The keratoconus with cataract locus on chromosome 15q was identified in a large Northern Irish family of three gen- erations affected by combined autosomal dominant early on- set anterior polar cataract and clinically severe keratoconus

Keratoconus (KC; OMIM 148300), the most common corneal dystrophy, is a bilateral, noninflammatory progressive corneal ectasia. Clinically, the cornea becomes progressively thin and conical which leads to myopia, irregular astigmatism, and corneal scarring. The transparency and refractive state of the cornea is a prerequisite for normal vision. The disease usually arises in the teenage years, eventually stabilizing in the third and fourth decades [1]. It occurs with no ethnic or gender preponderance and causes significant visual impairment in young adults. No specific treatment exists except to replace the corneal tissue by surgery (corneal transplantation) when the visual acuity can no longer be corrected by contact lenses. In the Western world, KC is the most common indication for corneal transplantation [2]. The underlying biochemical processes and pathobiology of keratoconus remain poorly understood. The incidence of KC is 1 in 2,000 in the general population [1,3]. A family history is present only in a minority of cases, however, one of the major etiological factors is genetic [1,4-6]. KC is believed to be inherited autosomally, because of familial occurrence [7], a higher concordance rate of the trait in monozygotic twins then dizygotic twins [8] and its prevalence in first degree relatives is 15-67 times higher than the general population [6]. Most studies describe autosomal dominant inheritance, with incomplete penetrance or variable expressivity [1,9,10]. Mutations in the VSX-1 transcription factor (OMIM 605020) were identified in 4.7% of patients with keratoconus (KTCN1; OMIM 148300) and also in posterior polymorphous corneal dystrophy (PPCD1; OMIM 122000) [11]. However, traditional mapping methods to identify the genetic basis of KC have been limited by the lack of large multigeneration families for study. Genome-wide scans to localize the KC gene or genes had not been reported until our group identified a large three-generation family with KC and anterior polar cataract and reported linkage to chromosome 15q22.32-24.2 [12]. Recently loci for autosomal dominantly inherited keratoconus have been mapped to chromosomes 21 [13], 16q22.3-q23.1 (KTCN2; OMIM 608932) [10], 3p14-q13 (KTCN3; OMIM 608586) [14], 2p24 (KTCN4; OMIM 609271) [15] and 5q14.1q21.3 (NCBI). The keratoconus with cataract locus on chromosome 15q was identified in a large Northern Irish family of three generations affected by combined autosomal dominant early onset anterior polar cataract and clinically severe keratoconus [12]. The disease gene in this family was successfully mapped to chromosome 15q22.32-24.2 within a 6.5 Mb region flanked by markers CYP11A and D15S211 [12]. CTSH, CRABP1, IREB2, and RASGRF1 were excluded previously as the causative gene for keratoconus with cataract [12]. The purpose of the present study was to narrow the critical region of linkage of keratoconus with cataract by genotyping novel microsatellite markers and single nucleotide polymorphisms identified during sequencing of candidate genes. Fine mapping of a keratoconus with cataract locus on 15q has reduced the linked region to 5.5 Mb, thereby excluding 28 potential candidate genes. A further 23 positional candidate genes were prioritized for ©2006 Molecular Vision