title: Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus.
abstract: Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to date.
authors.affiliation: Centre for Vision and Vascular Science, Queen's University Belfast, Belfast BT12 6BA, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Lechner
authors.affiliation: Institute of Human Development, The University of Manchester, Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WU, UK.
authors.forename: Louise F
authors.initials: LF
authors.lastname: Porter
authors.affiliation: Leeds Institute of Molecular Medicine, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Aine
authors.initials: A
authors.lastname: Rice
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.affiliation: Department of Ophthalmology, Royal Victoria Hospital, Belfast BT12 6BA, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Armstrong
authors.affiliation: IRO - Institute for Research in Ophthalmology, Sion, Switzerland Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
authors.affiliation: IRO - Institute for Research in Ophthalmology, Sion, Switzerland Jules-Gonin Eye Hospital, Lausanne, Switzerland.
authors.forename: Francis L
authors.initials: FL
authors.lastname: Munier
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.affiliation: Leeds Institute of Molecular Medicine, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
authors.affiliation: Institute of Human Development, The University of Manchester, Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WU, UK.
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Black
authors.affiliation: Centre for Vision and Vascular Science, Queen's University Belfast, Belfast BT12 6BA, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Simpson
authors.affiliation: Institute of Human Development, The University of Manchester, Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WU, UK.
authors.forename: Forbes
authors.initials: F
authors.lastname: Manson
authors.affiliation: Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L69 3GA, UK c.willoughby@liverpool.ac.uk.
authors.forename: Colin E
authors.initials: CE
authors.lastname: Willoughby
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics; D004535:Ehlers-Danlos Syndrome / Q000235:genetics / Q000473:pathology; D005124:Eye Abnormalities; D056726:Genetic Association Studies; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007593:Joint Instability / Q000151:congenital; D007640:Keratoconus / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012868:Skin Abnormalities; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C487762:PRDM5 protein, human; D014157:Transcription Factors; C530065:ZNF469 protein, human