A New Locus for Autosomal Recessive Sclerocornea on Chromosome 1q

Abstract

Purpose: : Sclerocornea is a nonprogressive, noninflammatory sclerization of the cornea either limited to the corneal periphery or involving the entire cornea. The limbus is ill defined and superficial vessels that are extensions of normal sclera, episcleral and conjunctival vessels cross the cornea. Most cases appear sporadically, although pedigrees showing autosomal dominant and recessive patterns of inheritance have been described. The purpose of this study was to look at a recessive pedigree with sclerocornea and to investigate the underlying genetic abnormality.

Methods: : We investigated a recessive pedigree from Pakistan in which individuals from five nuclear families connected by multiple consanguineous loops were affected by congenital sclerocornea. Phenotype consisted of absence of corneal limbus/normal sized eye and fitted with a diagnosis of sclerocornea. Following informed consent and ethical approval all the family members underwent ophthalmic examinations.

Results: : In a consanguineous family, regions of homozygosity shared between affected individuals point to the gene involved. A mixed sample containing DNA from five affected individuals was therefore analysed on a single Affymetrix SNP array. Homozygosity was highlighted on chromosomes 1, 12 and 17. Microsatellite markers on chromosome 1 gave a LOD score greater than 4 between markers D1S255 and D1S2652, defining an 18cM interval within which the gene and mutation must lie. Literature review found a phenotype which was similar but not identical, associated with a single mutation in the FOXE3 gene on chromosome 1 (Valleix et al 2006, Am J Hum Genet 79:58-364). Sequencing of this strong candidate gene is now underway. In addition we are investigating differences between the phenotype described herein and that of the published FOXE3 family, in particular to determine whether individuals in the Pakistani family are aphakic.

Conclusions: : This is the first locus for recessively inherited sclerocornea, identifying a new form of the disease mapping on chromosome 1. This clarifies the risk to other family members and could highlight genotype/phenotype correlations that are of predictive value in prioritising genes for screening in similar families.

Keywords: genetics • cornea: epithelium • cornea: stroma and keratocytes