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Indian Journal of Experimental Biology

Vol. 47, October 2009, pp. 779-791

Review Article

Comparative genomic hybridization array study and its utility in detection of

constitutional and acquired anomalies
Joris Andrieux & Frenny Sheth*
Laboratory of Medical Genetics, Jeanne de Flandre Hospital CHRU de Lille, Lille Cedex, France

The last decade has witnessed an upsurge in the knowledge of cytogenetic disorders and putting the old technology in a
new basket with molecular genetics. As conventional cytogenetic can detect the genetic alteration of 10-15 Mb, many of the
micro-deletions and micro-duplications are missed. However, with the advent of technology of fluorescence in situ
hybridization (FISH), the resolution of genetic aberrations can reach to 3-5 Mb, nonetheless the anomalies smaller than the
above, need further precision which has been achieved using comparative genomic hybridization array (CGH-array).
Introduction of array-CGH has brought higher sensitivity with automated DNA fragment analyzer and DNA chip for
submicroscopic chromosomal anomalies that are missed till date in many of the acquired and constitutional genetic
disorders. The resolution of the technology varies from several Kb to 1 Mb depending upon the type of array selected. With
the recent improvement in the array-CGH technology, a link between cytogenetic and molecular biology has been
established without replacing conventional cytogenetic technique. The wider accessibility of the technology shall certainly
provide a clue to the many unidentified/unexplained genetic disorders which shall prove to be a boon to the clinicians.

Keywords: Acquired anomalies, Array-CGH, Constitutional disorders, Molecular karyotyping

Cytogenetic study has remained the clinicians’ Table 1—Landmark in the history of conventional cytogenetic
favorite for many of the genetic disorders especially and molecular cytogenetic
in unexplained psychomotor retardation [with/without Year Discovery Ref.
dysmorphism], abnormality of sexual differentiation 1
1959 First Chromosomal anomaly Lejune J
and development, infertility, recurrent pregnancy loss, detected [Trisomy 21]
pregnancy at risk for aneuploidy, chromosome 1969 Molecular hybridization of Pardue & Gall2
breakage syndrome and cancer. However, limitation radioactive DNA to the DNA of
of band resolution has added the plethora of research cytological preparations
studies in search for technology that can visualize 1976 High resolution banding Yunis3
chromosomal anomalies which are thought to be not technique
existing or missed. This has transformed cytogenetics 1981 Isotopic in situ hybridization Harper & Saunders4
to the molecular cytogenetics with an unmatched 1984 Direct FISH Landegent5
precision and knowledge gained so far. Though 1986 Interphase FISH Cremer et al6 & Pinkel
et al7
chromosomal abnormalities remain a major cause of
1989 Combinatorial labeling Nederlof et al8
most of the genetic disorders, limitations of high 1989 Primed in situ hybridization Koch et al9
resolution, missed many of the genetic disorders [PRINS]
while molecular biology has its limitations of known 1990 Identification of translocation in Tkachuk et al10
targeted anomalies identification. These limitations Interphase cell by FISH
have transformed the newer innovation with high end 1990 Technique of ratio labeling Nederlof et al11
precision of cytogenetic techniques (Table 1). 1992 Comparative Genomic Kallioniemi et al12
Nonetheless all these technology have their limitation Hybridization [CGH]
that uses comprehensive analysis of the disorders 1993 Fiber FISH Parra & Windle13
—————— 1996 Multiplex FISH [M-FISH] Speicher et al14
*Correspondent author’s present address: 1996 SKY Schrock et al15
FRIGE (Foundation for Research in Genetics and Endocrinology), 1997 Cross species color Banding Muller et al16
Institute of Human Genetics, FRIGE House, Jodhpur Road, [Rx FISH]
Satellite, Ahmedabad 380 015, India 1997 DNA array (matrix) CGH Solinas-Toldo17
Telephone: 079-26921414
1997 Padlock probe FISH Nilsson et al18
Fax: 079-26921415
E-mail: 1998 Array CGH using BAC clones Pinkel et al19

using cytogenetics to molecular cytogenetics to Molecular biology allows precise analysis of

