title: Brittle cornea syndrome ZNF469 mutation carrier phenotype and segregation analysis of rare ZNF469 variants in familial keratoconus.
abstract: OBJECTIVE
  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.
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Alice E
authors.initials: AE
authors.lastname: Davidson
authors.affiliation: Moorfields Eye Hospital, Al Razi Building, Dubai Healthcare City, Dubai, United Arab Emirates.
authors.forename: Edmondo
authors.initials: E
authors.lastname: Borasio
authors.affiliation: Moorfields Eye Hospital, London, United Kingdom Institute of Inherited Metabolic Diseases and First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Liskova
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Arif O
authors.initials: AO
authors.lastname: Khan
authors.affiliation: Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Hala
authors.initials: H
authors.lastname: Hassan
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.affiliation: UCL Genetics Institute, London, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tuft
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hardcastle
mesh_terms: D000328:Adult; D019781:Corneal Topography; D004252:DNA Mutational Analysis; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000473:pathology; D005124:Eye Abnormalities; D005260:Female; D006579:Heterozygote; D006801:Humans; D007593:Joint Instability / Q000151:congenital; D007640:Keratoconus / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012868:Skin Abnormalities; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: D014157:Transcription Factors; C530065:ZNF469 protein, human
keywords: ZNF469; brittle cornea syndrome; familial keratoconus; keratoconus