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DNA copy-number analysis of the 22q11 deletion-syndrome region using array-CGH with genomic and PCR-based targets
KTH, Superseded Departments, Biotechnology.
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2004 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 13, no 2, 273-279 p.Article in journal (Refereed) Published
Abstract [en]

Deletions and duplications of genomic segments commonly cause developmental disorders. The resolution and efficiency in diagnosing such gene-dosage alterations can be drastically increased using microarray-based comparative genomic hybridization (array-CGH). However, array-CGH currently relies on spotting genomic clones as targets, which confers severe limitations to the approach including resolution of analysis and reliable gene-dosage assessment of regions with high content of redundant sequences. To improve the methodology for analysis, we compared the use of genomic clones, repeat-free pools of amplified genomic DNA and cDNAs (single and pooled) as targets on the array. For this purpose, we chose q11.2 locus on chromosome 22 as a testing ground. Microdeletions at 22q11 cause birth defects collectively described as the DiGeorge/velocardiofacial syndrome. The majority of patients present 3 Mb typical deletions. Here, we report the construction of a gene-dosage array, covering 6 Mb of 22q11 and including the typically deleted region. We hybridized DNA from six DiGeorge syndrome patients to the array, and show that as little as 11.5 kb non-redundant, repeat-free PCR-generated sequence can be used for reliable detection of hemizygous deletions. By extrapolation, this would allow analysis of the genome with an average resolution of 25 kb. In the case of cDNAs our results indicate that 3.5 kb sequence is necessary for accurate identification of haploid/diploid dosage alterations. Thus, for regions rich in redundant sequences and repeats, such as 22q11, a specifically tailored array-CGH approach is good for gene copy number profiling.

Place, publisher, year, edition, pages
2004. Vol. 13, no 2, 273-279 p.
Keyword [en]
array-CGH, DNA dosage analysis, DiGeorge syndrome, chromosome 22, DGS/VCFS, comparative genomic hybridization, digeorge-syndrome, digeorge/velocardiofacial syndrome, defects, mice, tbx1, microarrays, gene
National Category
Medical and Health Sciences
URN: urn:nbn:se:kth:diva-23095ISI: 000188200500011OAI: diva2:341793
QC 20100525 QC 20111031Available from: 2010-08-10 Created: 2010-08-10 Last updated: 2011-10-31Bibliographically approved

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