array—comparative genomic hybridization (CGH). variations at the nucleotide level. Molecular
Table 2 shows comparison of each technology, its cytogenetic techniques, mainly Fluorescence in situ
uses and limitations for understanding genomic hybridization (FISH), which is currently useful on
imbalances in various genetic disorders. both metaphase chromosomes and interphase cells,
utilize genomic sequence-probes in bacterial
Techniques and levels of resolution artificial chromosome [BAC 100-200 kb] cloned in
Conventional cytogenetic [CC] technique, the Escherichia coli or P1 artificial chromosome [PAC
standard karyotype (400-bands per haploid genome) 100-150 kb] cloned in phage. These sequences are
allows a level of resolution, from 10-15 Mb (million tagged with fluorochrome, which allows the
base pairs). In the best conditions, the high-resolution detection of genomic imbalances involving
karyotype (550-bands) allows to reveal anomalies of chromosome segments smaller than 1 Mb for
about 3 to 5 Mb according to the regions of the deletions and more than 2 Mb for duplications. This
genome and the technique used (G-bands, R-bands). technique is more useful to detect micro-deletion and
The limitation of enhance resolution of the karyotype alteration at the telomeric region, which are not
is not only linked to the cytogenetic technique used (it identifiable with conventional cytogenetics (CC).
is possible to get karyotypes up to 850-bands), but This can be confirmed and correlated with the
also the region of interest. clinical symptoms. It is important to know that this
Secondly, the cytogenetic technique is only partly technique can identify only the specific region of the
automated; need insight, indebt knowledge and interest [specific sequence used as probe] and not the
experience of the cytogeneticists. whole genome in a single assay.
Table 2—Comparison of technical details between conventional cytogenetic and major molecular approaches
Method Analysis Resolution Applications Limitation

Conventional Cell culturing: Whole genome 10-15 Mb Detection of balance and unbalance Minor rearrangements
cytogenetics arresting cell in defects cannot be detected
High resolution arresting cell in Whole genome 3-5 Mb Detection of balance and unbalance Micro-deletions and
banding technique metaphase defects terminal aberrations can
not be detected.
Conventional Molecular Identify 1-3 Mb Detect all types of balanced and Structural anomalies
FISH biology specific region Metaphase unbalanced defects in metaphase, cannot be detected in non-
technique interphase cell, frozen section and dividing cells. Smaller
50 Kb dead cells. FISH is highly sensitive
Interphase cells for trisomy than
Spectral arresting cell in Whole genome 1-2 Mb Detect numerical and structural Inability to detect
Karyoytping/ M- metaphase aberrations including subtle paracentromeric inversion,
FISH rearrangements, complex small deletion/duplications
translocation, small marker, ring and cryptic translocation
and double minute chromosomes in
a single experiments with all 24
CGH Molecular Whole genome 3-5 Mb No need for cell culture or Cannot detect Balanced
biology technique metaphase, does not require fresh translocation, gain/loss of
sample, frozen or fixed sample can <4 Mb, multiplication of
be used, interpretation of highly 2n
complex karyotype with accurate
chromosomal location of imbalance
Array-CGH Molecular Whole genome 20 - 150 Kb Specifications are same as above. Cannot detect balanced
biology technique Can identify cryptic translocation, mosaicism
rearrangements, More sensitive and less than 50%, and
can be use for both quantitative heterochromatic region
genomic imbalance and gene
expression as well

