{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,14]],"date-time":"2026-11-14T06:43:19Z","timestamp":1794638599761,"version":"4.9.1"},"reference-count":44,"publisher":"BMJ","issue":"10","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370350"],"award-info":[{"award-number":["82370350"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Special Fund for High Quality Development Project","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"Tianjin Key Medical Discipline Construction Project","award":["TJYXZDXK-3-036C"],"award-info":[{"award-number":["TJYXZDXK-3-036C"]}]},{"name":"TEDA International Cardiovascular Hospital","award":["2021-ZX-002"],"award-info":[{"award-number":["2021-ZX-002"]}],"id":[{"id":"https:\/\/ror.org\/0247xav12","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2026,5,31]]},"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Tetralogy of Fallot (TOF) is the most common cyanotic form of congenital heart disease (CHD). The myocyte enhancer factor 2C\n                      <jats:italic>(MEF2C<\/jats:italic>\n                      ) transcription factor is a crucial regulator of cardiac development, and variants in the coding region of this gene are a known cause of CHD. However, a significant gap exists in understanding the role of non-coding regulatory variants, specifically those within the\n                      <jats:italic>MEF2C<\/jats:italic>\n                      promoter. This study seeks to fill this gap by investigating whether such promoter variants contribute to TOF pathogenesis and providing functional evidence for their impact.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Targeted sequencing of the\n                      <jats:italic>MEF2C<\/jats:italic>\n                      promoter was performed in 305 TOF patients and 306 controls. Identified rare variants were functionally characterised using dual-luciferase reporter assays in AC16 cardiomyocytes. Bioinformatic predictions and electrophoretic mobility shift assays (EMSA) were applied to assess the impact on transcription factor binding.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Five variants (g.24599 G&gt;A, g.24918 T&gt;G, g.25270 T&gt;A (rs904793941), g.25701 C&gt;A and g.25769 T&gt;C (rs886060871)) were identified exclusively in TOF patients. Four of the five variants significantly reduced transcriptional activity at a conservative threshold of p&lt;0.01, with reductions ranging from 56.5% to 87.8% of wild-type. Bioinformatic analysis and EMSA confirmed that these variants alter key transcription factor binding sites (eg, for ETS1, GATA3, NFATC2) and disrupt DNA-protein interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study provides the first functional evidence that\n                      <jats:italic>MEF2C<\/jats:italic>\n                      promoter variants are associated with TOF and affect transcriptional regulation, offering new insights into the potential genetic mechanisms of TOF.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2026-111657","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T17:20:25Z","timestamp":1782753625000},"page":"620-629","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Functional characterisation and pathological significance of variants of\n                    <i>MEF2C<\/i>\n                    promoter in tetralogy of Fallot"],"prefix":"10.1136","volume":"63","author":[{"given":"Shao-Jie","family":"Wang","sequence":"first","affiliation":[{"name":"Chengde Medical University, Chengde, China & Department of Cardiovascular Surgery & The Center for Basic Medical Research, TEDA International Cardiovascular Hospital, Tianjin University, Tianjin, China"},{"name":"Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin, China"},{"name":"The Institute of Cardiovascular Diseases, Tianjin University, Tianjin, Tianjin, China"},{"name":"TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Tianjin, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Fei","family":"Zheng","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin, China"},{"name":"The Institute of Cardiovascular Diseases, Tianjin University, Tianjin, Tianjin, China"},{"name":"TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Tianjin, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan-Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin, China"},{"name":"The Institute of Cardiovascular Diseases, Tianjin University, Tianjin, Tianjin, China"},{"name":"TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Tianjin, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Yang","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin, China"},{"name":"The Institute of Cardiovascular Diseases, Tianjin University, Tianjin, Tianjin, China"},{"name":"TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Tianjin, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6497-876X","authenticated-orcid":false,"given":"Guo-Wei","family":"He","sequence":"additional","affiliation":[{"name":"Chengde