Research Highlight Heterozygous Coding ZNF469 Variants Enriched in New Zealand Patients With Isolated Keratoconus Elfride De Baere Center for Medical Genetics, Ghent University, Ghent, Belgium; [email protected] 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 ¼ 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. References 1. Lu Y, Dimasi DP, Hysi PG, et al. Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 influence the blinding disease risk factor central corneal thickness. PLoS Genet. 2010;13:e1000947. 2. LuY, Vitart V, Burdon KP, et al. Genome-wide association analysesidentify multiple loci associated with central corneal thickness and keratoconus. Nat Genet. 2013;45:155–163. 3. Abu A, Frydman M, Marek D, et al. Deleterious mutations in the zinc-finger 469 gene cause Brittle Cornea Syndrome. Am J Hum Genet. 2008;82:1217–1222. 4. Vincent AL, Jordan CA, Cadzow MJ, Merriman TR, McGhee CN. Mutations in the zinc finger protein gene, ZNF469, contribute to the pathogenesis of keratoconus. Invest Ophthalmol Vis Sci. 2014;55:5629–5635. 5. Lechner J, Porter LF, Rice A, et al. Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus [published online ahead of print June 3, 2014]. Hum Mol Genet. doi:10.1093/hmg/ddu253. DOI: 10.1167/iovs.14-15486 Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc. www.iovs.org j ISSN: 1552-5783 5636

Heterozygous Coding ZNF469 Variants Enriched in New Zealand Patients With Isolated Keratoconus

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Research Highlight

Heterozygous Coding ZNF469 Variants Enriched in NewZealand Patients With Isolated Keratoconus

Elfride De Baere

Center for Medical Genetics, Ghent University, Ghent, Belgium; [email protected]

Keratoconus (Online Mendelian Inheritance of Man [MIM] 148300) is a common bilateral ocular disease characterized byprogressive corneal thinning and ectasia. The progressive corneal thinning (mean central corneal thickness [CCT]) results inmyopia and corneal astigmatism. Genome-wide association studies (GWAS) in different populations have showed that commonnoncoding 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 autosomalrecessive connective tissue disease associated with abnormal thin corneas.3 Since homozygous ZNF469 mutations result in acorneal 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, thecoding regions of ZNF469 were investigated in 43 patients from New Zealand (one-half of which are Maori or Polynesian) withisolated keratoconus. Potentially pathogenic missense variants were found in 23% of this population. Interestingly, the currentstudy converges well with a recent study by Lechner et al.5 revealing heterozygous coding variants in ZNF469 in 12.5% of threeEuropean cohorts with isolated keratoconus (two from the United Kingdom, and one from Switzerland, respectively), representinga significant enrichment of ZNF469 heterozygous alleles (P¼0.00102). 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 geneticfactors contributing to the pathogenesis of keratoconus.

References

1. Lu Y, Dimasi DP, Hysi PG, et al. Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 influence the blinding diseaserisk factor central corneal thickness. PLoS Genet. 2010;13:e1000947.

2. Lu Y, Vitart V, Burdon KP, et al. Genome-wide association analyses identify multiple loci associated with central corneal thickness andkeratoconus. Nat Genet. 2013;45:155–163.

3. Abu A, Frydman M, Marek D, et al. Deleterious mutations in the zinc-finger 469 gene cause Brittle Cornea Syndrome. Am J Hum Genet.2008;82:1217–1222.

4. Vincent AL, Jordan CA, Cadzow MJ, Merriman TR, McGhee CN. Mutations in the zinc finger protein gene, ZNF469, contribute to thepathogenesis of keratoconus. Invest Ophthalmol Vis Sci. 2014;55:5629–5635.

5. Lechner J, Porter LF, Rice A, et al. Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus [published onlineahead of print June 3, 2014]. Hum Mol Genet. doi:10.1093/hmg/ddu253.

DOI: 10.1167/iovs.14-15486

www.iovs.org j ISSN: 1552-5783 5636

http://dx.doi.org/10.1167/iovs.14-14532