":"5","key":"10.1016\/j.gim.2024.101267_bib32","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1002\/mgg3.234","article-title":"A\u00a0novel de novo TBX5 mutation in a patient with Holt-Oram syndrome leading to a dramatically reduced biological function","volume":"4","author":"Dre\u00dfen","year":"2016","journal-title":"Mol Genet Genomic Med"},{"issue":"10","key":"10.1016\/j.gim.2024.101267_bib33","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1136\/jmg.37.10.785","article-title":"The mutation spectrum in Holt-Oram syndrome","volume":"37","author":"Cross","year":"2000","journal-title":"J\u00a0Med Genet"},{"issue":"38","key":"10.1016\/j.gim.2024.101267_bib34","doi-asserted-by":"crossref","first-page":"25653","DOI":"10.1074\/jbc.M109.041368","article-title":"Functional role of transcriptional factor TBX5 in pre-mRNA splicing and Holt-Oram syndrome via association with SC35","volume":"284","author":"Fan","year":"2009","journal-title":"J\u00a0Biol Chem"},{"issue":"11","key":"10.1016\/j.gim.2024.101267_bib35","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1161\/CIRCRESAHA.107.168294","article-title":"A\u00a0gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome\u00a0and paroxysmal atrial fibrillation","volume":"102","author":"Postma","year":"2008","journal-title":"Circ Res"},{"key":"10.1016\/j.gim.2024.101267_bib36","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmg.2024.104920","article-title":"TBX5 variants and cardiac phenotype: a systematic review of the literature and a novel variant","volume":"68","author":"M\u00f8ller Nielsen","year":"2024","journal-title":"Eur J Med Genet"},{"issue":"3","key":"10.1016\/j.gim.2024.101267_bib37","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.devcel.2016.01.009","article-title":"The cardiac TBX5 interactome reveals a chromatin remodeling network essential for cardiac septation","volume":"36","author":"Waldron","year":"2016","journal-title":"Dev Cell"},{"issue":"14","key":"10.1016\/j.gim.2024.101267_bib38","doi-asserted-by":"crossref","first-page":"3801","DOI":"10.1093\/hmg\/ddu093","article-title":"Histone deacetylase 3 modulates Tbx5 activity to regulate early cardiogenesis","volume":"23","author":"Lewandowski","year":"2014","journal-title":"Hum Mol Genet"},{"issue":"1","key":"10.1016\/j.gim.2024.101267_bib39","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.ydbio.2006.09.023","article-title":"Differential regulation of Tbx5 protein expression and sub-cellular localization during heart development","volume":"302","author":"Bimber","year":"2007","journal-title":"Dev Biol"},{"issue":"3","key":"10.1016\/j.gim.2024.101267_bib40","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1083\/jcb.200511109","article-title":"LMP4 regulates Tbx5 protein subcellular localization and activity","volume":"174","author":"Camarata","year":"2006","journal-title":"J\u00a0Cell Biol"},{"key":"10.1016\/j.gim.2024.101267_bib41","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/1471-213X-10-104","article-title":"Pdlim7 is required for maintenance of the mesenchymal\/epidermal Fgf signaling feedback loop during zebrafish pectoral fin development","volume":"10","author":"Camarata","year":"2010","journal-title":"BMC Dev Biol"},{"issue":"1","key":"10.1016\/j.gim.2024.101267_bib42","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1005756","article-title":"Exonic splicing mutations are more prevalent than currently estimated and can be predicted by using in silico tools","volume":"12","author":"Soukarieh","year":"2016","journal-title":"PLoS Genet"},{"issue":"8","key":"10.1016\/j.gim.2024.101267_bib43","doi-asserted-by":"crossref","DOI":"10.15252\/msb.202211474","article-title":"Updated benchmarking of variant effect predictors using deep mutational scanning","volume":"19","author":"Livesey","year":"2023","journal-title":"Mol Syst Biol"},{"issue":"1","key":"10.1016\/j.gim.2024.101267_bib44","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/s13059-023-02986-x","article-title":"An Atlas of Variant Effects to understand the genome at nucleotide resolution","volume":"24","author":"Fowler","year":"2023","journal-title":"Genome Biol"},{"issue":"7","key":"10.1016\/j.gim.2024.101267_bib45","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1038\/s44320-024-00043-8","article-title":"Deep Mutational Scanning Quantifies DNA Binding and Predicts Clinical Outcomes of PAX6 Variants","volume":"20","author":"McDonnell","year":"2024","journal-title":"Mol Syst Biol"},{"issue":"11","key":"10.1016\/j.gim.2024.101267_bib46","doi-asserted-by":"crossref","first-page":"2208","DOI":"10.1038\/s41436-021-01254-2","article-title":"Disease-specific ACMG\/AMP guidelines improve sequence variant interpretation for hearing loss","volume":"23","author":"Patel","year":"2021","journal-title":"Genet Med"}],"container-title":["Genetics in Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1098360024002016?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1098360024002016?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T02:15:30Z","timestamp":1764555330000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1098360024002016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12]]},"references-count":47,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["S1098360024002016"],"URL":"https:\/\/doi.org\/10.1016\/j.gim.2024.101267","relation":{},"ISSN":["1098-3600"],"issn-type":[{"value":"1098-3600","type":"print"}],"subject":[],"published":{"date-parts":[[2024,12]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Functional characterization vs in silico prediction for TBX5 missense and splice variants in Holt-Oram syndrome","name":"articletitle","label":"Article Title"},{"value":"Genetics in Medicine","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.gim.2024.101267","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc.","name":"copyright","label":"Copyright"}],"article-number":"101267"}}