{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T21:23:30Z","timestamp":1788989010490,"version":"build-2803163510"},"reference-count":23,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,2,25]],"date-time":"2024-02-25T00:00:00Z","timestamp":1708819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ocular malformations (OMs) arise from early defects during embryonic eye development. Despite the identification of over 100 genes linked to this heterogeneous group of disorders, the genetic cause remains unknown for half of the individuals following Whole-Exome Sequencing. Diagnosis procedures are further hampered by the difficulty of studying samples from clinically relevant tissue, which is one of the main obstacles in OMs. Whole-Genome Sequencing (WGS) to screen for non-coding regions and structural variants may unveil new diagnoses for OM individuals. In this study, we report a patient exhibiting a syndromic OM with a de novo 3.15 Mb inversion in the 6p25 region identified by WGS. This balanced structural variant was located 100 kb away from the FOXC1 gene, previously associated with ocular defects in the literature. We hypothesized that the inversion disrupts the topologically associating domain of FOXC1 and impairs the expression of the gene. Using a new type of samples to study transcripts, we were able to show that the patient presented monoallelic expression of FOXC1 in conjunctival cells, consistent with the abolition of the expression of the inverted allele. This report underscores the importance of investigating structural variants, even in non-coding regions, in individuals affected by ocular malformations.<\/jats:p>","DOI":"10.3390\/ijms25052669","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T06:50:23Z","timestamp":1708930223000},"page":"2669","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Structural Variant Disrupting the Expression of the Remote FOXC1 Gene in a Patient with Syndromic Complex Microphthalmia"],"prefix":"10.3390","volume":"25","author":[{"given":"Julie","family":"Plaisanci\u00e9","sequence":"first","affiliation":[{"name":"Laboratoire de R\u00e9f\u00e9rence des Anomalies Malformatives de l\u2019\u0152il, Institut F\u00e9d\u00e9ratif de Biologie, Centre Hospitalier Universitaire de Toulouse, 31300 Toulouse, France"},{"name":"Centre de R\u00e9f\u00e9rence des Affections Rares en G\u00e9n\u00e9tique Ophtalmologique (CARGO), Centre Hospitalier Universitaire de Toulouse, 31300 Toulouse, France"},{"name":"Molecular, Cellular and Developmental Biology Unit (MCD), Centre de Biologie Int\u00e9grative (CBI), (CNRS), Universit\u00e9 Toulouse III Paul Sabatier (UPS), Universit\u00e9 de Toulouse, 31062 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9729-7346","authenticated-orcid":false,"given":"Bertrand","family":"Chesneau","sequence":"additional","affiliation":[{"name":"Laboratoire de R\u00e9f\u00e9rence des Anomalies Malformatives de l\u2019\u0152il, Institut F\u00e9d\u00e9ratif de Biologie, Centre Hospitalier Universitaire de Toulouse, 31300 Toulouse, France"},{"name":"Centre de R\u00e9f\u00e9rence des Affections Rares en G\u00e9n\u00e9tique Ophtalmologique (CARGO), Centre Hospitalier Universitaire de Toulouse, 31300 Toulouse, France"},{"name":"Molecular, Cellular and Developmental Biology Unit (MCD), Centre de Biologie Int\u00e9grative (CBI), (CNRS), Universit\u00e9 Toulouse III Paul Sabatier (UPS), Universit\u00e9 de Toulouse, 31062 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4613-0711","authenticated-orcid":false,"given":"Lucas","family":"Fares-Taie","sequence":"additional","affiliation":[{"name":"Laboratoire de G\u00e9n\u00e9tique Ophtalmologique, Institut national de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U1163, Institut Imagine, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7951-7886","authenticated-orcid":false,"given":"Jean-Michel","family":"Rozet","sequence":"additional","affiliation":[{"name":"Laboratoire de G\u00e9n\u00e9tique Ophtalmologique, Institut national de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U1163, Institut Imagine, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacmine","family":"Pechmeja","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence