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.

Department of Ophthalmology 1st Faculty of Medicine Charles University and General University Hospital Prague 128 08 Prague Czech Republic

Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague 128 08 Prague Czech Republic

GENNET 170 00 Prague Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague and General University Hospital Prague 128 08 Prague Czech Republic

Moorfields Eye Hospital London EC1V 2PD UK

UCL Institute of Ophthalmology London EC1V 9EL UK

Zobrazit více v PubMed

Reis L.M., Semina E.V. Genetics of anterior segment dysgenesis disorders. Curr. Opin. Ophthalmol. 2011;22:314–324. doi: 10.1097/ICU.0b013e328349412b. PubMed DOI PMC

Ma A.S., Grigg J.R., Jamieson R.V. Phenotype-genotype correlations and emerging pathways in ocular anterior segment dysgenesis. Hum. Genet. 2019;138:899–915. doi: 10.1007/s00439-018-1935-7. PubMed DOI

Mirzayans F., Gould D.B., Heon E., Billingsley G.D., Cheung J.C., Mears A.J., Walter M.A. Axenfeld-Rieger syndrome resulting from mutation of the FKHL7 gene on chromosome 6p25. Eur. J. Hum. Genet. 2000;8:71–74. doi: 10.1038/sj.ejhg.5200354. PubMed DOI

Reis L.M., Maheshwari M., Capasso J., Atilla H., Dudakova L., Thompson S., Zitano L., Lay-Son G., Lowry R.B., Black J., et al. Axenfeld-Rieger syndrome: More than meets the eye. J. Med. Genet. 2022 doi: 10.1136/jmg-2022-108646. Epub ahead of print . PubMed DOI PMC

Berry F.B., Lines M.A., Oas J.M., Footz T., Underhill D.A., Gage P.J., Walter M.A. Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Hum. Mol. Genet. 2006;15:905–919. doi: 10.1093/hmg/ddl008. PubMed DOI

Kidson S.H., Kume T., Deng K., Winfrey V., Hogan B.L. 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. Dev. Biol. 1999;211:306–322. doi: 10.1006/dbio.1999.9314. PubMed DOI

Gage P.J., Rhoades W., Prucka S.K., Hjalt T. Fate maps of neural crest and mesoderm in the mammalian eye. Investig. Ophthalmol. Vis. Sci. 2005;46:4200–4208. doi: 10.1167/iovs.05-0691. PubMed DOI

Oliveira M.B., Mitraud R.S., Yamane R. Anomalia de Axenfeld-Rieger e distrofia corneana endotelial: Uma série de casos. Rev. Bras. Oftalmol. 2008;67:303–308. doi: 10.1590/S0034-72802008000600007. DOI

Kniestedt C., Taralczak M., Thiel M.A., Stuermer J., Baumer A., Gloor B.P. A novel PITX2 mutation and a polymorphism in a 5-generation family with Axenfeld-Rieger anomaly and coexisting Fuchs’ endothelial dystrophy. Ophthalmology. 2006;113:e1791–e1798. doi: 10.1016/j.ophtha.2006.05.017. PubMed DOI

Jun A.S., Broman K.W., Do D.V., Akpek E.K., Stark W.J., Gottsch J.D. Endothelial dystrophy, iris hypoplasia, congenital cataract, and stromal thinning (edict) syndrome maps to chromosome 15q22.1-q25.3. Am. J. Ophthalmol. 2002;134:172–176. doi: 10.1016/S0002-9394(02)01401-0. PubMed DOI

Zarouchlioti C., Sanchez-Pintado B., Hafford Tear N.J., Klein P., Liskova P., Dulla K., Semo M., Vugler A.A., Muthusamy K., Dudakova L., et al. Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat Expansion-Mediated Toxicity. Am. J. Hum. Genet. 2018;102:528–539. doi: 10.1016/j.ajhg.2018.02.010. PubMed DOI PMC

Fautsch M.P., Wieben E.D., Baratz K.H., Bhattacharyya N., Sadan A.N., Hafford-Tear N.J., Tuft S.J., Davidson A.E. TCF4-mediated Fuchs endothelial corneal dystrophy: Insights into a common trinucleotide repeat-associated disease. Prog. Retin. Eye Res. 2021;81:100883. doi: 10.1016/j.preteyeres.2020.100883. PubMed DOI PMC

Liskova P., Hafford-Tear N.J., Skalicka P., Malinka F., Jedlickova J., Dudakova L., Pontikos N., Davidson A.E., Tuft S. Posterior corneal vesicles are not associated with the genetic variants that cause posterior polymorphous corneal dystrophy. Acta Ophthalmol. 2022 doi: 10.1111/aos.15114. PubMed DOI

Davidson A.E., Liskova P., Evans C.J., Dudakova L., Noskova L., Pontikos N., Hartmannova H., Hodanova K., Stranecky V., Kozmik Z., et al. Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2. Am. J. Hum. Genet. 2016;98:75–89. doi: 10.1016/j.ajhg.2015.11.018. PubMed DOI PMC

Liskova P., Dudakova L., Evans C.J., Rojas Lopez K.E., Pontikos N., Athanasiou D., Jama H., Sach J., Skalicka P., Stranecky V., et al. Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4. Am. J. Hum. Genet. 2018;102:447–459. doi: 10.1016/j.ajhg.2018.02.002. PubMed DOI PMC

