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Ian M. MacDonald, Jonathan Y. Chi, Stacey Hume; Choroideremia May Be Caused By Partial Gene Duplication. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4548.
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To test for copy number variants in the CHM gene. Choroideremia (CHM) is an X-linked progressive chorioretinal degenerative disease that affects 1 in 50,000 males. CHM results from relative deficiency or absence of Rab escort protein-1 which is encoded by the CHM gene; however, the exact pathogenesis remains to be determined. Through genetic studies, we have determined that CHM can arise from partial and complete deletions, insertions, frameshifts, point mutations (missense and nonsense) and splice site mutations in the CHM gene.
Case control, non-randomized, study design. One female and eight male subjects were identified with fundus features consistent with a clinical diagnosis of CHM. In all cases, previous sequencing of the coding region and adjacent intronic splice sites had not found a mutation. We designed a multiplex ligation-dependent probe amplification (MLPA) assay kit for the detection of copy number variants in the CHM gene. Using this MLPA assay, we tested the DNA of those CHM patients that screened negative for mutations in the CHM gene.
A duplication of consecutive exons 3 to 8 of the CHM gene was found in one patient sample.
Prior to this study, only deletions in the CHM gene, as examples of copy number variation, have been linked to CHM pathology. The duplication in the CHM gene observed in this study represents another mechanism of mutation in the CHM gene. Based on our results, we would conservatively estimate that copy number variants in the CHM gene are likely to be found in no more that 10 per cent of cases in which no mutation is found by sequencing. MLPA or an array based test may serve as a useful first pass test for the molecular analysis of CHM cases. These tests will have the utility of excluding copy number variants in the gene as the cause of CHM.
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