Identification of a New Locus for Isolated Familial Keratoconus at 2p24

Abstract

Abstract: : Purpose: Keratoconus (KC; MIM #148300), a progressive blinding disorder of the cornea, is the leading cause of corneal transplantation in developed countries. The prevalence of KC is 1–4/2000 in the general population and at least 10% of these cases have positive family history. This aim of this work is to localize and identify the first causal gene for keratoconus. Methods: We performed genome–wide linkage analysis on 7 keratoconus pedigrees with 382 highly polymorphic microsatellite markers spaced over the whole genome at approximately 10 cM intervals. Chromosome 2 locus refinement was then performed on a larger set of 28 pedigrees. LOD scores were calculated using Merlin and Genehunter algorithms. Results: Evidence of linkage (multipoint nonparametric LOD score = 3.26) was obtained at marker D2S305. Genetic heterogeneity was apparent and a maximum HLOD of 5.13 was attained with α = 0.52 using an autosomal dominant model with incomplete penetrance. Analysis of critical recombinants mapped the KC locus between markers D2S305 and D2S2373 to two small intervals (respectively 0.4 Mb and 0.5 Mb) for which haplotypes in 17 out the 28 families studied segregated together with the KC phenotype. Conclusions: We report the assignment of a KC gene (implicated in 50–60% of familial KC cases studied) to 2p24. This study reports the first genome–wide scan in an outbred population (Caucasoid, Arab and Caribbean African) and is the first step to the positional cloning of a KC gene.

Keywords: keratoconus • genetics • linkage analysis