{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T10:52:17Z","timestamp":1788519137125,"version":"build-2803163510"},"reference-count":31,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T00:00:00Z","timestamp":1661904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"GACR","award":["20-19278S"],"award-info":[{"award-number":["20-19278S"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>We report the phenotype of a 15-year-old female patient with anterior segment dysgenesis (ASD) caused by a novel heterozygous loss-of-function FOXC1 variant. The proband underwent an ophthalmic examination as well as a molecular genetic investigation comprising exome sequencing, a single nucleotide polymorphism array to access copy number and Sanger sequencing to exclude non-coding causal variants. There was bilateral mild iris hypoplasia with pupil deformation and iridocorneal adhesions. In addition to these features of ASD, the corneas were flat, with mean keratometry readings of 38.8 diopters in the right eye and 39.5 diopters in the left eye. There was a snail track lesion of the left cornea at the level of the Descemet membrane. The central corneal endothelial cell density was reduced bilaterally at 1964 and 1373 cells\/mm2 in the right and left eyes, respectively. Molecular genetic analysis revealed that the proband was a carrier of a novel heterozygous frameshifting variant in FOXC1, c.605del p.(Pro202Argfs*113). Neither parent had this change, suggesting a de novo origin which was supported by paternity testing. We found no possibly pathogenic variants in the other genes associated with posterior corneal dystrophies or ASD. Further studies are warranted to verify whether there is a true association between snail track lesions, corneal flattening, and pathogenic variants in FOXC1.<\/jats:p>","DOI":"10.3390\/jcm11175166","type":"journal-article","created":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T01:50:51Z","timestamp":1661997051000},"page":"5166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Snail Track Lesion with Flat Keratometry in Anterior Segment Dysgenesis Caused by a Novel FOXC1 Variant"],"prefix":"10.3390","volume":"11","author":[{"given":"Pavlina","family":"Skalicka","sequence":"first","affiliation":[{"name":"Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech Republic"},{"name":"Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1769-1659","authenticated-orcid":false,"given":"Jana","family":"Jedlickova","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ales","family":"Horinek","sequence":"additional","affiliation":[{"name":"Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague and General University Hospital in Prague, 128 08 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Trkova","sequence":"additional","affiliation":[{"name":"GENNET, 170 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1816-6151","authenticated-orcid":false,"given":"Alice E.","family":"Davidson","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Tuft","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology, London EC1V 9EL, UK"},{"name":"Moorfields Eye Hospital, London EC1V 2PD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubica","family":"Dudakova","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7834-8486","authenticated-orcid":false,"given":"Petra","family":"Liskova","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech Republic"},{"name":"Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech Republic"},{"name":"UCL Institute of Ophthalmology, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,31]]},"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":"899","DOI":"10.1007\/s00439-018-1935-7","article-title":"Phenotype-genotype correlations and emerging pathways in ocular anterior segment dysgenesis","volume":"138","author":"Ma","year":"2019","journal-title":"Hum. Genet."},{"key":"ref_3","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_4","doi-asserted-by":"crossref","unstructured":"Reis, L.M., Maheshwari, M., Capasso, J., Atilla, H., Dudakova, L., Thompson, S., Zitano, L., Lay-Son, G., Lowry, R.B., and Black, J. (2022). Axenfeld-Rieger syndrome: More than meets the eye. J. Med. Genet., Epub ahead of print.","DOI":"10.1136\/jmg-2022-108646"},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1006\/dbio.1999.9314","article-title":"The forkhead\/winged-helix gene, Mf1, is necessary for the normal development of the cornea and formation of the anterior chamber in the mouse eye","volume":"211","author":"Kidson","year":"1999","journal-title":"Dev. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4200","DOI":"10.1167\/iovs.05-0691","article-title":"Fate maps of neural crest and mesoderm in the mammalian eye","volume":"46","author":"Gage","year":"2005","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1590\/S0034-72802008000600007","article-title":"Anomalia de Axenfeld-Rieger e distrofia corneana endotelial: Uma s\u00e9rie de casos","volume":"67","author":"Oliveira","year":"2008","journal-title":"Rev. Bras. Oftalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e1791","DOI":"10.1016\/j.ophtha.2006.05.017","article-title":"A novel PITX2 mutation and a polymorphism in a 5-generation family with Axenfeld-Rieger anomaly and coexisting Fuchs\u2019 endothelial dystrophy","volume":"113","author":"Kniestedt","year":"2006","journal-title":"Ophthalmology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/S0002-9394(02)01401-0","article-title":"Endothelial dystrophy, iris hypoplasia, congenital cataract, and stromal thinning (edict) syndrome maps to chromosome 15q22.1-q25.3","volume":"134","author":"Jun","year":"2002","journal-title":"Am. J. