{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:14:05Z","timestamp":1790475245622,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T00:00:00Z","timestamp":1645660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["ZIAEY000564"],"award-info":[{"award-number":["ZIAEY000564"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["ZIAEY000565"],"award-info":[{"award-number":["ZIAEY000565"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Anterior segment dysgenesis (ASD) encompasses a wide spectrum of developmental abnormalities of the anterior ocular segment, including congenital cataract, iris hypoplasia, aniridia, iridocorneal synechiae, as well as Peters, Axenfeld, and Rieger anomalies. Here, we report a large five-generation Caucasian family exhibiting atypical syndromic ASD segregating with a novel truncating variant of FOXC1. The family history is consistent with highly variable autosomal dominant symptoms including isolated glaucoma, iris hypoplasia, aniridia, cataract, hypothyroidism, and congenital heart anomalies. Whole-exome sequencing revealed a novel variant [c.313_314insA; p.(Tyr105*)] in FOXC1 that disrupts the \u03b1-helical region of the DNA-binding forkhead box domain. In vitro studies using a heterologous cell system revealed aberrant cytoplasmic localization of FOXC1 harboring the Tyr105* variant, likely precluding downstream transcription function. Meta-analysis of the literature highlighted the intrafamilial variability related to FOXC1 truncating alleles. This study highlights the clinical variability in ASD and signifies the importance of combining both clinical and molecular analysis approaches to establish a complete diagnosis.<\/jats:p>","DOI":"10.3390\/genes13030411","type":"journal-article","created":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T21:11:07Z","timestamp":1645737067000},"page":"411","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Variable Anterior Segment Dysgenesis and Cardiac Anomalies Caused by a Novel Truncating Variant of FOXC1"],"prefix":"10.3390","volume":"13","author":[{"given":"Mariya R.","family":"Ahmed","sequence":"first","affiliation":[{"name":"Medical Genetics and Ophthalmic Genomics Unit, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"Department of Otorhinolaryngology\u2014Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saumil","family":"Sethna","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\u2014Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"Krueger","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Division of Pediatric Ophthalmology, Abrahamson Pediatric Eye Institute, University of Cincinnati College of Medicine, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B.","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Division of Pediatric Ophthalmology, Abrahamson Pediatric Eye Institute, University of Cincinnati College of Medicine, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3015-3545","authenticated-orcid":false,"given":"Robert B.","family":"Hufnagel","sequence":"additional","affiliation":[{"name":"Medical Genetics and Ophthalmic Genomics Unit, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1097\/ICU.0b013e328349412b","article-title":"Genetics of anterior segment dysgenesis disorders","volume":"22","author":"Reis","year":"2011","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1093\/hmg\/ddl008","article-title":"Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis","volume":"15","author":"Berry","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1097\/00061198-200202000-00010","article-title":"Genetic analysis of PITX2 and FOXC1 in Rieger Syndrome patients from Brazil","volume":"11","author":"Borges","year":"2002","journal-title":"J. Glaucoma"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1177\/154405910308201214","article-title":"Novel identification of a four-base-pair deletion mutation in PITX2 in a Rieger syndrome family","volume":"82","author":"Wang","year":"2003","journal-title":"J. Dent. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1097\/01.ijg.0000243467.28590.6a","article-title":"Novel CYP1B1 and known PAX6 mutations in anterior segment dysgenesis (ASD)","volume":"15","author":"Caliebe","year":"2006","journal-title":"J. Glaucoma"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1167\/iovs.05-0979","article-title":"Structural assessment of PITX2, FOXC1, CYP1B1, and GJA1 genes in patients with Axenfeld-Rieger syndrome with developmental glaucoma","volume":"47","author":"Cella","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_7","first-page":"111","article-title":"A Novel Mutation of FOXC1 (R127L) in an Axenfeld-Rieger Syndrome Family with Glaucoma and Multiple Congenital Heart Diseases","volume":"37","author":"Du","year":"2014","journal-title":"Ophthalmic Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1007\/s13312-011-0108-8","article-title":"Dysmyelination of the cerebral white matter with microdeletion at 6p25","volume":"48","author":"Kapoor","year":"2011","journal-title":"Indian Pediatr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0002-9394(00)00525-0","article-title":"Axenfeld-Rieger syndrome in the age of molecular genetics","volume":"130","author":"Alward","year":"2000","journal-title":"Am. J. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/ceo.12152","article-title":"Genomics and anterior segment dysgenesis: A review","volume":"42","author":"Ito","year":"2014","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.survophthal.2006.02.006","article-title":"A Review of Anterior Segment Dysgeneses","volume":"51","author":"Idrees","year":"2006","journal-title":"Surv. Ophthalmol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1038\/ejhg.2009.93","article-title":"Axenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations","volume":"17","author":"Tumer","year":"2009","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/S0002-9394(02)02061-5","article-title":"A family with Axenfeld-Rieger syndrome and Peters Anomaly caused by a point mutation (Phe112Ser) in the FOXC1 gene","volume":"135","author":"Honkanen","year":"2003","journal-title":"Am. J. Ophthalmol."