Medical University, Chengde, China & Department of Cardiovascular Surgery & The Center for Basic Medical Research, TEDA International Cardiovascular Hospital, Tianjin University, Tianjin, China"},{"name":"Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin, China"},{"name":"The Institute of Cardiovascular Diseases, Tianjin University, Tianjin, Tianjin, China"},{"name":"TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Tianjin, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"2026092903151194000_63.10.620.1","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1016\/j.jacc.2025.08.015","article-title":"Global, Regional, and National Burden of Cardiovascular Diseases and Risk Factors in 204 Countries and Territories, 1990-2023","volume":"86","author":"Stark","year":"2025","journal-title":"JACC"},{"key":"2026092903151194000_63.10.620.2","doi-asserted-by":"publisher","DOI":"10.1161\/cir.0000000000001303"},{"key":"2026092903151194000_63.10.620.3","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S2352-4642(19)30402-X","article-title":"Global, regional, and national burden of congenital heart disease, 1990\u20132017: a systematic analysis for the Global Burden of Disease Study 2017","volume":"4","author":"Zimmerman","year":"2020","journal-title":"The Lancet Child & Adolescent Health"},{"key":"2026092903151194000_63.10.620.4","doi-asserted-by":"publisher","DOI":"10.1002\/BDR2.1589"},{"key":"2026092903151194000_63.10.620.5","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1172-4-2","article-title":"Tetralogy of Fallot","volume":"4","author":"Bailliard","year":"2009","journal-title":"Orphanet J Rare Dis"},{"key":"2026092903151194000_63.10.620.6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200002033420507"},{"key":"2026092903151194000_63.10.620.7","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1161\/JAHA.117.007907","article-title":"Adult Congenital Heart Disease in a Nationwide Population 2000-2014: Epidemiological Trends, Arrhythmia, and Standardized Mortality Ratio","volume":"7","author":"Wu","year":"2018","journal-title":"J Am Heart Assoc"},{"key":"2026092903151194000_63.10.620.8","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.009454"},{"key":"2026092903151194000_63.10.620.9","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.183056"},{"key":"2026092903151194000_63.10.620.10","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90139-6"},{"key":"2026092903151194000_63.10.620.11","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6223"},{"key":"2026092903151194000_63.10.620.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2007.01.001"},{"key":"2026092903151194000_63.10.620.13","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.21353"},{"key":"2026092903151194000_63.10.620.14","doi-asserted-by":"publisher","DOI":"10.1007\/s00246-018-1822-y"},{"key":"2026092903151194000_63.10.620.15","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1002\/ajmg.a.62871","article-title":"Functional significance of novel variants of the MEF2C gene promoter in congenital ventricular septal defects","volume":"188","author":"Zeng","year":"2022","journal-title":"Am J Med Genet A"},{"key":"2026092903151194000_63.10.620.16","doi-asserted-by":"publisher","DOI":"10.1126\/science.276.5317.1404"},{"key":"2026092903151194000_63.10.620.17","doi-asserted-by":"crossref","unstructured":"Zheng Z-F , Chen H-X , Qi J-L , et al . Identification and pathological significance of variants in the promoter region of ACTC1 gene in congenital ventricular septal defect. Gene 2025;967. doi:10.1016\/j.gene.2025.149733","DOI":"10.1016\/j.gene.2025.149733"},{"key":"2026092903151194000_63.10.620.18","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1038\/s41390-024-03707-1","article-title":"Identification and functional validation of variants in the promoter region of HAND1 gene in sporadic tetralogy of Fallot","volume":"97","author":"Qi","year":"2025","journal-title":"Pediatr Res"},{"key":"2026092903151194000_63.10.620.19","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1007\/s11010-024-05088-9","article-title":"Molecular and cellular role of variants of the promoter region of HAND1 gene in sporadic and isolated ventricular septal defect","volume":"480","author":"Qi","year":"2025","journal-title":"Mol Cell Biochem"},{"key":"2026092903151194000_63.10.620.20","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/s41390-023-02955-x","article-title":"Tetralogy of Fallot: variants of MYH6 gene promoter and cellular functional analyses","volume":"96","author":"Zuo","year":"2024","journal-title":"Pediatr Res"},{"key":"2026092903151194000_63.10.620.21","doi-asserted-by":"crossref","first-page":"16204","DOI":"10.3390\/ijms242216204","article-title":"Identification