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However, whether <jats:italic>BCOR<\/jats:italic> variants represent the genetic etiology underlying CHD needs further investigation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed whole exome sequencing on CHD nuclear families and identified a candidate gene, <jats:italic>BCOR<\/jats:italic>, by robust bioinformatic analysis and medical literature searches. Targeted DNA sequencing of the candidate gene was conducted and then the association between variants and the risk of developing CHD was analyzed. The effects of <jats:italic>BCOR<\/jats:italic> mutations on gene expression, localization, protein interaction, and signaling pathways were evaluated <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a <jats:italic>BCOR<\/jats:italic> hemizygous missense variant (c.1448C&gt;T, p.Pro483Leu) in a male proband presented with CHD\/heterotaxy. Sanger sequencing confirmed that this variant was inherited from his asymptomatic mother. Interestingly, through literature searches, we observed another novel <jats:italic>BCOR<\/jats:italic> hemizygous missense variant (c.1619G&gt;A, p.Arg540Gln) in a CHD patient with heterotaxy, supporting the pathogenic evidence of <jats:italic>BCOR<\/jats:italic> variants. Functional experiments conducted <jats:italic>in vitro<\/jats:italic> revealed that the variant p.Pro483Leu altered the subcellular localization of BCOR protein, disrupted its interaction with BCL6, and significantly promoted cell proliferation, whereas the variant p.Arg540Gln displayed no obvious effects. Nevertheless, transcriptional analysis revealed that down\u2010regulation of <jats:italic>BCOR<\/jats:italic> substantially enhanced the activities of mitogen\u2010activated protein and phosphoinositide 3\u2010kinase\u2010AKT signaling pathways, which are closely attributed to heart development. Targeted sequencing of 932 sporadic CHD patients enriched nine variants of <jats:italic>BCOR<\/jats:italic> predicted as likely rare and damaging and a septal defect was present in 81.8% (9\/11) of them, including the two probands, which was consistent with the possible phenotype caused by <jats:italic>BCOR<\/jats:italic> defects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The findings of the present study indicate that variants in <jats:italic>BCOR<\/jats:italic> may predispose individuals to CHD in the Chinese Han population.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jgm.3461","type":"journal-article","created":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T08:06:04Z","timestamp":1667203564000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["X\u2010linked <i>BCOR<\/i> variants identified in Chinese Han patients with congenital heart disease"],"prefix":"10.1002","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5776-4760","authenticated-orcid":false,"given":"Mei\u2010Jiao","family":"Suo","sequence":"first","affiliation":[{"name":"Children's Hospital of Fudan University  Shanghai China"},{"name":"Shanghai Key Laboratory of Birth Defects  Shanghai China"},{"name":"Research Unit of Early Intervention of Genetically Related Childhood Cardiovascular Diseases (2018RU002), Chinese Academy of Medical Sciences  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei\u2010Cheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Children's Hospital of Fudan University  Shanghai China"},{"name":"Shanghai Key Laboratory of Birth Defects  Shanghai China"},{"name":"Research Unit of Early Intervention of Genetically Related Childhood Cardiovascular Diseases (2018RU002), Chinese Academy of Medical Sciences  Shanghai 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