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R. Allikmets, J. Zernant, K. Jaakson, I. Lopez, E. Haamer, A. den Hollander, C. Ayuso, S. Banfi, F.P. M. Cremers, R.K. Koenekoop; Analysis of Autosomal Recessive Retinitis Pigmentosa Patients on the ARRP Genotyping Microarray (Disease Chip) . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1700.
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© ARVO (1962-2015); The Authors (2016-present)
Autosomal recessive retinitis pigmentosa (ARRP) is the most common type of RP. Genetically heterogeneous inheritance (18 known genes) complicates the analyses of ARRP cases, where conventional methods are of limited value. Previously, we designed genotyping microarrays for ABCA4, responsible for Stargardt macular dystrophy (STGD) and cone–rod dystrophy (CRD), for Leber Congenital Amaurosis (LCA), and for Usher Syndrome (USH). These arrays have been used to determine disease–associated variation in USH, LCA, STGD and CRD patients with high efficiency. The purpose of this study was to design and validate a comprehensive ARRP disease microarray, containing all known ARRP–associated genes, and to test it on a large international cohort of ARRP patients.
Over 250 patients with documented recessive inheritance (>1 affected sibs with normal parents, or consanguinity) were included in the study. The ARRP microarray was constructed by the allele–specific primer extension (APEX) technology. We included every known disease–associated sequence change described in 18 ARRP genes (>420) and a selection of common polymorphisms on the chip via allele–specific oligonucleotides. In addition to 13 ARRP genes, the array contains all variants of the CRX, CRB1, and RPE65 genes from the LCA chip, as well as the USH2A and USH3 genes from the USH array.
The microarray was >99% effective in determining the existing genetic variation, and yielded at least one disease–associated allele in 40–50% of patients, as we found mutations in USH2A, PDE6A, PDE6B, RGR, CERKL and CRB1. A large number of patients harbored USH2A variants. More than two (expected) variants were discovered in many patients, suggesting a modifier effect from more than one ARRP gene.
The ARRP array offers the most comprehensive and cost–effective tool for molecular diagnostics and basic science, representing the first complete "disease chip" for ARRP. Simultaneous screening for all known ARRP associated variants in large RP cohorts allows systematic detection and analysis of genetic variation, facilitating prospective diagnosis and, ultimately, predicting the disease progression.
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