{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:58:34Z","timestamp":1792789114521,"version":"4.5.0"},"reference-count":77,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Basic Research Project of Shanghai, China","award":["20JC1418800"],"award-info":[{"award-number":["20JC1418800"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Background\/Objectives: Congenital heart disease (CHD) occurs in ~1% of all live neonates globally, rendering it the most prevalent developmental anomaly affecting humans; this condition confers substantial infant morbidity and mortality worldwide. Although there is ample evidence to suggest a paramount genetic basis for CHD, the genetic etiologies underpinning the majority of CHD remain elusive. In the present study, SOX4 was selected as a significant candidate gene for human CHD, mainly because SOX4 is abundantly expressed in both human and murine hearts during embryogenesis, and the knockout of Sox4 in mice causes embryonic demise predominantly attributable to cardiovascular developmental defects. Methods: Sequencing analysis of SOX4 was fulfilled in 248 probands affected with various types of CHD and the available relatives of the identified variation carrier as well as 262 unrelated healthy individuals. Functional analysis of the mutant SOX4 protein was conducted by utilizing a dual-reporter gene system. Results: a novel heterozygous SOX4 variation, NM_003107.3:c.331G&gt;T;p.(Glu111*), was discovered in a male proband with Coffin\u2013Siris syndromic CHD. Genetic investigation of the proband\u2019s available relatives revealed that the truncating variation co-segregated with the phenotype in the whole family. The nonsense variation was absent from 262 healthy controls. Functional analysis demonstrated that the Glu111*-mutant SOX4 lost transactivation on NKX2.5 and GATA4, two well-established genes that are causative factors for CHD. Moreover, the Glu111* mutation nullified the synergistic transactivation between SOX4 and TBX20, another CHD-causing gene. Conclusions: These findings support SOX4 as a causative gene accountable for familial Coffin\u2013Siris syndromic CHD in humans. These findings may aid in developing personalized preventive and therapeutic strategies for patients with Coffin\u2013Siris syndromic CHD.<\/jats:p>","DOI":"10.3390\/children12050608","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T04:20:26Z","timestamp":1746591626000},"page":"608","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification and Functional Characterization of a Novel SOX4 Mutation Predisposing to Coffin\u2013Siris Syndromic Congenital Heart Disease"],"prefix":"10.3390","volume":"12","author":[{"given":"Zi","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin-Bin","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Jie","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Xi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Fifth People\u2032s Hospital, Fudan University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Jia","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Fifth People\u2032s Hospital, Fudan University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ri-Tai","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing-Yuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Qing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Fifth People\u2032s Hospital, Fudan University, Shanghai 200240, China"},{"name":"Department of Cardiovascular Research Laboratory, Shanghai Fifth People\u2019s Hospital, Fudan University, Shanghai 200240, China"},{"name":"Department of Central Laboratory, Shanghai Fifth People\u2019s Hospital, Fudan University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e347","DOI":"10.1161\/CIR.0000000000001209","article-title":"2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association","volume":"149","author":"Martin","year":"2024","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3892\/etm.2024.12379","article-title":"Somatic GATA4 mutation contributes to tetralogy of Fallot","volume":"27","author":"Abhinav","year":"2024","journal-title":"Exp. 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