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We recruited a two-generation Chinese family with hereditary ARS, which manifested as posterior embryotoxon, corneal leucoplakia, ectopic pupil, and extensive iris stromal atrophy with iridocorneal adhesion. Whole-exome sequencing (WES) was utilized for the initial screening, followed by Sanger sequencing to identify pathogenic gene mutations. A novel missense variant in <jats:italic>FOXC1<\/jats:italic> (c.382C\u2009&gt;\u2009T, p.H128Y) was identified. The FOXC1 protein is highly evolutionarily conserved. The potential effects of this mutation on protein structure were studied using 3D modelling and molecular dynamics (MD) simulation techniques. 3D modelling revealed that the mutation altered the conformation of the FOXC1 protein. The MD results suggested that the mutation could reduce the stability of the protein structure. Western blotting revealed that the expression of the mutant FOXC1 (c.382C\u2009&gt;\u2009T, p.H128Y) was lower than that of the wild type. In summary, a novel <jats:italic>FOXC1<\/jats:italic> variant was discovered within a Chinese family with ARS, broadening the spectrum of ARS mutations. This study also elucidated the underlying mechanisms by which <jats:italic>FOXC1<\/jats:italic> gene deficiency causes ARS.<\/jats:p>","DOI":"10.1038\/s41598-025-04872-x","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T10:05:58Z","timestamp":1749204358000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identification and functional study of a novel FOXC1 missense mutation in a Chinese family with Axenfeld\u2013Rieger syndrome"],"prefix":"10.1038","volume":"15","author":[{"given":"Xue","family":"Gong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinlan","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaohui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqiao","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,6]]},"reference":[{"issue":"6","key":"4872_CR1","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1111\/cge.13148","volume":"93","author":"M Seifi","year":"2018","unstructured":"Seifi, M. & Walter, M. 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