Corneal dystrophies are a group of predominantly rare inherited disorders. They are by definition bilateral, relatively symmetrical, and without systemic involvement, affecting corneal transparency and/or refraction. Traditional classification of corneal dystrophies is based on slit-lamp appearance, affected corneal layer and histological features. Molecular genetics has provided ultimate proof for the existence of distinct corneal dystrophies and discarded duplicates in their terminology. Currently, there are at least 16 genes with identified pathogenic variants implicated in corneal dystrophies. Herein, we summarise contemporary knowledge on genotype-phenotype correlations of corneal dystrophies, including a critical review of some reported variants, along with the understanding of the underlying pathogenic dystrophic process; essential knowledge for the development of targeted therapies.

• Keywords
• corneal dystrophy, genetics, hereditary, molecular biology,
• MeSH
• Corneal Dystrophies, Hereditary * genetics   therapy   MeSH
• Phenotype MeSH
• Genetic Association Studies * MeSH
• Genotype MeSH
• Humans MeSH
• Molecular Biology MeSH
• Mutation * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

The genetic architecture of corneal endothelial dystrophies remains unknown in a substantial number of affected individuals. The proband investigated in the current study was diagnosed in the neonatal period with bilateral corneal opacification due to primary endothelial cell dysfunction. Neither his parents nor his sister had signs of corneal disease. Conventional karyotyping revealed a de novo translocation involving chromosomes 3 and 20, t(3;20)(q25;p11-12). Following genome and targeted Sanger sequencing analysis, the breakpoints were mapped at the nucleotide level. Notably, the breakpoint on chromosome 20 was identified to lie within the same topologically associated domain (TAD) as corneal endothelial dystrophy-associated gene OVOL2, and it is predicted to disrupt distal enhancers. The breakpoint at chromosome 3 is located within intron 2 of PFN2, which is currently not associated with any human disease. Further interrogation of the proband's genome failed to identify any additional potentially pathogenic variants in corneal endothelial dystrophy-associated genes. Disruption of a candidate cis-regulatory element and/or positional effects induced by translocation of OVOL2 to a novel genomic context may lead to an aberrant OVOL2 expression, a previously characterized disease mechanism of corneal endothelial dystrophy. Further research is necessary to explore how disruption of regulatory elements may elucidate genetically unsolved corneal endothelial dystrophies.

• MeSH
• Corneal Dystrophies, Hereditary * genetics   diagnosis   MeSH
• Genetic Predisposition to Disease MeSH
• Humans MeSH
• Chromosomes, Human, Pair 3 genetics   MeSH
• Infant, Newborn MeSH
• Regulatory Sequences, Nucleic Acid * MeSH
• Pedigree MeSH
• Transcription Factors * genetics   MeSH
• Translocation, Genetic MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Ovol2 protein, human MeSH Browser
• Transcription Factors * MeSH

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.

• Keywords
• FOXC1, anterior segment dysgenesis, corneal dystrophy, corneal endothelium, keratometry,
• Publication type
• Journal Article MeSH

The aim of this study was to describe the ocular phenotype in a case with Kearns-Sayre syndrome (KSS) spectrum and to determine if corneal endothelial cell dysfunction could be attributed to other known distinct genetic causes. Herein, genomic DNA was extracted from blood and exome sequencing was performed. Non-coding gene regions implicated in corneal endothelial dystrophies were screened by Sanger sequencing. In addition, a repeat expansion situated within an intron of TCF4 (termed CTG18.1) was genotyped using the short tandem repeat assay. The diagnosis of KSS spectrum was based on the presence of ptosis, chronic progressive external ophthalmoplegia, pigmentary retinopathy, hearing loss, and muscle weakness, which were further supported by the detection of ~6.5 kb mtDNA deletion. At the age of 33 years, the proband's best corrected visual acuity was reduced to 0.04 in the right eye and 0.2 in the left eye. Rare ocular findings included marked corneal oedema with central corneal thickness of 824 and 844 µm in the right and left eye, respectively. No pathogenic variants in the genes, which are associated with corneal endothelial dystrophies, were identified. Furthermore, the CTG18.1 genotype was 12/33, which exceeds a previously determined critical threshold for toxic RNA foci appearance in corneal endothelial cells.

