Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus

Judith Lechner, Louise F Porter, Aine Rice, Veronique Vitart, David J Armstrong, Daniel F Schorderet, Francis L Munier, Alan F Wright, Chris F Inglehearn, Graeme C Black, David A Simpson, Forbes Manson, Colin E Willoughby

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)5527–5535
JournalHuman Molecular Genetics
Volume23
Issue number20
Early online date03 Jun 2014
DOIs
Publication statusPublished - 15 Oct 2014

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