Mutational Founder Effects Associated to Conserved Haplotypes Revealed by RP Cosegregation Chip

Abstract

Purpose: : Retinitis Pigmentosa (RP), the major cause for blindness in the adults, is an extremely heterogeneous monogenic disorder that shows all mendelian types of inheritance. The high number of RP candidates (with no major gene neither mutation sites) makes conventional mutational screening time-consuming and costly for a small/medium sized laboratory. We previously designed a high-throughput strategy for cosegregation analysis with SNPs closely located to the RP genes. We have used this chip for the identification of common haplotypes in RP families from the same geographical region.

Methods: : This innovative high-throughput strategy genotypes 240 SNPs, covering 40 genes responsible for RP and LCA. We analysed a pannel of autosomal dominant and recessive Spanish families and constructed the cosegregating haplotypes.

Results: : After a single and fast genotyping step, we focused on the candidate genes that cosegregated with the disease. In one large family, all but one gene were discarded. Direct mutational screening revealed a novel pathogenic nonsense mutation, together with the associated haplotype. Analysis of two small families cosegregating with the same gene allowed us to identify a shared haplotype, suggestive of a mutational founder effect. This hypothesis was subsequently verified by direct sequencing.

Conclusions: : Our RP cosegregation chip has been shown to be rapid, efficient and cost-effective. Moreover, it highlights the haplotypes associated to pathogenic mutations, and therefore, becomes a powerful tool in identifying mutational founder effects.

Keywords: retinitis • gene microarray • gene screening