Genomewide linkage scan in a multigeneration Caucasian pedigree identifies a novel locus for keratoconus on chromosome 5q14.3-q21.1

Purpose: Keratoconus is a corneal dystrophy with an incidence of 1 in 2000 and a leading cause for cornea transplantation in Western developed countries. Both clinical observations and segregation analyses suggest a major role for genes in its pathogenesis. It is genetically heterogenous, most commonly sporadic, but inherited patterns with recessive or dominant modes have also been reported. We studied a four-generation autosomaldominant pedigree to identify disease loci for keratoconus. Methods: A two-stage genome-wide scan was applied to 27 family members. First linkage analysis was performed with 343 microsatellite markers along the 22 autosomal chromosomes at Ϸ10 cM density. This was followed by fine mapping at Ϸ2 cM density, in regions suggestive of linkage. Multipoint linkage analysis was performed using GeneHunter2. Results: Evidence of suggestive linkage from the initial scan was observed at the 82 to 112 cM region of chromosome 5q14.1-q21.3 with a maximum lod score (LOD) of 3.48 (penetrance ϭ 0.5). Fine mapping by testing an additional 11 microsatellite markers at 1 to 3 cM intervals revealed a narrower and higher peak (99 -119 cM) with LOD 3.53. By analysis of the recombination of haplotypes, the putative locus of keratoconus was further narrowed to a 6 cM region (8