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Move over karyotypesgenetic disorder detection has vastly improved. Researchers are
now using array CGH (aCGH), to quickly scan through an entire genome for imbalances.
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It is important to note that aCGH data can be verified using FISH analysis (Figure
2). For instance, Ballif and others (2007b) recently characterized 169 cases with
subtelomeric abnormalities identified by aCGH. Although the coverage was
sufficient to define the breakpoints in over half (56%) of the subtelomeric
abnormalities, 44% of the abnormalities extended outside the coverage,
suggesting that many such abnormalities are greater than 5 Mb in size. Of these
169 cases, 42 had interstitial deletions. These deletions would have been missed
or incorrectly characterized by subtelomeric FISH panels that use a single clone
to the most distal unique sequence for each region. In addition, six (3.5%) of the
individuals had complex rearrangements that showed deletions along with
duplications or additional deletions. The identification of these sorts of complex
rearrangements suggests that chromosomal abnormalities are often more
complex than previously thought.
Pericentromeric Rearrangements
aCGH has also allowed for the detection of rearrangements in the
pericentromeric regions directly adjacent to the repetitive centromeric regions in
all chromosomes. The pericentromeric regions are known to be prone to
instability because numerous microdeletions, including those causing Williams,
DiGeorge, and Prader-Willi syndromes, occur in these regions. Because of the
high levels of repetitive sequences present in the pericentromeric regions and the
variability in presentation associated with traditional G-banding, rearrangements
in these regions are inherently difficult to assess by chromosome analysis.
However, the recent construction of microarrays targeted to the pericentromeric
regions has allowed for the assessment of copy number imbalances in these
regions. For example, in one study of 8,789 individuals with mental retardation
and/or birth defects (Shaffer et al., 2007), 94 individuals were found to have a
microdeletion in a pericentromeric region, and 42 individuals were found to have
reciprocal duplications in these regions. In addition, 22 individuals had novel
deletions, while 11 individuals had novel duplications of other pericentromeric
regions that were found in two or more patients. Among these individuals were
four with recurrent de novo interstitial deletion in band p11.2p12.2 on the short
arm of chromosome 16. The common clinical features of these patients suggest
that deletion of 16p11.2p12.2 constitutes a novel microdeletion syndrome (Bailif
et al., 2007a). Two other individuals with recurrent interstitial deletions on the long
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del Gaudio, D., et al. Increased MECP2 gene copy number as the result of
genomic duplication in neurodevelopmentally delayed males. Genetics in Medicine
8, 784792 (2006)
DeRisi, J., et al. Use of a cDNA microarray to analyse gene expression patterns in
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de Vries, B. B. A., et al. Diagnostic genome profiling in mental retardation.
American Journal of Human Genetics 77, 606616 (2005)
Ensenauer, R. E., et al. Microduplication 22q11.2, an emerging syndrome: Clinical,
cytogenetic, and molecular analysis of thirteen patients. American Journal of
Human Genetics 73, 10271040 (2003)
Flint, J., et al. The detection of subtelomeric chromosomal rearrangements in
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Hassed, S. J., et al. A new genomic duplication syndrome complementary to the
velocardiofacial (22q11 deletion) syndrome. Clinical Genetics 65, 400404 (2004)
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Kallioniemi, A., et al. Comparative genomic hybridization for molecular cytogenetic
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Journal of Medical Genetics 38, 740744 (2001) doi:10.1136/jmg.38.11.740
Knight, S. J., et al. Subtle chromosomal rearrangements in children with
unexplained mental retardation. Lancet 354, 16761681 (1999)
Kriek, M., et al. Copy number variation in regions flanked (or unflanked) by
duplicons among patients with developmental delay and/or congenital
malformations; detection of reciprocal and partial Williams-Beuren duplications.
European Journal of Human Genetics 14, 180189 (2006)
doi:10.1038/sj.ejhg.5201540 (link to article)
Lichter, P., et al. Comparative genomic hybridization: Uses and limitations.
Seminars in Hematology 37, 348357 (2000)
Lu, X., et al. Clinical implementation of chromosomal microarray analysis:
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