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R. Allikmets, J. Zernant, H. Roomere, I. Lopez, C. Ayuso, S. Banfi, F. P. M. Cremers, R. K. Koenekoop; Analysis of Autosomal Dominant and X-Linked Retinitis Pigmentosa Patients on the ADRP and XlRP Genotyping Microarrays (Disease Chips). Invest. Ophthalmol. Vis. Sci. 2007;48(13):2335.
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Retinitis pigmentosa (RP) is a common group of retinal dystrophies with extensive genetic heterogeneity and overlapping phenotypes that do not allow defining the exact underlying genetic defects. Rapid and accurate genotyping is essential for suggesting proper management options. Currently, 13 genes have been associated with ADRP and two with XLRP which complicates the genetic analyses of RP cases. Previously, we designed genotyping microarrays for ARRP (20 genes), for Stargardt macular dystrophy (STGD), cone-rod dystrophy (CRD), for Leber Congenital Amaurosis (LCA), and for Usher Syndrome (USH) and found them to be robust, efficient, and cost effective. The purpose of this study was to design and validate two comprehensive RP disease microarrays, one for ADRP, and one for XLRP, containing all known associated genes and mutations, and to test it on a large cohort of RP patients.
Over 200 RP patients from four cohorts of French-Canadian, Italian, Spanish and Dutch origin with documented dominant or x-linked inheritance were included in the study. The two RP arrays were constructed by the arrayed primer extension (APEX) technology. Every known disease-associated sequence change described in the 15 genes (>500) and a selection of common polymorphisms were included on the chip via allele-specific oligonucleotides.
The micro arrays were >99% effective in determining the existing genetic variation, and yielded disease-associated allele(s) in ~30-40% of ADRP and ~40-50% of XLRP patients. Differences were found in the relative burdens of RP genes in cohorts of different ethnic origins.
The ADRP and XLRP arrays offer comprehensive and cost-effective tools for molecular diagnostics and basic science, representing the first complete "disease chips" for dominant and X-linked RP. Simultaneous screening for all known RP-associated variants in large RP cohorts allows systematic detection and analysis of genetic variation, facilitating prospective diagnosis and identifying patients for future clinical trials.
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