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: frennysheth@hotmail.com 1998 Array CGH using BAC clones Pinkel et al19
780 INDIAN J EXP BIOL, OCTOBER 2009

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

array—comparative genomic hybridization (CGH).
Table 2 shows comparison of each technology, its
uses and limitations for understanding genomic
imbalances in various genetic disorders.
Techniques and levels of resolution
Conventional cytogenetic [CC] technique, the
standard karyotype (400-bands per haploid genome)
allows a level of resolution, from 10-15 Mb (million
base pairs). In the best conditions, the high-resolution
karyotype (550-bands) allows to reveal anomalies of
about 3 to 5 Mb according to the regions of the
genome and the technique used (G-bands, R-bands).
The limitation of enhance resolution of the karyotype
is not only linked to the cytogenetic technique used (it
is possible to get karyotypes up to 850-bands), but
also the region of interest.
Secondly, the cytogenetic technique is only partly
automated; need insight, indebt knowledge and
experience of the cytogeneticists.
Table 2—Comparison of technical details between conventional cytogenetic and major molecular approaches
Method Analysis
variations at the nucleotide level. Molecular
cytogenetic techniques, mainly Fluorescence in situ
hybridization (FISH), which is currently useful on
both metaphase chromosomes and interphase cells,
utilize genomic sequence-probes in bacterial
artificial chromosome [BAC 100-200 kb] cloned in
Escherichia coli or P1 artificial chromosome [PAC
100-150 kb] cloned in phage. These sequences are
tagged with fluorochrome, which allows the
detection of genomic imbalances involving
chromosome segments smaller than 1 Mb for
deletions and more than 2 Mb for duplications. This
technique is more useful to detect micro-deletion and
alteration at the telomeric region, which are not
identifiable with conventional cytogenetics (CC).
This can be confirmed and correlated with the
clinical symptoms. It is important to know that this
technique can identify only the specific region of the
interest [specific sequence used as probe] and not the
whole genome in a single assay.
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
metaphase
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
monosomy
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
chromosomes
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
 ANDRIEUX & SHETH : CGH-ARRAY STUDY & ITS UTILITIES
Another molecular technique to analyse pange-
nomic alteration is CGH on metaphase. Here test
DNA (patient) and reference DNA (normal
individual) are differentially labeled with two
fluorescence dyes and co-hybridized on metaphase
spreads of a normal individual. A copy number
difference between test DNA and reference DNA will
be reflected in fluorescence ratio. These ratios of
fluorochromes are visualised under microscope using
appropriate filters and analysed with the aid of
software that discern genome structure variation
[deletion, duplication, amplifications, monosomies,
trisomies etc.] present in the DNA of the patient. This
technique has an advantage of identifying anomalies
in segments, which are not identified by G- or R-
banding technique. Secondly, DNA of the test subject
is used for the processing and hybridizes on the
normal male metaphase hence culturing of the cells
are not required. This is mainly useful in cases of
prenatal, onco-hematological and in tumor cases as
well. One of the limits of CGH on chromosomes, in
addition to poor reproducibility is its level of
resolution, which does not exceed 3-5 Mb [similar to
high-resolution banding] (Fig. 1).
Recent advancements in array-CGH has made it
possible to substitute the chromosome target with
DNA spotted on a glass slide. The processing
technique is similar to that of CGH metaphase. Equal
Fig. 1—CGH on chromosome (http:// www.sanger.ac.uk/ HGP/
Cytogenetics/)
781
quantities of DNA from the patient and control are
labelled with different fluorochromes and hybridized
on a glass slide coated with an ordered set of defined
nucleic acid sequences17. This technological
development allows screening of large number of
genomic DNA sequences in a single experiment,
depending on the size of the spotlength of DNA
[60bp]. Chromosomal imbalances across the genome
can be mapped and quantified by analyzing the
fluorescence ratio of the two dyes for each target.
DNA quantitative variation can be identified, only if
the DNA fragments used on the glass slide covers
regions of interest.
Technological progress accomplished in the last
years, allow spotting of more than a million fragments
of DNA. Particularly for pangenomic studies, the
resolution depends on the number of DNA probes
spotted on the coated glass and the resolution is very
close to few kilobases. This has made possible several
applications such as whole chromosome studies20, a
chromosome segment21, all sub-telomeric regions22, or
entire genome with a 1Mb resolution ranging from
(classical BACs/PACs array) to 10-100kb
(oligonucleotide array). Hence, this is going to
provide the “connecting link” between cytogenetic
and molecular biology for quantitative detection of
structural variation at genomic level. The term of
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
densities of clones from 15,000-1 million probes. This
increases the resolution up to 20-30 kb on the entire
782 INDIAN J EXP BIOL, OCTOBER 2009
genome with an increased density in the coding
region of the genome27.
Another approach is to use Single Nucleotide
Polymorphisms (SNP) micro-arrays, which allow
detection of partial/complete disomies28 when finding
losses of heterozygosity (LOH) without quantitative
DNA imbalances.
Databases and bio-computer science—Data
processing plays a central role in interpretation.
Various softwares have been developed allowing to
process the data, to facilitate the interpretation using
statistical algorithms and to generate a graph of the
results automatically. Nonetheless the interpretation
of these data is done only after studying whole
genome databases (Ensembl - Cambridge, UK-,
UCSC Genome Browser - Santa Cruz, USA) and
database of polymorphisms (Database of Genomic
Variants, Toronto, Canada) (Fig. 2).
Applications
Applications in onco-hematology and tumors—
From the literature survey it can be noticed that CGH
Fig. 2—Interpretation of the data using whole genome databases
micro-array was totally used to rule out genetic
alterations in onco-haematological and tumor
pathology until 2005 (Table 3).
In this domain, detection of quantitative genomic
alterations was linked to tumor progression and its
therapeutic approach92. Various pathologies studied
are shown in Table 3.
Though pathologies are secondary to the
anomalies, it helps not only in the diagnosis but in the
prognosis as well. There is specificity and limitations
linked in CGH-Array applied to cancers and to
leukaemias are as follows:
Clonal anomalies: Different cell population (tumor
and normal) are frequently observed in samples.
Minor clone anomalies can easily be detected by CC
as cell culture allows the immature cells to divide for
the analysis but in array-CGH, the DNA of normal
cells is mixed with DNA from abnormal cell
population. Hence, abnormal clone if less than 30%,
cannot be detected by array-CGH (Fig. 3).
Sample preparation: Especially in solid tumor,
sometimes DNA is extracted from the fixed histo
 ANDRIEUX & SHETH : CGH-ARRAY STUDY & ITS UTILITIES 783

