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 Willoughby

    Research output: Contribution to journalArticlepeer-review

    53 Citations (Scopus)
    45 Downloads (Pure)


    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
    Issue number20
    Publication statusAccepted/In press - 19 May 2014


    • keratoconus
    • genetics
    • brittle cornea syndrome
    • ZNF469


    Dive into the research topics of 'Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus'. Together they form a unique fingerprint.

    Cite this