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S. J. Bowne, L. S. Sullivan, D. K. Wheaton, D. G. Birch, J. R. Heckenlively, S. P. Daiger; Disease-causing Copy Number Variants (CNVs) in Genes Associated With Autosomal Recessive Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2307.
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© ARVO (1962-2015); The Authors (2016-present)
To determine if large deletions, rearrangements or other copy number variants (CNVs) in AIPL1, CRX, CRB1, RPE65, GUCY2D, RDH12, or RPGRIP1 cause an appreciable fraction of autosomal recessive retinitis pigmentosa (arRP) or Lebers congenital amaurosis (LCA) and if CNV detection needs to be a routine part of DNA mutation identification. CNVs have been shown to be associated with many inherited diseases including other retinal degenerations. The PCR based nature of most DNA mutation detection technologies make it likely that large deletions, insertions or rearrangements will not be detected by conventional methods.
DNAs from 44 arRP and 29 LCA patients were tested for the presence of CNVs using multiple ligation probe amplification (MLPA). DNA was hybridized with the SALSA® MLPA® P221 and P222 LCA kits (MRC Holland) according the manufacturers protocol. CRB1 deletions were further investigated using a set of custom MLPA probes designed in house. Deletion breakpoints were determined using PCR methods.
Deletions and other CNVs were not detected in AIPL1, CRX, and RPE65 in these patients. Identical deletions in the CRB1 gene were detected in two patients. Subsequent analysis of these two samples has determined that the CNV is a large deletion, approximately 25kb in size, encompassing exon 10 and exon 11 of CRB1. One sample, from a multiplex arRP family, is homozygous for this large CRB1 deletion. The second patient with this CRB1 deletion has isolated LCA. Sequence analysis identified a second CRB1 mutation, in trans, in this individual. Experiments in progress suggest the possibility of further disease-associated CNVs in the GUCY2D, RDH12, and RPGRIP1 genes.
Copy number variation appears to be a significant cause of arRP and LCA. All patients with the large CRB1 deletion are of Hispanic origin, raising the possibility that this particular CNV is a common cause of recessive retinal degeneration in the Hispanic population. Additional studies are underway to determine the exact CRB1 breakpoints and the frequency of the CRB1 CNV in this population.
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