Keratoconus (Online Mendelian Inheritance of Man [MIM] 148300) is a common bilateral ocular disease characterized by progressive corneal thinning and ectasia. The progressive corneal thinning (mean central corneal thickness [CCT]) results in myopia and corneal astigmatism. Genome-wide association studies (GWAS) in different populations have showed that common noncoding single nucleotide polymorphisms (SNPs) of zinc finger 469 (
ZNF469 [MIM 612078]) are strongly associated with CCT.
1,2 Moreover homozygous mutations in
ZNF469 lead to brittle cornea syndrome type 1 (BCS1 [MIM 229200]), a rare autosomal recessive connective tissue disease associated with abnormal thin corneas.
3 Since homozygous
ZNF469 mutations result in a corneal thinning disorder, and since common SNPs 100-kb upstream of
ZNF469 are strongly associated with CCT,
Vincent et al.
4 hypothesized that heterozygous variants in
ZNF469 might predispose to the development of isolated keratoconus. Therefore, the coding regions of
ZNF469 were investigated in 43 patients from New Zealand (one-half of which are Maori or Polynesian) with isolated keratoconus. Potentially pathogenic missense variants were found in 23% of this population. Interestingly, the current study converges well with a recent study by Lechner et al.
5 revealing heterozygous coding variants in
ZNF469 in 12.5% of three European cohorts with isolated keratoconus (two from the United Kingdom, and one from Switzerland, respectively), representing a significant enrichment of
ZNF469 heterozygous alleles (
P = 0.00102). In conclusion, the enrichment of rare mutations in
ZNF469 in a New Zealand population with keratoconus uncovers, for the first time, coding
ZNF469 alleles as potentially important genetic factors contributing to the pathogenesis of keratoconus.