},{"key":"ref_14","first-page":"43","article-title":"Mutation spectrum of FOXC1 and clinical genetic heterogeneity of Axenfeld-Rieger anomaly in India","volume":"9","author":"Komatireddy","year":"2003","journal-title":"Mol. Vis."},{"key":"ref_15","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_16","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1242\/dev.127.7.1387","article-title":"Murine forkhead\/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract","volume":"127","author":"Kume","year":"2000","journal-title":"Development"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2470","DOI":"10.1101\/gad.907301","article-title":"The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis","volume":"15","author":"Kume","year":"2001","journal-title":"Genes Dev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1093\/hmg\/9.7.1021","article-title":"Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development","volume":"9","author":"Smith","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1086\/318183","article-title":"A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye","volume":"68","author":"Nishimura","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Jaworek, T.J., Richard, E.M., Ivanova, A.A., Giese, A.P., Choo, D.I., Khan, S.N., Riazuddin, S., Kahn, R.A., and Riazuddin, S. (2013). An Alteration in ELMOD3, an Arl2 GTPase-Activating Protein, Is Associated with Hearing Impairment in Humans. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003774"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3906","DOI":"10.1038\/s41467-021-24056-1","article-title":"CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function","volume":"12","author":"Sethna","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10292","DOI":"10.1074\/jbc.M110266200","article-title":"FOXC1 transcriptional regulation is mediated by N- and C-terminal activation domains and contains a phosphorylated transcriptional inhibitory domain","volume":"277","author":"Berry","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1167\/iovs.08-2253","article-title":"The transcription factor gene FOXC1 exhibits a limited role in primary congenital glaucoma","volume":"50","author":"Chakrabarti","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/sj.ejhg.5200354","article-title":"Axenfeld-Rieger syndrome resulting from mutation of the FKHL7 gene on chromosome 6p25","volume":"8","author":"Mirzayans","year":"2000","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_25","first-page":"935","article-title":"A novel forkhead box C1 gene mutation in a Korean family with Axenfeld-Rieger syndrome","volume":"19","author":"Kim","year":"2013","journal-title":"Mol. Vis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1111\/j.1399-0004.2008.01025.x","article-title":"A novel mutation in the FOXC1 gene in a family with Axenfeld-Rieger syndrome and Peters\u2019 anomaly","volume":"74","author":"Weisschuh","year":"2008","journal-title":"Clin. Genet."},{"key":"ref_27","first-page":"1005","article-title":"Novel mutations in the FOXC1 gene in Japanese patients with Axenfeld-Rieger syndrome","volume":"13","author":"Fuse","year":"2007","journal-title":"Mol. Vis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.pediatrneurol.2016.08.020","article-title":"Axenfeld-Rieger Syndrome and Leukoencephalopathy Caused by a Mutation in FOXC1","volume":"66","author":"Kumar","year":"2017","journal-title":"Pediatr. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1002\/humu.21550","article-title":"Digenic inheritance of mutations in FOXC1 and PITX2: Correlating transcription factor function and Axenfeld-Rieger disease severity","volume":"32","author":"Kelberman","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_30","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","volume":"90","author":"Reis","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/ejhg.2017.59","article-title":"Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants","volume":"25","author":"Souzeau","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1136\/jmg.34.4.279","article-title":"The incidence of PAX6 mutation in patients with simple aniridia: An evaluation of mutation detection in 12 cases","volume":"34","author":"Axton","year":"1997","journal-title":"J. Med. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1167\/iovs.08-3032","article-title":"Severe Molecular Defects of a Novel FOXC1 W152G Mutation Result in Aniridia","volume":"50","author":"Ito","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_34","first-page":"261","article-title":"PAX6 molecular analysis and genotype-phenotype correlations in families with aniridia from Australasia and Southeast Asia","volume":"24","author":"Souzeau","year":"2018","journal-title":"Mol. Vis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1167\/iovs.06-0472","article-title":"Genotype-phenotype correlations in Axenfeld-Rieger malformation and glaucoma patients with FOXC1 and PITX2 mutations","volume":"48","author":"Strungaru","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1093\/hmg\/ddg324","article-title":"Structural and functional analyses of disease-causing missense mutations in the forkhead domain of FOXC1","volume":"12","author":"Saleem","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1111\/j.1399-0004.2009.01210.x","article-title":"Characterization of a novel FOXC1 mutation, P297S, identified in two individuals with anterior segment dysgenesis","volume":"76","author":"Fetterman","year":"2009","journal-title":"Clin. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/3\/411\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:26:59Z","timestamp":1760135219000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/3\/411"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,24]]},"references-count":37,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["genes13030411"],"URL":"https:\/\/doi.org\/10.3390\/genes13030411","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202201.0466.v1","asserted-by":"object"}]},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,24]]}}}