Detection of low-level mosaicism and placental mosaicism by oligonucleotide array comparative genomic hybridization

Abstract

Purpose:To determine the sensitivity of whole-genome oligonucleotide array comparative genomic hybridization for the detection of mosaic cytogenetic abnormalities. Methods: Mosaicism sensitivity was evaluated by testing artificially derived whole chromosome and segmental aneuploidies ranging from 0% to 100% abnormal and additional naturally occurring mosaic specimens. Results: Using combined dye-reversed replicates and an unfiltered analysis, oligonucleotide array comparative genomic hybridization detected as low as 10% and 20 -30% mosaicism from whole chromosome and segmental aneuploidies, respectively. To investigate discrepancies between cultured and uncultured specimens, array comparative genomic hybridization was performed on DNA from additional direct product of conception specimens with abnormal karyotypes in culture. Interestingly, 5 of 10 product of conception specimens with double trisomies on cultured cell analysis had only a single trisomy by array comparative genomic hybridization and quantitative polymerase chain reaction on DNA from the uncultured direct specimen, and all harbored the more commonly observed trisomy. Thus, oligonucleotide array comparative genomic hybridization revealed previously unidentified placental mosaicism in half of the products of conception with double-aneuploid conventional karyotypes. Conclusion: Oligonucleotide array comparative genomic hybridization can detect low-level mosaicism for whole chromosome (ϳ10%) and segmental (ϳ20 -30%) aneuploidies when using specific detection criteria. In addition, careful interpretation is required when performing array comparative genomic hybridization on DNA isolated from direct specimens as the results may differ from the cultured chromosome analysis. Genet Med 2010:12(2):85-92.

Genome-wide arrays: Quality criteria and platforms to be used in routine diagnostics

“…Mosaicism can and should be detected with the use of genomic arrays [Hoang et al, 2011;Scott et al, 2010;Valli et al, 2011]. Individual laboratories should determine the minimum level at which mosaicism can be detected on their array platform.…”

Defining the impact of maternal cell contamination on the interpretation of prenatal microarray analysis

“…The ability of aCGH to detect low-level mosaicism has been documented, [17][18][19] and it has been suggested that high levels of MCC may not impact the identification of fetal abnormalities by aCGH. 20 In this study, we sought to determine the sensitivity of our prenatal microarray to MCC and the threshold of our prenatal microarray to return diagnostic results in the presence of MCC.…”

“…However, such low-level MCC would only slightly alter the ability of the array to detect fetal mosaicism. Assuming that oligonucleotide-based aCGH can reliably detect mosaicism starting at a 30% level, 19,27 then with 10% MCC, the reliable detection level for fetal mosaicism only increases to 33%. Of note, the simulated MCC experiments presented here could also be viewed as simulated mosaicism experiments (when viewed inversely), and our data reveal that it may not be appropriate to use a single cutoff for detection of mosaicism; as shown, larger abnormalities, as well as deletions, remain detectable by the aCGH software at a much lower level of mosaicism A portion of these data was previously described.…”

Confirmation of mosaic trisomy 22 in an infant with failure to thrive

“…Genetic testing in a child with developmental delay and features suggestive of a mosaic disorder would begin with karyotyping but it is necessary to alert the laboratory for the need to count a larger number of cells on blood karyotype to identify a mosaicism of low frequency 13 . When available, comparative genomic hybridization is the preferred method of diagnosis 14 as its positive yield is higher than with conventional karyotyping. In addition, the use of a buccal cells 15 or fibroblasts 16 for testing is more likely to identify the abnormality.…”