• Keywords
• CTG18.1, Kearns-Sayre syndrome, TCF4, corneal dystrophy, corneal endothelium, endothelial failure, exome sequencing,
• MeSH
• Adult MeSH
• Phenotype MeSH
• Fuchs' Endothelial Dystrophy pathology   MeSH
• Genotype MeSH
• Cataract genetics   MeSH
• Kearns-Sayre Syndrome genetics   MeSH
• Humans MeSH
• DNA, Mitochondrial MeSH
• Endothelium, Corneal pathology   physiopathology   MeSH
• Sequence Deletion MeSH
• Exome Sequencing MeSH
• Transcription Factor 4 genetics   MeSH
• Trinucleotide Repeats * MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA, Mitochondrial MeSH
• TCF4 protein, human MeSH Browser
• Transcription Factor 4 MeSH

ZEB1 loss-of-function (LoF) alleles are known to cause a rare autosomal dominant disorder-posterior polymorphous corneal dystrophy type 3 (PPCD3). To date, 50 pathogenic LoF variants have been identified as disease-causing and familial studies have indicated that the PPCD3 phenotype is penetrant in approximately 95% of carriers. In this study, we interrogated in-house exomes (n = 3616) and genomes (n = 88) for the presence of putative heterozygous LoF variants in ZEB1. Next, we performed detailed phenotyping in a father and his son who carried a novel LoF c.1279C>T; p.(Glu427*) variant in ZEB1 (NM_030751.6) absent from the gnomAD v.2.1.1 dataset. Ocular examination of the two subjects did not show any abnormalities characteristic of PPCD3. GnomAD (n = 141,456 subjects) was also interrogated for LoF ZEB1 variants, notably 8 distinct heterozygous changes presumed to lead to ZEB1 haploinsufficiency, not reported to be associated with PPCD3, have been identified. The NM_030751.6 transcript has a pLI score ≥ 0.99, indicating extreme intolerance to haploinsufficiency. In conclusion, ZEB1 LoF variants are present in a general population at an extremely low frequency. As PPCD3 can be asymptomatic, the true penetrance of ZEB1 LoF variants remains currently unknown but is likely to be lower than estimated by the familial led approaches adopted to date.

• Keywords
• ZEB1, cornea, loss-of-function, penetrance,
• MeSH
• Corneal Dystrophies, Hereditary genetics   pathology   MeSH
• Haploinsufficiency MeSH
• Heterozygote MeSH
• Cells, Cultured MeSH
• Middle Aged MeSH
• Humans MeSH
• Loss of Function Mutation * MeSH
• Penetrance * MeSH
• Pedigree MeSH
• Zinc Finger E-box-Binding Homeobox 1 genetics   metabolism   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Zinc Finger E-box-Binding Homeobox 1 MeSH
• ZEB1 protein, human MeSH Browser

Name of the disease (synonyms) CUGC for posterior polymorphous corneal dystrophy (PPCD).OMIM# of the disease 122000; 609141; 618031.Name of the analysed genes or DNA/chromosome segments OVOL2 (PPCD1); ZEB1 (PPCD3); GRHL2 (PPCD4).OMIM# of the gene(s) 616441; 189909; 608576. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for variants in theOVOL2, ZEB1andGRHL2gene(s) in a diagnostic setting, predictive and parental settings and for risk assesment in relatives.

• MeSH
• Corneal Dystrophies, Hereditary diagnosis   genetics   MeSH
• DNA-Binding Proteins genetics   MeSH
• Genetic Testing methods   standards   MeSH
• Humans MeSH
• Sensitivity and Specificity MeSH
• Practice Guidelines as Topic MeSH
• Zinc Finger E-box-Binding Homeobox 1 genetics   MeSH
• Transcription Factors genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA-Binding Proteins MeSH
• GRHL2 protein, human MeSH Browser
• Ovol2 protein, human MeSH Browser
• Zinc Finger E-box-Binding Homeobox 1 MeSH
• Transcription Factors MeSH
• ZEB1 protein, human MeSH Browser