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.ajhg.2018.02.010","article-title":"Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat Expansion-Mediated Toxicity","volume":"102","author":"Zarouchlioti","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100883","DOI":"10.1016\/j.preteyeres.2020.100883","article-title":"TCF4-mediated Fuchs endothelial corneal dystrophy: Insights into a common trinucleotide repeat-associated disease","volume":"81","author":"Fautsch","year":"2021","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Liskova, P., Hafford-Tear, N.J., Skalicka, P., Malinka, F., Jedlickova, J., Dudakova, L., Pontikos, N., Davidson, A.E., and Tuft, S. (2022). Posterior corneal vesicles are not associated with the genetic variants that cause posterior polymorphous corneal dystrophy. Acta Ophthalmol.","DOI":"10.1111\/aos.15114"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ajhg.2015.11.018","article-title":"Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2","volume":"98","author":"Davidson","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.ajhg.2018.02.002","article-title":"Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4","volume":"102","author":"Liskova","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1086\/497348","article-title":"Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells","volume":"77","author":"Krafchak","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1016\/S0161-6420(89)32675-3","article-title":"Differentiation of posterior polymorphous dystrophy from other posterior corneal opacities by specular microscopy","volume":"96","author":"Brooks","year":"1989","journal-title":"Ophthalmology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1111\/aos.15022","article-title":"Novel disease-causing variants and phenotypic features of X-linked megalocornea","volume":"100","author":"Dudakova","year":"2022","journal-title":"Acta Ophthalmol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e87","DOI":"10.1111\/aos.13484","article-title":"Analysis of KERA in four families with cornea plana identifies two novel mutations","volume":"96","author":"Dudakova","year":"2018","journal-title":"Acta Ophthalmol."},{"key":"ref_20","first-page":"782","article-title":"Variant-level matching for diagnosis and discovery: Challenges and opportunities","volume":"43","author":"Rodrigues","year":"2022","journal-title":"Hum. Mutat."},{"key":"ref_21","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_22","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1038\/s41588-019-0528-2","article-title":"PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels","volume":"51","author":"Martin","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.fsigen.2009.10.007","article-title":"Developmental validation of the PowerPlex 16 HS System: An improved 16-locus fluorescent STR multiplex","volume":"4","author":"Ensenberger","year":"2010","journal-title":"Forensic. Sci. Int. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.2147\/OPTH.S31821","article-title":"Central corneal thickness and corneal endothelial characteristics in healthy, cataract, and glaucoma patients","volume":"6","author":"Galgauskas","year":"2012","journal-title":"Clin. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1016\/j.jcrs.2013.05.042","article-title":"Comprehensive anterior segment normal values generated by rotating Scheimpflug tomography","volume":"39","author":"Gilani","year":"2013","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0161-6420(92)32017-2","article-title":"Age-related decline of disc rim area in visually normal subjects","volume":"99","author":"Tsai","year":"1992","journal-title":"Ophthalmology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1167\/iovs.10-5309","article-title":"Expanding the spectrum of FOXC1 and PITX2 mutations and copy number changes in patients with anterior segment malformations","volume":"52","author":"Meire","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1159\/000472704","article-title":"Unilateral Posterior Polymorphous Corneal Dystrophy Presented as Anisometropic Astigmatism: 3 Case Reports","volume":"8","author":"Jeon","year":"2017","journal-title":"Case Rep. Ophthalmol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"252","DOI":"10.3109\/13816810.2013.811272","article-title":"Corneal endothelial findings in a Czech patient with compound heterozygous mutations in KERA","volume":"35","author":"Dudakova","year":"2014","journal-title":"Ophthalmic. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1038\/ejhg.2015.232","article-title":"Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3","volume":"24","author":"Liskova","year":"2016","journal-title":"Eur. J. Hum. Genet."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/17\/5166\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:21:23Z","timestamp":1760142083000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/17\/5166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,31]]},"references-count":31,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["jcm11175166"],"URL":"https:\/\/doi.org\/10.3390\/jcm11175166","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,31]]}}}