Fig. 2. Array-comparative genomic hybridization analysis of a renal cell carcinoma cell line. A single copy number loss of the distal part of the short arm of chromosome 1 and a single-copy gain of the distal part of the long arm.
single copy loss, whereas the terminal part of 1q shows single copy number gain. More recently, the improved resolution of aCGH has been applied to the identification of submicroscopic gains (microduplications) and losses (microdeletions) in patients with learning disability and/or dysmorphology. In a study of 50 patients with cytogenetically normal karyotypes but with learning disability and dysmorphology, we identified 12 small copy number changes in 12 patients (15) ranging in size from a single clone to as large as 14 Mb. Seven of these copy number changes were deletions (six de novo and one inherited from a phenotypically normal parent) and the remaining five copy number changes were duplications (one de novo but four inherited from phenotypically normal parents). Although it is reasonable to suggest that the de novo copy number changes are likely to be associated with the phenotype, the role of the inherited copy number changes is unclear. The inheritance of copy number changes that do not segregate with the phenotype may simply be the consequence of normal human variation, as suggested by recent reports of widespread large scale copy number variations in the normal population (16,17), but we cannot rule out that such changes in the context of the other allele might be associated with the phenotype.
Of particular interest is that none of the copy number changes we observed in these patients were recurrent or overlapped with each other. Indeed, microduplications and microdeletions in similar patients reported by others (18,19) are similarly unique. From this it is clear that the study of many more patients will be required before we will be able to define new microdeletion and microduplication syndromes, provide clinicians with information on probable outcome and dissect out genotype-phenotype associations. To aid collection of such data and collaboration on an international scale, we have developed a Web-based interactive database, DECIPHER (http://decipher.sanger.ac.uk). DECIPHER not only holds microdeletion or microduplication data with detailed patient phenotype information but also displays the genomic position of all copy number changes in the database (including known microdeletion/microduplication syndromes and normal copy number polymorphisms) within the genome browser Ensembl, with all of its tools relating to the annotation of the human genome available for analysis.
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