Identification of a new locus for isolated familial keratoconus at 2p24.

K eratoconus (KC; MIM 148300) is a non-inflammatory corneal thinning disorder. Progressive thinning and protrusion of the cornea lead to loss of visual acuity for which the only effective treatment is corneal transplantation. The estimated prevalence of KC is 1–4 per 2000 in the general population. The age of onset is often at puberty, and the disorder is progressive until the third or fourth decade of life when it usually arrests. KC is a major cause of corneal transplantation in developed countries. The cause of KC is still unknown. Histological observations have demonstrated degradation of the corneal epithelium basal membrane, diminution of the number of collagen fibrils, thinning of the corneal stroma, and keratocyte apoptosis. 3 Biochemical studies describe increased activity of metalloproteinases (MMP-2 and MMP-9) and lower expression of protease inhibitors such as a1-protease inhibitor. 5 Sporadic KC is the most common presentation; however, a positive familial history has been reported in at least 6–10% of patients. Twin studies performed since the advent of modern computerised videokeratoscopy have reported four monozygotic pairs concordant for KC and two monozygotic pairs which were discordant, suggesting a genetic component for KC. Keratoconus prevalence in first degree relatives of KC patients is significantly higher than in the general population, demonstrating familial aggregation of the trait. 11 Most published studies have suggested autosomal dominant inheritance of KC with incomplete penetrance or variable expression. 12 Autosomal recessive inheritance as well as rare cases of X linked inheritance have also been described. 13 In some rare cases, KC is associated with other genetic disorders such as trisomy 21, atopy, and Leber congenital amaurosis. 15 KC gene localisation efforts to date have been carried out in rare large families or in population isolates where genetic heterogeneity is minimised. Linkage studies include a genome scan of 20 Finnish families resulting in a multipoint LOD score of 4.1 on chromosome 16q, and a directed chromosome 21 scan in one large family with trisomy 21 leading to suggestive linkage. Association studies in eight unrelated patients in Tasmania have identified two putative loci on 18p and 20q12. 19 However, these results have not yet led to the identification of a causative gene for familial KC and, although KC is present in all human populations, no studies have tested for linkage in a mixed outbred population. In the present article, we identify a new candidate region at 2p24 mapped by linkage and haplotype analysis in a heterogeneous population.