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Alice Davidson, Edmondo Borasio, Valentina Cipriani, Petra Liskova, Vincent Plagnol, Stephen J Tuft, Alison J Hardcastle; Identification and segregation analysis of rare ZNF469 coding variants in familial Keratoconus. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6412.
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© ARVO (1962-2015); The Authors (2016-present)
Keratoconus is a bilateral condition characterized by progressive corneal thinning and ectasia. It is hypothesised to result from a combination of environmental and genetic factors. The majority of patients present as isolated cases, although familial aggregation has been observed indicating a strong genetic contribution to disease. Brittle cornea syndrome 1, an autosomal recessive connective tissue disorder associated with extreme corneal thinning, is caused by bi-allelic mutations in ZNF469. Several genome-wide association studies have highlighted that common variants located near ZNF469 are associated with central corneal thickness and more recently with KC. In this study we collected a cohort of patients in which familial aggregation of KC was observed, indicating that genetic variants of large or moderate effect may contribute to disease, and investigated whether rare coding and splice site variants in ZNF469 are associated with disease.
Patients with KC and available family members were recruited and underwent a comprehensive anterior segment examination including corneal topography. In the majority of cases corneal scans were examined by two or more experienced ophthalmologists. Blood samples were donated and genomic DNA was extracted. The coding sequence and flanking splice sites of ZNF469 were PCR amplified and Sanger sequenced. In total, 42 affected and 24 unaffected individuals from 11 families of varied ethnicities, each consisting of two or more affected members, were analysed.
In total, we identified rare (minor allele frequency <0.01) ZNF469 variants in 19/42 affected members. Due to the familial aggregation of KC in our selected cohort we were able to test each variant for segregation with disease. In each instance the rare variant(s) identified did not segregate with disease.
We observed a number of rare coding or splice site ZNF469 variants in our familial KC cohort at higher than expected population frequency. However, in each instance the observed sequence change(s) failed to segregate with disease. The rare ZNF469 variants identified may contribute to mutational load, but segregation analysis demonstrates the complexity of KC etiology and suggests that each rare variant identified cannot in isolation be considered causative of disease.
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