Lechner, J, Porter, LF, Rice, A et al. (10 more authors) (2014) Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus. Human Molecular Genetics, 23 (20). 5527 - 5535. ISSN 0964-6906
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) The Author 2014. Published by Oxford University Press. All rights reserved. This is a pre-copyedited, author-produced PDF of an article accepted for publication in Human Molecualr Genetics following peer review. The version of record Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus, Hum. Mol. Genet. (2014) 23 (20): 5527-5535 is available online at: http://dx.doi.org/10.1093/hmg/ddu253. |
Keywords: | DNA-Binding Proteins; Ehlers-Danlos Syndrome; Genetic Association Studies; Heterozygote; Homozygote; Humans; Keratoconus; Mutation; Polymorphism, Single Nucleotide; Transcription Factors |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Biomed & Clin Sciences (LIBACS) (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 27 Jul 2015 10:47 |
Last Modified: | 16 Jan 2018 17:13 |
Published Version: | http://dx.doi.org/10.1093/hmg/ddu253 |
Status: | Published |
Publisher: | Oxford University Press |
Identification Number: | 10.1093/hmg/ddu253 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:87454 |