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

784 INDIAN J EXP BIOL, OCTOBER 2009

confirmed deletion of 8.3Mb on #8 and duplication
of 42.2 Mb of #15 leading to partial monosomy of
#8p and partial trisomy of #15q (Fig. 4 a-c). To
date several chromosomal regions or whole
chromosomes were studied using tiling path or
high-resolution array21.
• To identify de novo marker chromosomes: measure
precisely gain and/or loss of chromosomal
segment, in a single assay (Fig. 5 a-b) 93-96
• In the vast majority of cases, apparently balanced
structural chromosome abnormalities are not
associated with an abnormal phenotype. However,
some carriers of apparently balanced de novo or
inherited rearrangements present abnormal
phenotypic features. The abnormal phenotype may
be explained by the disruption of a gene, a
positional effect or a cryptic genomic imbalance at
the breakpoint or in another region of the genome
as seen in Fig. 4c where duplication of 15q23q26.3
involving IGF1R is associated with clinical
features of macrocephaly, over growth and mental
retardation. Indeed high resolution array-CGH can
be successfully used to detect cryptic imbalances at
the chromosomal breakpoints97.
• To rule out genomic alterations in clinically suspected
cases having normal chromosomal constitution25,97-106
Since several years various international centres are
actively involved for diagnosis in constitutional
genetics using array-CGH and came to a conclusion
that in cases of psychomotor delay/congenital
malformation, when the results of CC are normal, the
pick-up rate of interstitial micro-deletion/duplication
after proper clinical history is around 2-3% using
high-resolution karyotype and additional 2-5% cases
are diagnosed using targeted telomeric region studies
(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
 ANDRIEUX & SHETH : CGH-ARRAY STUDY & ITS UTILITIES
Fig. 5 – (a): Metaphase showing presence of marker chromosome
[47,XX,+mar] (b): Schematic representation shows
18p11.332p11.31 duplication of 14.9 Mb
Nonetheless, around 6-30% abnormities were
detected using array- CGH after selecting various
criteria such as cytogenetic interpretation, molecular
analysis along with clinical sign and symptoms107-113.
Array- CGH distinguishes on average 10-20% of
anomaly in patients having psychomotor delay along
with more or less congenital malformations. Deletion
is observed in two third and duplication in one third
of the cases114.
The published results point out the potential of this
technology and its power concerning the detection of
cryptic chromosomal alterations in cases having
mental retardation (Fig. 6)112,113,115,116.
785
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.
Limitations
• 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
order and orientation of the rearranged segments
cannot be determined. Also, low-level mosaicism
(i.e. < 30%) may be difficult to detect.
• Structural alteration involving heterochromatic
region cannot be detected. [unpublished data]
• DNA of same sex is used as control in array-CGH,
however in cases where the case subject is female
having two X chromosomes and marker is of
Y origin, then this Y chromosome cannot be
identified117.
• The choice between the uses of BAC/PAC or
oligonucleotide array solely depends on the quality
of manufacture’s slides and designing of the
probes, reproducibility of the technology,
robustness of the developed statistical tool, analysis
of the results and level of resolution. The choice of
786 INDIAN J EXP BIOL, OCTOBER 2009
technology is the result of comparison between
cost and resolution we expect.
• Most of the false results (negative / positive) are
consequential from poor hybridization, linked to
bad quality DNA or it is above recognizable
threshold.
• Last but not the least is the differentiation between
real polymorphism and potentially pathogenic
polymorphism as it is also present in a normal
parent. Therefore, before applying array-CGH as a
routine diagnostic tool, a better knowledge of these
polymorphisms is obligatory.
Conclusion
Array-CGH allow testing a huge number of loci in
one experiment and it is likely that it will replace
FISH approach to characterize deletion/duplication
breakpoints or to screen for known micro-deletion
syndromes and sub-telomeric imbalances. Array-CGH
is faster, has a better resolution, is a wonderful tool to
screen pangenomic and constitutes the “Connecting
Link” between CC and molecular biology for the
detection of cryptic quantitative genomic alterations.
Array-CGH is still at a high cost and requires
expensive apparatus for analysis and an expensive
technical environment, as well as a good level of
expertise. This can be partly supplemented by the
choice of the appropriate array and its resolution in
the quantification (losses or gains) of the genomic
modifications.
Acknowledgement
This work was supported by UICC (International
Union against Cancer), Geneva, Switzerland and
Department of Biotechnology, India (BT/PR/9111
/MED/12/337/2007). Thanks are also due to Dr.
Jayesh Sheth for comments.
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