Evidence against ZNF469 being causative for keratoconus in Polish patients

Abstract

Purpose: Keratoconus (KTCN) is a degenerative disorder characterized by stromal thinning and protrusion of the cornea, resulting in severe impairment of visual function. A recent study proposed that rare heterozygous mutations in ZNF469 determine KTCN aetiology.

Methods: To investigate the contribution of ZNF469 to KTCN, we Sanger sequenced ZNF469 in 42 unrelated Polish patients with KTCN and 49 Polish individuals with high myopia (HM) and compared the results with whole-exome sequencing (WES) data performed in 268 Polish individuals without ocular abnormalities.

Results: The average number of ZNF469 non-synonymous variants was 16.31 and 16.0 for individuals with KTCN and HM, respectively (p = 0.3724). All identified variants were previously reported. Alternative allele frequency (AAF) was determined based on the WES results. Among missense variants, only one (rs528085780) has AAF ≤ 0.001 and was identified in one patient with sporadic KTCN. However, the resulting Arg1864Lys substitution was not predicted to be deleterious.

Conclusion: In summary, we have not found a significant enrichment of sequence variants in ZNF469 in Polish patients with KTCN. High prevalence of ZNF469 variants identified in our KTCN group is typical for a common genetic variation observed in general population. Our findings indicate that variation in ZNF469 is not responsible for KTCN and other genetic variants are involved in the development and progression of this disease in Polish patients.

Keywords: Sanger sequencing; ZNF469; keratoconus; keratoconus genetics; whole-exome sequencing.