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R. Koenekoop, I. Lopez, M.A. Musarella, T. Strom, T. Meitinger, F.P. M. Cremers, A.I. den Hollander; Genome–Wide SNP Microarrays as a Diagnostic Tool in Consanguineous LCA Patients . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1688.
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© ARVO (1962-2015); The Authors (2016-present)
Mapping of genes involved in recessive diseases using linkage analysis is usually difficult because most families are small, with only one or a few affected individuals. A method that can be used to overcome this problem is homozygosity mapping in patients from consanguineous marriages or isolated populations. Genome–wide SNP microarrays represent a fast and cost–effective method to genotype patients’ DNA samples for polymorphic markers spread throughout the genome. The purpose of this study is to test the efficacy of SNP microarrays to identify the causative gene defect in patients with Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP).
Twenty–nine LCA and juv RP patients from consanguineous marriages and isolated populations were genotyped with Affymetrix 10K SNP microarrays, and analysed for chromosomal regions that are identical–by–descent. Phenotypes of affected individuals and carriers were documented after detailed eye examinations, including ERGs, mfERGs, Goldmann visual fields (GVF), and retinal photos.
In a consanguineous patient from Afghanistan we previously identified a heterozygous CRB1 mutation and a homozygous sequence change in the 5’UTR of the GUCY2D gene, but the phenotype did not correlate with CRB1 or GUCY2D mutations. SNP genotyping revealed only one large, 49–cM homozygous region that harbored the TULP1 gene. Sequence analysis identified a novel homozygous splice donor mutation in intron 7 of TULP1. The patient has a characteristic yellow foveal annulus, early central vision loss, and sparing of the V4e isopter, while the carriers have distinct peripheral hypo–pigmentations. In another LCA patient of consanguineous descent we identified 5 large homozygous regions. The second largest region, encompassing 37 cM of genomic DNA, contained the RPE65 gene. Sequence analysis revealed a homozygous missense mutation in the RPE65 gene. In three other patients we identified large homozygous regions containing the RP1, RPE65 and CRB1 genes, which we are currently screening for mutations.
SNP genotyping is an excellent tool to pinpoint the causal gene in LCA and juvenile RP patients from consanguineous descent. Several patients were not homozygous for any of the regions containing the known LCA or RP genes, and may be instrumental to identify new LCA genes.
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