and Functional Verification of CITED2 Gene Promoter Region in Patients with Patent Ductus Arteriosus","volume":"24","author":"Chen","year":"2023","journal-title":"IJMS"},{"key":"2026092903151194000_63.10.620.22","doi-asserted-by":"crossref","DOI":"10.3390\/biom13020358","article-title":"Genetic Variants of ISL1 Gene Promoter Identified from Congenital Tetralogy of Fallot Patients Alter Cellular Function Forming Disease Basis","volume":"13","author":"Yin","year":"2023","journal-title":"Biomolecules"},{"key":"2026092903151194000_63.10.620.23","doi-asserted-by":"crossref","DOI":"10.1002\/jgm.3450","article-title":"Identification and functional analysis of genetic variants of ISL1 gene promoter in human atrial septal defects","volume":"24","author":"Yin","year":"2022","journal-title":"J Gene Med"},{"key":"2026092903151194000_63.10.620.24","doi-asserted-by":"crossref","DOI":"10.3390\/biom12111644","article-title":"Pathophysiological Role of Variants of the Promoter Region of CITED2 Gene in Sporadic Tetralogy of Fallot Patients with Cellular Function Verification","volume":"12","author":"Chen","year":"2022","journal-title":"Biomolecules"},{"key":"2026092903151194000_63.10.620.25","doi-asserted-by":"crossref","DOI":"10.1186\/s12920-022-01365-y","article-title":"Identification and functional analysis of variants of MYH6 gene promoter in isolated ventricular septal defects","volume":"15","author":"Zuo","year":"2022","journal-title":"BMC Med Genomics"},{"key":"2026092903151194000_63.10.620.26","doi-asserted-by":"crossref","first-page":"C443","DOI":"10.1152\/ajpcell.00167.2021","article-title":"Identification of variants of ISL1 gene promoter and cellular functions in isolated ventricular septal defects","volume":"321","author":"Zheng","year":"2021","journal-title":"Am J Physiol Cell Physiol"},{"key":"2026092903151194000_63.10.620.27","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1111\/jcmm.16218","article-title":"Genetic analysis of the CITED2 gene promoter in isolated and sporadic congenital ventricular septal defects","volume":"25","author":"Zheng","year":"2021","journal-title":"J Cell Mol Med"},{"key":"2026092903151194000_63.10.620.28","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.069732"},{"key":"2026092903151194000_63.10.620.29","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21253"},{"key":"2026092903151194000_63.10.620.30","doi-asserted-by":"publisher","DOI":"10.1126\/science.1132292"},{"key":"2026092903151194000_63.10.620.31","doi-asserted-by":"publisher","DOI":"10.1038\/nature11139"},{"key":"2026092903151194000_63.10.620.32","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.305547"},{"key":"2026092903151194000_63.10.620.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.04.010"},{"key":"2026092903151194000_63.10.620.34","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2008.120931"},{"key":"2026092903151194000_63.10.620.35","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.4.2853"},{"key":"2026092903151194000_63.10.620.36","doi-asserted-by":"crossref","DOI":"10.3390\/cells14161257","article-title":"Mechanistic Insights and Clinical Implications of ELK1 in Solid Tumors: A Narrative Review","volume":"14","author":"Kalampounias","year":"2025","journal-title":"Cells"},{"key":"2026092903151194000_63.10.620.37","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(01)01377-8"},{"key":"2026092903151194000_63.10.620.38","doi-asserted-by":"publisher","DOI":"10.1247\/csf.26.19"},{"key":"2026092903151194000_63.10.620.39","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/cbf.3729","article-title":"HDACs regulate the differentiation of endothelial cells from human iPSCs","volume":"40","author":"Li","year":"2022","journal-title":"Cell Biochem Funct"},{"key":"2026092903151194000_63.10.620.40","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-03-211391"},{"key":"2026092903151194000_63.10.620.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.mod.2008.10.001"},{"key":"2026092903151194000_63.10.620.42","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.87.9.731"},{"key":"2026092903151194000_63.10.620.43","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000109415.17511.18"},{"key":"2026092903151194000_63.10.620.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2005.03.003"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2026-111657","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:15:37Z","timestamp":1790676937000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2026-111657"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":44,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,9,29]]},"published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1136\/jmg-2026-111657"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2026-111657","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]}}}