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Copy number variations and clinical cytogenetic diagnosis of constitutional disorders

Abstract

The recent appreciation of widespread copy number variation in the genomes of healthy human beings has presented a significant challenge to clinical cytogeneticists who wish to use genome-wide array comparative genomic hybridization (CGH) assays for clinical diagnostic purposes. Clinical cytogeneticists need to differentiate between copy number variants (CNVs) that are likely to be pathogenic and CNVs that are less likely to contribute to an affected individual's clinical presentation. Unfortunately, our knowledge of the phenotypic effects of most CNVs is minimal, leading to the classification of many CNVs as genomic imbalances of unknown clinical significance. This has caused many laboratories to resist the use of higher-resolution genome-wide array CGH assays for clinical purposes. Ironically, the accumulation and annotation of such array CGH data can lead to the rapid identification of pathogenic CNVs and the definition of new genomic syndromes that, in turn, are useful for accurate clinical genetic diagnoses.

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Figure 1: Detection of CNVs using a dye-reversal strategy on a 1-Mb resolution array platform (Spectral Genomics) and subsequent validation using multicolor FISH.
Figure 2: Array CGH results on an Affymetrix 500K-EA array show a 266-kb deletion CNV at chromosome (chr) region 22q11.23 in a child (denoted by the arrow on the child's chromosome 22 profile) and a similar 266-kb deletion CNV in the mother (denoted by the arrow on mother's chromosome 22 profile).
Figure 3: An example of a homozygous deletion in a clinically affected individual.
Figure 4: Individuals with a single-copy deletion CNV or a single recessive mutation can be healthy.
Figure 5: Two affected individuals with different CNVs may produce an indistinguishable array CGH result.
Figure 6: Overlap of CNVs with chromosomal regions associated with genomic disorders.

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Acknowledgements

The authors thank S. Hislop for her assistance with the figures in this paper, S. Ishikawa and H. Aburatani of the University of Tokyo for providing Figure 2 and J. Vermeesch of the University of Leuven for sharing unpublished data on the clinical consequences of certain amplified CNVs.

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Lee, C., Iafrate, A. & Brothman, A. Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nat Genet 39 (Suppl 7), S48–S54 (2007). https://doi.org/10.1038/ng2092

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