Another molecular technique to analyse pange- quantities of DNA from the patient and control are
nomic alteration is CGH on metaphase. Here test labelled with different fluorochromes and hybridized
DNA (patient) and reference DNA (normal on a glass slide coated with an ordered set of defined
individual) are differentially labeled with two nucleic acid sequences17. This technological
fluorescence dyes and co-hybridized on metaphase development allows screening of large number of
spreads of a normal individual. A copy number genomic DNA sequences in a single experiment,
difference between test DNA and reference DNA will depending on the size of the spotlength of DNA
be reflected in fluorescence ratio. These ratios of [60bp]. Chromosomal imbalances across the genome
fluorochromes are visualised under microscope using can be mapped and quantified by analyzing the
appropriate filters and analysed with the aid of fluorescence ratio of the two dyes for each target.
software that discern genome structure variation DNA quantitative variation can be identified, only if
[deletion, duplication, amplifications, monosomies, the DNA fragments used on the glass slide covers
trisomies etc.] present in the DNA of the patient. This regions of interest.
technique has an advantage of identifying anomalies Technological progress accomplished in the last
in segments, which are not identified by G- or R- years, allow spotting of more than a million fragments
banding technique. Secondly, DNA of the test subject of DNA. Particularly for pangenomic studies, the
is used for the processing and hybridizes on the resolution depends on the number of DNA probes
normal male metaphase hence culturing of the cells spotted on the coated glass and the resolution is very
are not required. This is mainly useful in cases of close to few kilobases. This has made possible several
prenatal, onco-hematological and in tumor cases as applications such as whole chromosome studies20, a
well. One of the limits of CGH on chromosomes, in chromosome segment21, all sub-telomeric regions22, or
addition to poor reproducibility is its level of entire genome with a 1Mb resolution ranging from
resolution, which does not exceed 3-5 Mb [similar to (classical BACs/PACs array) to 10-100kb
high-resolution banding] (Fig. 1). (oligonucleotide array). Hence, this is going to
Recent advancements in array-CGH has made it provide the “connecting link” between cytogenetic
possible to substitute the chromosome target with and molecular biology for quantitative detection of
DNA spotted on a glass slide. The processing structural variation at genomic level. The term of
technique is similar to that of CGH metaphase. Equal molecular karyotype is now closer to reality23,24.
Types of CGH-array
BAC/PAC arrays— The use of DNA from cosmid,
P1, BAC and other large insert clones as targets were
first shown by Pinkel et al19. 1 Mb resolution can be
achieved by using 3200-3500 clones covering the
entire genome. Using this array, many cryptic
polymorphisms have been detected. However, array-
CGH using BACs/PACs create difficulties to
differentiate between potentially pathogenic and poly-
morphisms as around 10% of the used clones are
polymorphic25. In addition presence of Common
Number Variations / Polymorphisms (CNV/CNP)
further confounds analysis.
Recently overlapping clones [tiling path array
using 32,433 clones]26 have been used which provide
resolution of ~200kb on average. These have higher
cost than the 3200-3500 but allows detection of more
number of variations.
Oligonucleotide array — Commercially available
array-CGH oligonucleotides are available with
Fig. 1—CGH on chromosome (http:// HGP/ densities of clones from 15,000-1 million probes. This
Cytogenetics/) increases the resolution up to 20-30 kb on the entire

genome with an increased density in the coding micro-array was totally used to rule out genetic
region of the genome27. alterations in onco-haematological and tumor
Another approach is to use Single Nucleotide pathology until 2005 (Table 3).
Polymorphisms (SNP) micro-arrays, which allow In this domain, detection of quantitative genomic
detection of partial/complete disomies28 when finding alterations was linked to tumor progression and its
losses of heterozygosity (LOH) without quantitative therapeutic approach92. Various pathologies studied
DNA imbalances. are shown in Table 3.
Databases and bio-computer science—Data Though pathologies are secondary to the
processing plays a central role in interpretation. anomalies, it helps not only in the diagnosis but in the
Various softwares have been developed allowing to prognosis as well. There is specificity and limitations
process the data, to facilitate the interpretation using linked in CGH-Array applied to cancers and to
statistical algorithms and to generate a graph of the leukaemias are as follows:
results automatically. Nonetheless the interpretation Clonal anomalies: Different cell population (tumor
of these data is done only after studying whole and normal) are frequently observed in samples.
genome databases (Ensembl - Cambridge, UK-, Minor clone anomalies can easily be detected by CC
UCSC Genome Browser - Santa Cruz, USA) and as cell culture allows the immature cells to divide for
database of polymorphisms (Database of Genomic the analysis but in array-CGH, the DNA of normal
Variants, Toronto, Canada) (Fig. 2). cells is mixed with DNA from abnormal cell
population. Hence, abnormal clone if less than 30%,
Applications cannot be detected by array-CGH (Fig. 3).
Applications in onco-hematology and tumors— Sample preparation: Especially in solid tumor,
From the literature survey it can be noticed that CGH sometimes DNA is extracted from the fixed histo

Fig. 2—Interpretation of the data using whole genome databases


Table 3—Examples of onco-hematology and solid tumors studied pathological tissue that often generates poor quality
by array-CGH DNA leading to improper hybridization and inter-
Diseases Ref. pretation difficulties.
Acute myeloid leukemia, myelodysplasia 29-34 Patient data: Large number of patients DNA is
Acute lymphocytic leukemia 35-41 required for same clinical diagnosis to identify
Chronic myelogenous leukemia 42 recurrent anomalies by array-CGH.
Chronic lymphocytic leukemia 43,44 Applications in constitutional abnormalities— In
Lymphoma 45-50
term of diagnosis, array-CGH is particularly well
Multiple myeloma 51,52
Mesothelioma 53-55
suitable for the constitutional anomalies where they
Breast cancer 56-63 find, more often causative genetic alterations than in
Ovary cancer 64,65 onco-haematology and cancers, where they find
Colorectal adenocarcinoma 66-68 anomalies often consequence to the disease.
Liver cancer 69-71 • Application of array: CGH in constitutional genetic
Pancreatic cancer 72,73 is validation and measurement of the abnormality
Bladder cancer 74-76 detected by CC. Array-CGH is very useful to map
Prostate cancer 77-79
and measure precisely the size of the aberration
Neuroblastoma 80-83
Glioblastoma 84-86
using region specific arrays. CC analysis showed
Medulloblastoma 87,88 additional genetic material on #8p arm to a 3 yrs
Thyroid cancer 89,90 old female having MCA and developmental
Thymoma 91 delay [ 46, XX,add(8) † (8;?)(p23;?)]. Array - CGH