Krafchak C.M., Pawar H., Moroi S.E., Sugar A., Lichter P.R., Mackey D.A., Mian S., Nairus T., Elner V., Schteingart M.T., et al. Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells. Am. J. Hum. Genet. 2005;77:694–708. doi: 10.1086/497348. PubMed DOI PMC

Brooks A.M., Grant G., Gillies W.E. Differentiation of posterior polymorphous dystrophy from other posterior corneal opacities by specular microscopy. Ophthalmology. 1989;96:1639–1645. doi: 10.1016/S0161-6420(89)32675-3. PubMed DOI

Dudakova L., Tuft S., Cheong S.S., Skalicka P., Jedlickova J., Fichtl M., Hlozanek M., Filous A., Vaneckova M., Vincent A.L., et al. Novel disease-causing variants and phenotypic features of X-linked megalocornea. Acta Ophthalmol. 2022;100:431–439. doi: 10.1111/aos.15022. PubMed DOI

Dudakova L., Vercruyssen J.H.J., Balikova I., Postolache L., Leroy B.P., Skalicka P., Liskova P. Analysis of KERA in four families with cornea plana identifies two novel mutations. Acta Ophthalmol. 2018;96:e87–e91. doi: 10.1111/aos.13484. PubMed DOI

Rodrigues E.D.S., Griffith S., Martin R., Antonescu C., Posey J.E., Coban-Akdemir Z., Jhangiani S.N., Doheny K.F., Lupski J.R., Valle D., et al. Variant-level matching for diagnosis and discovery: Challenges and opportunities. Hum. Mutat. 2022;43:782–790. doi: 10.1002/humu.24359. PubMed DOI PMC

Karczewski K.J., Francioli L.C., Tiao G., Cummings B.B., Alfoldi J., Wang Q., Collins R.L., Laricchia K.M., Ganna A., Birnbaum D.P., et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–443. doi: 10.1038/s41586-020-2308-7. PubMed DOI PMC

Martin A.R., Williams E., Foulger R.E., Leigh S., Daugherty L.C., Niblock O., Leong I.U.S., Smith K.R., Gerasimenko O., Haraldsdottir E., et al. PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat. Genet. 2019;51:1560–1565. doi: 10.1038/s41588-019-0528-2. PubMed DOI

Ensenberger M.G., Thompson J., Hill B., Homick K., Kearney V., Mayntz-Press K.A., Mazur P., McGuckian A., Myers J., Raley K., et al. Developmental validation of the PowerPlex 16 HS System: An improved 16-locus fluorescent STR multiplex. Forensic. Sci. Int. Genet. 2010;4:257–264. doi: 10.1016/j.fsigen.2009.10.007. PubMed DOI

Galgauskas S., Krasauskaite D., Pajaujis M., Juodkaite G., Asoklis R.S. Central corneal thickness and corneal endothelial characteristics in healthy, cataract, and glaucoma patients. Clin. Ophthalmol. 2012;6:1195–1199. doi: 10.2147/OPTH.S31821. PubMed DOI PMC

Gilani F., Cortese M., Ambrosio R.R., Jr., Lopes B., Ramos I., Harvey E.M., Belin M.W. Comprehensive anterior segment normal values generated by rotating Scheimpflug tomography. J. Cataract Refract. Surg. 2013;39:1707–1712. doi: 10.1016/j.jcrs.2013.05.042. PubMed DOI

Tsai C.S., Ritch R., Shin D.H., Wan J.Y., Chi T. Age-related decline of disc rim area in visually normal subjects. Ophthalmology. 1992;99:29–35. doi: 10.1016/S0161-6420(92)32017-2. PubMed DOI

Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J., Grody W.W., Hegde M., Lyon E., Spector E., et al. 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. Genet. Med. 2015;17:405–424. doi: 10.1038/gim.2015.30. PubMed DOI PMC

D’Haene B., Meire F., Claerhout I., Kroes H.Y., Plomp A., Arens Y.H., de Ravel T., Casteels I., De Jaegere S., Hooghe S., et al. Expanding the spectrum of FOXC1 and PITX2 mutations and copy number changes in patients with anterior segment malformations. Investig. Ophthalmol. Vis. Sci. 2011;52:324–333. doi: 10.1167/iovs.10-5309. PubMed DOI

Jeon H.S., Hyon J.Y. Unilateral Posterior Polymorphous Corneal Dystrophy Presented as Anisometropic Astigmatism: 3 Case Reports. Case Rep. Ophthalmol. 2017;8:250–258. doi: 10.1159/000472704. PubMed DOI PMC

Dudakova L., Palos M., Hardcastle A.J., Liskova P. Corneal endothelial findings in a Czech patient with compound heterozygous mutations in KERA. Ophthalmic. Genet. 2014;35:252–254. doi: 10.3109/13816810.2013.811272. PubMed DOI

Liskova P., Evans C.J., Davidson A.E., Zaliova M., Dudakova L., Trkova M., Stranecky V., Carnt N., Plagnol V., Vincent A.L., et al. Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3. Eur. J. Hum. Genet. 2016;24:985–991. doi: 10.1038/ejhg.2015.232. PubMed DOI PMC