des Affections Rares en G\u00e9n\u00e9tique Ophtalmologique (CARGO), Centre Hospitalier Universitaire de Toulouse, 31300 Toulouse, France"},{"name":"Service d\u2019Ophtalmologie, H\u00f4pital Purpan, Centre Hospitalier Universitaire de Toulouse, 31300 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Noero","sequence":"additional","affiliation":[{"name":"Laboratoire de R\u00e9f\u00e9rence des Anomalies Malformatives de l\u2019\u0152il, Institut F\u00e9d\u00e9ratif de Biologie, Centre Hospitalier Universitaire de Toulouse, 31300 Toulouse, France"},{"name":"Molecular, Cellular and Developmental Biology Unit (MCD), Centre de Biologie Int\u00e9grative (CBI), (CNRS), Universit\u00e9 Toulouse III Paul Sabatier (UPS), Universit\u00e9 de Toulouse, 31062 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Gaston","sequence":"additional","affiliation":[{"name":"Laboratoire de R\u00e9f\u00e9rence des Anomalies Malformatives de l\u2019\u0152il, Institut F\u00e9d\u00e9ratif de Biologie, Centre Hospitalier Universitaire de Toulouse, 31300 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Bailleul-Forestier","sequence":"additional","affiliation":[{"name":"Competence Centre of Oral Diseases, Centre Hospitalier Universitaire de Toulouse, 31300 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Calvas","sequence":"additional","affiliation":[{"name":"Laboratoire de R\u00e9f\u00e9rence des Anomalies Malformatives de l\u2019\u0152il, Institut F\u00e9d\u00e9ratif de Biologie, Centre Hospitalier Universitaire de Toulouse, 31300 Toulouse, France"},{"name":"Centre de R\u00e9f\u00e9rence des Affections Rares en G\u00e9n\u00e9tique Ophtalmologique (CARGO), Centre Hospitalier Universitaire de Toulouse, 31300 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Chassaing","sequence":"additional","affiliation":[{"name":"Laboratoire de R\u00e9f\u00e9rence des Anomalies Malformatives de l\u2019\u0152il, Institut F\u00e9d\u00e9ratif de Biologie, Centre Hospitalier Universitaire de Toulouse, 31300 Toulouse, France"},{"name":"Centre de R\u00e9f\u00e9rence des Affections Rares en G\u00e9n\u00e9tique Ophtalmologique (CARGO), Centre Hospitalier Universitaire de Toulouse, 31300 Toulouse, France"},{"name":"Laboratoire AURAGEN, 69003 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/(SICI)1096-8628(19980217)75:5<497::AID-AJMG8>3.0.CO;2-K","article-title":"Congenital Eye Malformations: Clinical-Epidemiological Analysis of 1,124,654 Consecutive Births in Spain","volume":"75","author":"Bermejo","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1007\/s00439-019-01977-y","article-title":"Genetics of Anophthalmia and Microphthalmia. Part 1: Non-Syndromic Anophthalmia\/Microphthalmia","volume":"138","author":"Ceroni","year":"2019","journal-title":"Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1111\/cge.13239","article-title":"Genetic Investigation of 93 Families with Microphthalmia or Posterior Microphthalmos","volume":"93","author":"Patel","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Haug, P., Koller, S., Maggi, J., Lang, E., Feil, S., Wlodarczyk, A., B\u00e4hr, L., Steindl, K., Rohrbach, M., and Gerth-Kahlert, C. (2021). Whole Exome Sequencing in Coloboma\/Microphthalmia: Identification of Novel and Recurrent Variants in Seven Genes. Genes, 12.","DOI":"10.3390\/genes12010065"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1136\/bjo-2022-321991","article-title":"Real-World Clinical and Molecular Management of 50 Prospective Patients with Microphthalmia, Anophthalmia and\/or Ocular Coloboma","volume":"107","author":"Harding","year":"2023","journal-title":"Br. J. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41525-024-00391-2","article-title":"Whole Genome Sequencing Enables New Genetic Diagnosis for Inherited Retinal Diseases by Identifying Pathogenic Variants","volume":"9","author":"Liu","year":"2024","journal-title":"NPJ Genom. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/j.ajhg.2013.10.028","article-title":"Disruption of Autoregulatory Feedback by a Mutation in a Remote, Ultraconserved PAX6 Enhancer Causes Aniridia","volume":"93","author":"Bhatia","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1136\/jmg-2023-109181","article-title":"Short-Read Whole Genome Sequencing Identifies Causative Variants in Most Individuals with Previously Unexplained Aniridia","volume":"61","author":"Hall","year":"2024","journal-title":"J. Med. Genet."