Abstract
BackgroundComparative genomic hybridization microarrays for the detection of constitutional chromosomal aberrations is the application of microarray technology coming fastest into routine clinical application. Through genotype-phenotype association, it is also an important technique towards the discovery of disease causing genes and genomewide functional annotation in human. When using a two-channel microarray of genomic DNA probes for array CGH, the basic setup consists in hybridizing a patient against a normal reference sample. Two major disadvantages of this setup are (1) the use of half of the resources to measure a (little informative) reference sample and (2) the possibility that deviating signals are caused by benign copy number variation in the "normal" reference instead of a patient aberration. Instead, we apply an experimental loop design that compares three patients in three hybridizations.ResultsWe develop and compare two statistical methods (linear models of log ratios and mixed models of absolute measurements). In an analysis of 27 patients seen at our genetics center, we observed that the linear models of the log ratios are advantageous over the mixed models of the absolute intensities.ConclusionThe loop design and the performance of the statistical analysis contribute to the quick adoption of array CGH as a routine diagnostic tool. They lower the detection limit of mosaicisms and improve the assignment of copy number variation for genetic association studies.
Highlights
Comparative genomic hybridization microarrays for the detection of constitutional chromosomal aberrations is the application of microarray technology coming fastest into routine clinical application
Compared to, for example, expression microarrays, array CGH enjoys several technical advantages: (1) genomic DNA samples are less prone to degradation than mRNA samples, (2) genomic DNA sam
They formulate these dependencies as a set of linear relations that are inverted to obtain tighter estimates for a smaller set of independent statistical effects
Summary
Comparative genomic hybridization microarrays for the detection of constitutional chromosomal aberrations is the application of microarray technology coming fastest into routine clinical application. When using a two-channel microarray of genomic DNA probes for array CGH, the basic setup consists in hybridizing a patient against a normal reference sample. Array Comparative Genomic Hybridization (array CGH) [1,2], called molecular karyotyping [3], detects copy number aberrations and variations at high resolution on a genomewide scale [4,5]. Wolf-Hirschhorn can be detected with array CGH by comparing a genomic DNA sample of the patient (test) with that of a normal individual (reference). The microarray is scanned by two-channel laser scanner and aneuploid chromosomal regions are detected as probes with a deviant log ratio This example clearly indicates a deviation of the log ratios at the end of the short arm of chromosome 4 and allows to confirm the hypothesis of Wolf-Hirschhorn syndrome
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