Demonstration of Linkage Disequilibrium and Exclusion of Positional Candidate Gene Coding Region Mutations in the Common Posterior Polymorphous Corneal Dystrophy 1 Candidate Gene Interval

Abstract

Purpose: : Posterior polymorphous corneal dystrophy (PPCD1) is an autosomal dominant disorder of the corneal endothelium associated with visually significant corneal edema and glaucoma. Linkage analysis in four families with PPCD1 has demonstrated linkage to a 2.4 cM common support interval bordered by the markers D20S182 and D20S139. We sought to identify the genetic basis of PPCD1 thorough screening of the 20 positional candidate genes between these markers in the fourth PPCD1 family mapped to this interval.

Methods: : The coding regions of the 20 positional candidate genes mapped to the common PPCD1 support interval were amplified and sequenced in 11 affected and 11 unaffected individuals from a family previously linked to the PPCD1 locus. Seven other genes positioned just outside of the common PPCD1 support interval but within the autosomal dominant congenital hereditary endothelial dystrophy (CHED1) interval were also screened.

Results: : Four DNA sequence variants in three of the positional candidate genes demonstrated complete segregation with the affected phenotype: p.Thr109Thr (rs6111803) in OVOL2, p.Arg56Gln in RPS19P1, and p.Thr85Thr (rs1053834) and p.Pro99Ser (rs1053839) in C20orf79. While three of the identified sequence variants are known SNPs, p.Arg56Gln is a novel variant, although it was identified in 9/56 unaffected control individuals. Each of these four sequence variants demonstrated significant association with the PPCD1 disease allele in this family (p-value 0.00018 for p.Arg56Gln, rs1053834 and rs1053839; p-value 0.00023 for rs611803). While a number of other previously described and novel SNPs were identified in the 27 positional candidate genes located within the PPCD1 and CHED1 intervals, none segregated with the affected phenotype.

Conclusions: : We report the distorted transmission of four SNPs in the common support interval for PPCD1, providing the initial evidence of linkage disequilibrium with the PPCD1 disease allele and further support for the localization of the pathogenic mutation in the family we report to the refined PPCD1 locus.

Keywords: gene screening • cornea: endothelium • degenerations/dystrophies