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.

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Figures

Figure 1.

Corneal topography of the 28-year-old European patient from the UK with a c.3119A > C (p.Lys1040Thr) ZNF469 pathogenic allele (Table 1) using Pentacam corneal topography; OD indicates right eye and OS left eye. The topography shows the anterior corneal steepening associated with keratoconus with a large cone centrally in the right eye and paracentrally in the left eye associated with corneal thinning underlying the cones; minimum corneal thickness of 318 µm (OD) and 438 µm (OS). The keratoconus is Stage III in both eyes (Amsler–Krumeich classification) with a best corrected Snellen acuity of 6/36 right and 6/24 left. The patient subsequently underwent a deep anterior lamellar keratoplasty (corneal transplant) in the right eye.

Figure 2.

Hierarchical flow diagram of filtering process performed on sequence variants identified in ZNF469 in keratoconus cohort by Sanger sequencing.