Abstract
BackgroundMicroarray-based comparative genomic hybridization (aCGH) is a powerful diagnostic tool for the detection of DNA copy number gains and losses associated with chromosome abnormalities, many of which are below the resolution of conventional chromosome analysis. It has been presumed that whole-genome oligonucleotide (oligo) arrays identify more clinically significant copy-number abnormalities than whole-genome bacterial artificial chromosome (BAC) arrays, yet this has not been systematically studied in a clinical diagnostic setting.ResultsTo determine the difference in detection rate between similarly designed BAC and oligo arrays, we developed whole-genome BAC and oligonucleotide microarrays and validated them in a side-by-side comparison of 466 consecutive clinical specimens submitted to our laboratory for aCGH. Of the 466 cases studied, 67 (14.3%) had a copy-number imbalance of potential clinical significance detectable by the whole-genome BAC array, and 73 (15.6%) had a copy-number imbalance of potential clinical significance detectable by the whole-genome oligo array. However, because both platforms identified copy number variants of unclear clinical significance, we designed a systematic method for the interpretation of copy number alterations and tested an additional 3,443 cases by BAC array and 3,096 cases by oligo array. Of those cases tested on the BAC array, 17.6% were found to have a copy-number abnormality of potential clinical significance, whereas the detection rate increased to 22.5% for the cases tested by oligo array. In addition, we validated the oligo array for detection of mosaicism and found that it could routinely detect mosaicism at levels of 30% and greater.ConclusionsAlthough BAC arrays have faster turnaround times, the increased detection rate of oligo arrays makes them attractive for clinical cytogenetic testing.
Highlights
Molecular cytogenetic techniques such as array-based comparative genomic hybridization have revolutionized cytogenetic diagnostics and, in turn, the clinical management of patients with developmental delays and multiple congenital anomalies [1,2]
Targeted microarrays constructed from bacterial artificial chromosomes (BAC) were developed for the clinical laboratory because of their ability to clearly identify copy number changes in discrete regions of the human genome known to play a role in genetic disease [16]
The coverage of microarrays has expanded to include more comprehensive coverage of the human genome, leading many to suggest that whole-genome BAC or oligo arrays are the step in the continued improvement in the detection rate of cytogenetic abnormalities
Summary
Platform comparison study From the 466 cases analyzed by the BAC array, using the previously described algorithm, we excluded 347 cases that only had aberrations located within regions that contained no genes and/or aberrations that had been established to be normal population variants by Signature Genomic Laboratories or identified in the Toronto Database of Genomic Variants (DGV, http:// projects.tcag.ca/variation/) After these cases were excluded, 138 copy number alterations in 119 cases (25.5% of the original 466 cases) remained that required FISH analysis. The same 56 (12.0%) cases that were identified by the BAC platform were considered to contain clinically significant alterations (Table 1) and 17 (3.7%) were determined to contain copy number variants of unclear clinical significance.
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