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A novel variant, T\u2010box transcription factor 5 (<jats:italic>TBX5<\/jats:italic>) c.755\u2009+\u20091\u00a0G\u2009&gt;\u2009A, was identified in the proband via whole exome sequencing and validated using Sanger sequencing. Pedigree analysis and clinical examinations revealed three\/seven individuals over three generations within the family, with features suggestive of HOS. Deep amplicon sequencing confirmed that the allele frequencies of the novel variant in the proband (III\u20101), her brother (III\u20102), and her mother (II\u20102) were 50%, 48.3%, and 38.1%, respectively, indicating that III\u20101 and III\u20102 harbored heterozygous variants, while II\u20102 harbored mosaic heterozygous variants. The minigene splicing assay showed that the novel variant affected the normal splicing of exon 7, resulting in the production of abnormal <jats:italic>TBX5<\/jats:italic> transcripts. Reverse transcription\u2010quantitative polymerase chain reaction and western blot analyses revealed that the novel variant upregulated <jats:italic>TBX5<\/jats:italic> expression at the transcriptional and translational levels. Nuclear localization assay demonstrated impaired nuclear localization of the mutant TBX5. Cell viability assay revealed the inhibition of cell activity by the mutant TBX5. Our findings indicate that the novel variant was potentially induced HOS, probably by causing aberrant splicing, reducing the enrichment of nuclear TBX5 protein, and inhibiting cellular proliferation.<\/jats:p>","DOI":"10.1002\/ajmg.a.62488","type":"journal-article","created":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T05:33:02Z","timestamp":1630992782000},"page":"58-70","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of a novel <scp><i>TBX5<\/i><\/scp> c.755\u2009+\u20091\u00a0G\u2009&gt;\u2009A variant and related pathogenesis in a family with <scp>Holt\u2013Oram<\/scp> syndrome"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0059-4518","authenticated-orcid":false,"given":"De\u2010Gang","family":"Wang","sequence":"first","affiliation":[{"name":"Research Center for Reproductive Medicine Shantou University Medical College  Shantou China"},{"name":"Prenatal Diagnosis Center Boai Hospital of Zhongshan  Zhongshan China"},{"name":"The Second School of Clinical Medicine, Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing\u2010Sheng","family":"Dong","sequence":"additional","affiliation":[{"name":"Prenatal Diagnosis Center Boai Hospital of Zhongshan  Zhongshan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Xiong","sequence":"additional","affiliation":[{"name":"Prenatal Diagnosis Center Boai Hospital of Zhongshan  Zhongshan China"},{"name":"The Second School of Clinical Medicine, Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi\u2010Ming","family":"Li","sequence":"additional","affiliation":[{"name":"Prenatal Diagnosis Center Boai Hospital of Zhongshan  Zhongshan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying\u2010Jun","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province The Third Affiliated Hospital of Guangzhou Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu\u2010Hua","family":"Liang","sequence":"additional","affiliation":[{"name":"The Second School of Clinical Medicine, Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tian\u2010Hua","family":"Huang","sequence":"additional","affiliation":[{"name":"Research Center for Reproductive Medicine Shantou University Medical College  Shantou China"},{"name":"Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,9,6]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq178"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(01)00493-7"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2646"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0050536"},{"key":"e_1_2_9_7_1","unstructured":"ClinVar database. 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