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Hannah Verdin, Bart P. Leroy, Barbara D'haene, Frauke Coppieters, Steve Lefever, Philippe G. Kestelyn, Elfride De Baere; Identity-by-Descent Mapping Reveals a New Locus for Primary Congenital Glaucoma, GLC3E, on Chromosome 19p13.2. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5289.
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Primary congenital glaucoma (PCG) is caused by developmental anomalies of the trabecular meshwork and the anterior chamber angle, resulting in an increased ocular pressure (IOP) and optic nerve damage from birth or early infancy. The prevalence of PCG is estimated to be 1:10.000 in Western populations with higher prevalences in inbred populations. In general PCG displays an autosomal recessive inheritance and is genetically heterogeneous. To date, four PCG loci are known (GLC3A-D), in which two genes have been identified, CYP1B1 and LTBP2. Here, we aimed to map the disease gene in a large, four-generation consanguineous family with PCG, originating from Jordan.
Mutations in known PCG genes (CYP1B1 and LTBP2) as well as anterior segment dysgenesis genes (FOXC1 and PITX2) were excluded respectively. Identity-by-descent (IBD) mapping was performed in six affected members using genomewide SNP genotyping with 250K arrays (Affymetrix). Several gene prioritization tools were used to make a selection of candidate genes for Sanger sequencing (Tranchevent LC et al. Brief Bioinform. 2011 12:22-32).Two affected individuals underwent exome enrichment (TruSeq Exome Enrichment Kit, Illumina) and sequencing (2x100 cycles, HiSeq, Illumina). The CLC Genomics Workbench (CLC bio) was employed for read mapping and variant calling.
The common IBD regions did not overlap with any known PCG loci. Filtering on both size of the region and number of consecutive homozygous SNPs revealed a new candidate region on 19p13.2, named GLC3E. This region measures 2.67 Mb and contains 93 genes. Using prioritization tools, BEST2 was selected as the best candidate gene. Indeed, Best2 is expressed in non-pigmented epithelial (NPE) cells of ciliary body, which is responsible for formation of aqueous humour. Also, Best2-/- mice have significantly lower IOP than wild type littermates. Sanger sequencing of the BEST2 coding region in affected individuals revealed no mutations however. Exome sequencing was performed in two affected individuals. Data analysis is ongoing.
We identified a potential new PCG locus, named GLC3E, confirming the genetic heterogeneity of PCG, and representing a unique opportunity to identify the third PCG gene.
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