Brittle cornea syndrome ZNF469 mutation carrier phenotype and segregation analysis of rare ZNF469 variants in familial keratoconus
Language English Country United States Media electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25564447
DOI
10.1167/iovs.14-15792
PII: iovs.14-15792
Knihovny.cz E-resources
- Keywords
- ZNF469, brittle cornea syndrome, familial keratoconus, keratoconus,
- MeSH
- Eye Abnormalities MeSH
- Adult MeSH
- Ehlers-Danlos Syndrome genetics pathology MeSH
- Phenotype MeSH
- Heterozygote MeSH
- Polymorphism, Single Nucleotide MeSH
- Keratoconus genetics pathology MeSH
- Skin Abnormalities MeSH
- Humans MeSH
- Young Adult MeSH
- Mutation * MeSH
- DNA Mutational Analysis MeSH
- Joint Instability congenital MeSH
- Polymerase Chain Reaction MeSH
- Pedigree MeSH
- Corneal Topography MeSH
- Transcription Factors genetics MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Transcription Factors MeSH
- ZNF469 protein, human MeSH Browser
PURPOSE: Brittle cornea syndrome 1 (BCS1) is a rare recessive condition characterized by extreme thinning of the cornea and sclera, caused by mutations in ZNF469. Keratoconus is a relatively common disease characterized by progressive thinning and ectasia of the cornea. The etiology of keratoconus is complex and not yet understood, but rare ZNF469 variants have recently been associated with disease. We investigated the phenotype of BCS1 carriers with known pathogenic ZNF469 mutations, and recruited families in which aggregation of keratoconus was observed to establish if rare variants in ZNF469 segregated with disease. METHODS: Patients and family members were recruited and underwent comprehensive anterior segment examination, including corneal topography. Blood samples were donated and genomic DNA was extracted. The coding sequence and splice sites of ZNF469 were PCR amplified and Sanger sequenced. RESULTS: Four carriers of three BCS1-associated ZNF469 loss-of-function mutations (p.[Glu1392Ter], p.[Gln1930Argfs*6], p.[Gln1930fs*133]) were examined and none had keratoconus. One carrier had partially penetrant features of BCS1, including joint hypermobility. ZNF469 sequencing in 11 keratoconus families identified 9 rare (minor allele frequency [MAF] ≤ 0.025) variants predicted to be potentially damaging. However, in each instance the rare variant(s) identified, including two previously reported as potentially keratoconus-associated, did not segregate with the disease. CONCLUSIONS: The presence of heterozygous loss-of-function alleles in the ZNF469 gene did not cause keratoconus in the individuals examined. None of the rare nonsynonymous ZNF469 variants identified in the familial cohort conferred a high risk of keratoconus; therefore, genetic variants contributing to disease pathogenesis in these 11 families remain to be identified.
Department of Genetics King Faisal Specialist Hospital and Research Center Riyadh Saudi Arabia
Moorfields Eye Hospital Al Razi Building Dubai Healthcare City Dubai United Arab Emirates
Moorfields Eye Hospital London United Kingdom
UCL Genetics Institute London United Kingdom
UCL Institute of Ophthalmology London United Kingdom
UCL Institute of Ophthalmology London United Kingdom Moorfields Eye Hospital London United Kingdom
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