Fig. 3–Minor clones [~50%] cannot be detected by array-CGH


confirmed deletion of 8.3Mb on #8 and duplication as seen in Fig. 4c where duplication of 15q23q26.3
of 42.2 Mb of #15 leading to partial monosomy of involving IGF1R is associated with clinical
#8p and partial trisomy of #15q (Fig. 4 a-c). To features of macrocephaly, over growth and mental
date several chromosomal regions or whole retardation. Indeed high resolution array-CGH can
chromosomes were studied using tiling path or be successfully used to detect cryptic imbalances at
high-resolution array21. the chromosomal breakpoints97.
• To identify de novo marker chromosomes: measure • To rule out genomic alterations in clinically suspected
precisely gain and/or loss of chromosomal cases having normal chromosomal constitution25,97-106
segment, in a single assay (Fig. 5 a-b) 93-96 Since several years various international centres are
• In the vast majority of cases, apparently balanced actively involved for diagnosis in constitutional
structural chromosome abnormalities are not genetics using array-CGH and came to a conclusion
associated with an abnormal phenotype. However, that in cases of psychomotor delay/congenital
some carriers of apparently balanced de novo or malformation, when the results of CC are normal, the
inherited rearrangements present abnormal pick-up rate of interstitial micro-deletion/duplication
phenotypic features. The abnormal phenotype may after proper clinical history is around 2-3% using
be explained by the disruption of a gene, a high-resolution karyotype and additional 2-5% cases
positional effect or a cryptic genomic imbalance at are diagnosed using targeted telomeric region studies
the breakpoint or in another region of the genome (FISH or MLPA).

Fig. 4–(a): metaphase showing additional genetic material on #8p:46,XX,add(8) † (8;?)(p23;?) (b): Schematic representation shows
8p23.3p23.1 deletion of 8.3 Mb (c): Schematic representation shows 15q23q26.3 duplication of 42.2 Mb

Fig. 6–Potential of array-CGH in mental retardation

CGH-array can replace high resolution karyotyping

in confirming clinical diagnosis in the medium term
and the standard cytogenetics will always remain the
gold standard at the time of reference and the
anomalies detected by array-CGH will be further
validated using FISH analysis for deletions and
quantitative-PCR for duplications smaller than 2 Mb.

• Although array-CGH has proved to be an efficient
and reproducible technique, there are some
limitations. Array-CGH could not easily
characterize the structural configuration of
balanced chromosomal anomalies. Particularly the
Fig. 5 – (a): Metaphase showing presence of marker chromosome order and orientation of the rearranged segments
[47,XX,+mar] (b): Schematic representation shows cannot be determined. Also, low-level mosaicism
18p11.332p11.31 duplication of 14.9 Mb (i.e. < 30%) may be difficult to detect.
Nonetheless, around 6-30% abnormities were • Structural alteration involving heterochromatic
detected using array- CGH after selecting various region cannot be detected. [unpublished data]
criteria such as cytogenetic interpretation, molecular • DNA of same sex is used as control in array-CGH,
analysis along with clinical sign and symptoms107-113. however in cases where the case subject is female
Array- CGH distinguishes on average 10-20% of having two X chromosomes and marker is of
anomaly in patients having psychomotor delay along Y origin, then this Y chromosome cannot be
with more or less congenital malformations. Deletion identified117.
is observed in two third and duplication in one third • The choice between the uses of BAC/PAC or
of the cases114. oligonucleotide array solely depends on the quality
The published results point out the potential of this of manufacture’s slides and designing of the
technology and its power concerning the detection of probes, reproducibility of the technology,
cryptic chromosomal alterations in cases having robustness of the developed statistical tool, analysis
mental retardation (Fig. 6)112,113,115,116. of the results and level of resolution. The choice of

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