},{"key":"ref_9","first-page":"1366","article-title":"Molecular Analysis of FOXC1 in Subjects Presenting with Severe Developmental Eye Anomalies","volume":"15","author":"Kaur","year":"2009","journal-title":"Mol. Vis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1136\/jmg.2009.072785","article-title":"The Revised Ghent Nosology for the Marfan Syndrome","volume":"47","author":"Loeys","year":"2010","journal-title":"J. Med. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1136\/jmg-2022-108646","article-title":"Axenfeld-Rieger Syndrome: More than Meets the Eye","volume":"60","author":"Reis","year":"2023","journal-title":"J. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"D\u2019Aurizio, R., Catona, O., Pitasi, M., Li, Y.E., Ren, B., and Nicolis, S.K. (2022). Bridging between Mouse and Human Enhancer-Promoter Long-Range Interactions in Neural Stem Cells, to Understand Enhancer Function in Neurodevelopmental Disease. Int. J. Mol. Sci., 23.","DOI":"10.1101\/2022.05.26.493430"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1387\/ijdb.041865dg","article-title":"Anterior Segment Development Relevant to Glaucoma","volume":"48","author":"Gould","year":"2004","journal-title":"Int. J. Dev. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1111\/cge.12816","article-title":"Whole Exome Sequencing Identifies Multiple Diagnoses in Congenital Glaucoma with Systemic Anomalies: WES in Congenital Glaucoma with Systemic Anomalies","volume":"90","author":"Reis","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3109\/13816810.2016.1164191","article-title":"The 6p25 Deletion Syndrome: An Update on a Rare Neurocristopathy","volume":"38","author":"Stegmann","year":"2017","journal-title":"Ophthalmic Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1038\/ng.422","article-title":"FOXC1 Is Required for Normal Cerebellar Development and Is a Major Contributor to Chromosome 6p25.3 Dandy-Walker Malformation","volume":"41","author":"Aldinger","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"14582","DOI":"10.1074\/jbc.273.23.14582","article-title":"Molecular Cloning and Expression of GDP-D-Mannose-4,6-Dehydratase, a Key Enzyme for Fucose Metabolism Defective in Lec13 Cells","volume":"273","author":"Ohyama","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"19626","DOI":"10.1074\/jbc.M802655200","article-title":"Specificity of the Chromodomain Y Chromosome Family of Chromodomains for Lysine-Methylated ARK(S\/T) Motifs","volume":"283","author":"Fischle","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The Mutational Constraint Spectrum Quantified from Variation in 141,456 Humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1016\/j.ajhg.2019.11.003","article-title":"Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders","volume":"105","author":"Turner","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1002\/ajmg.c.31837","article-title":"Molecular Diagnostic Challenges for Non-Retinal Developmental Eye Disorders in the United Kingdom","volume":"184","author":"Jackson","year":"2020","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s40246-023-00490-8","article-title":"Long-Read Genome Sequencing Identifies Cryptic Structural Variants in Congenital Aniridia Cases","volume":"17","author":"Jubin","year":"2023","journal-title":"Hum. Genom."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e54","DOI":"10.1093\/nar\/gkad225","article-title":"POSTRE: A Tool to Predict the Pathological Effects of Human Structural Variants","volume":"51","year":"2023","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/5\/2669\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:04:42Z","timestamp":1760105082000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/5\/2669"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,25]]},"references-count":23,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["ijms25052669"],"URL":"https:\/\/doi.org\/10.3390\/ijms25052669","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,25]]}}}