Molecular characterisation of congenital glaucoma in a consanguineous Canadian community: a step towards preventing glaucoma related blindness

Glaucoma is a leading cause of irreversible blindness in Canada. Congenital glaucoma usually manifests during the first years of life and is character ised by severe visual loss and autosomal recessive inheritance. Two disease loci, on chromosomes 1p36 and 2p21, have been associated with various form s of congenital glaucoma. A branch of a large six generation family from a consanguineous Amish community in south western Ontario was affected with c ongenital glaucoma and was studied by linkage and mutational analysis to id entify the glaucoma related genetic defects. Linkage analysis using the MLI NK component of the LINKAGE package (v 5.1) showed evidence of linkage to t he 2p21 region (Zmax=3.34, 0=0, D2S1348 and D2S1346). Mutational analysis o f the primary candidate gene, CYP1B1, was done by direct cycle sequencing, dideoxy fingerprinting analysis, and fragment analysis. Two different disea se causing mutations in exon 3, 1410del13 and 1505G --> A, both segregated with the disease phenotype. The two different combinations of these alleles appeared to result in a variable expressivity of the phenotype. The compou nd heterozygote appeared to have a milder phenotype when compared to the ho mozygotes for the 13 bp deletion. The congenital glaucoma phenotype for thi s large inbred Amish family is the result of mutations in CYP1B1 (2p21). Th e molecular information derived from this study will be used to help identi fy carriers of the CYP1B1 mutation in this community and optimise the manag ement of those at risk of developing glaucoma.