{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T18:11:35Z","timestamp":1755799895924,"version":"3.44.0"},"reference-count":17,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:00:00Z","timestamp":1755648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Mediator of RNA polymerase II transcription subunit 25 (<jats:italic>MED25<\/jats:italic>), a crucial component of the transcriptional coactivator complex, plays a significant role in the transcription of most RNA polymerase II-dependent genes. Mutations in <jats:italic>MED25<\/jats:italic> have been linked to various genetic syndromes, including Basel-Vanagaite-Smirin-Yosef Syndrome (BVSYS) and Intellectual Disability (ID). This study elucidated the molecular mechanism through which compound heterozygous mutations in the <jats:italic>MED25<\/jats:italic> gene impaired pre-mRNA splicing, ultimately causing BVSYS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole exome sequencing (WES) was performed to identify genetic variants, followed by Sanger sequencing for validation. Clinical data were correlated with established <jats:italic>MED25<\/jats:italic>-related syndrome phenotypes. Bioinformatics tools were utilized to predict splicing effects and protein structural alterations. Functional characterization involved in vitro minigene splicing assays for the c.1965+1dup mutation and RT-PCR analysis of patient-derived transcripts, while the impact of p.R224G was assessed through protein structure modeling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The proband presented with clinical manifestations such as cognitive impairment, language difficulties, intellectual disability, and microcephaly. The study identified a compound heterozygous mutation in the <jats:italic>MED25<\/jats:italic> gene (NM_030973.4), consisting of c.670C&amp;gt;G (p.R224G) and c.1965+1dup, which was associated with the observed clinical phenotype. Bioinformatics analysis and in vivo\/in vitro splicing assays demonstrated that the c.1965+1dup mutation disrupts <jats:italic>MED25<\/jats:italic> pre-mRNA splicing, whereas the c.670C&amp;gt;G (p.R224G) variant does not exhibit this effect. However, bioinformatics analysis suggested that the mutation c.670C&amp;gt;G (p.R224G) may affect gene function by altering the structure of the <jats:italic>MED25<\/jats:italic> protein.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conculsion<\/jats:title><jats:p>These findings demonstrated that two mutation sites identified in the <jats:italic>MED25<\/jats:italic> gene in this case are pathogenic or likely pathogenic and may be associated with the clinical phenotype of the proband in this study.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2025.1654336","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T05:36:00Z","timestamp":1755668160000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS"],"prefix":"10.3389","volume":"16","author":[{"given":"Linbing","family":"Zou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruikang","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhijun","family":"Dai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yulei","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunjiao","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1007\/s00774-011-0273-9","article-title":"Unraveling the transcriptional regulatory machinery in chondrogenesis","volume":"29","author":"Akiyama","year":"2011","journal-title":"J. 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