Human Molecular Genetics 2005 14(Review Issue 2):R215-R223; doi:10.1093/hmg/ddi268
© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Identification of disease genes by whole genome CGH arrays
Lisenka E.L.M. Vissers,
Joris A. Veltman*,
Ad Geurts van Kessel and
Han G. Brunner
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, PO Box 9101 6500 HB Nijmegen, The Netherlands
* To whom correspondence should be addressed. Tel: +31 243614941; Fax: +31 243668752; Email: j.veltman{at}antrg.umcn.nl
Received June 30, 2005; Accepted July 14, 2005
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ABSTRACT
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Small, submicroscopic, genomic deletions and duplications (1 kb
to 10 Mb) constitute up to 15% of all mutations underlying
human monogenic diseases. Novel genomic technologies such as
microarray-based comparative genomic hybridization (array CGH)
allow the mapping of genomic copy number alterations at this
submicroscopic level, thereby directly linking disease phenotypes
to gene dosage alterations. At present, the entire human genome
can be scanned for deletions and duplications at over 30 000
loci simultaneously by array CGH (
100 kb resolution), thus
entailing an attractive gene discovery approach for monogenic
conditions, in particular those that are associated with reproductive
lethality. Here, we review the present and future potential
of microarray-based mapping of genes underlying monogenic diseases
and discuss our own experience with the identification of the
gene for CHARGE syndrome. We expect that, ultimately, genomic
copy number scanning of all 250 000 exons in the human
genome will enable immediate disease gene discovery in cases
exhibiting single exon duplications and/or deletions.
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INTRODUCTION
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Mendelian cytogenetics refers to the association between structural
chromosome anomalies and single gene disorders, either alone
or in contiguous gene syndromes (1
). Translocations of Xp21,
for instance, suggested for the first time that the Duchenne
muscular dystrophy gene (
DMD) might map to this chromosomal
region (2
). Although
de novo translocations have been most widely
used for the mapping and identification of disease genes, small
deletions have been instrumental for cloning the genes for familial
adenomatous polyposis (3
), retinoblastoma (4
), WAGR syndrome
(5
) and a number of other contiguous gene syndromes (6
). In
particular, successful application of systematic deletion analysis
has identified a number of genes for holoprosencephaly including
SHH, ZIC2,
SIX3 and
TGIF (7
–11
). However, such cytogenetically
visible deletions and/or duplications are rare and commonly
remain below the detection limit of traditional karyotyping
(5–10 Mb). In addition, the contribution of individual
genes to disease may not always be apparent in patients with
complex phenotypes due to cytogenetically visible alterations.
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DELETIONS AND DUPLICATIONS IN MONOGENIC DISEASES
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It is becoming increasingly clear that many so-called microdeletion
syndromes are largely or completely due to the phenotypic effects
of haploinsufficiency for single genes. Pertinent examples are
the
RAI1 gene in Smith–Magenis syndrome (12
), the
UBE3A gene in Angelman syndrome (13
) and the
TBX1 gene in deletion
22q11 syndrome (14
). For the
LIS1 gene in Miller-Dieker syndrome,
however, the situation is more complex. Although the deletion
of this gene is responsible for lissencephaly (15
), the concomitant
deletion of the
14-3-3 epsilon gene also contributes to this
brain phenotype (16
,17
). The reason that these conditions are
usually caused by microdeletions and rarely by intragenic mutations
reflects their chromosomal context rather than the intrinsic
features of the causative gene itself (18
). In fact, the only
real requirement for a microdeletion syndrome gene is that it
should be dosage-sensitive. In case of microduplications, the
effect of having a complete extra copy of a gene may produce
a phenotype that is not mirrored by other mutations in this
gene. For example,
PMP22 gene duplications result in Charcot–Marie–Tooth
Type 1A, whereas point mutations in this gene may lead to hereditary
liability to pressure palsies (19
,20
). However, this does not
hold for all cases, because both duplications and deletions
of the
PLP gene are common causes of Pelizaeus-Merzbacher disease
(21
). In addition, deletions and duplications of the
SOX3 gene
yield a similar phenotype of infundibular hypoplasia and hypopituitarism
(22
). Currently, the frequency of gross deletions and duplications
in the Human Mutation Database is
5% (23
). In this database,
large deletions and duplications are likely to be underrepresented,
except for those on the X chromosome, where numerous deletion-associated
phenotypes have been defined (Table
1) (24
). The frequencies
of microdeletions and microduplications in monogenic diseases
differ markedly. For example, there are monogenic diseases that
are mostly caused by gene mutations and rarely by deletions
or duplications, such as von Recklinghausen Neurofibromatosis,
Rubinstein–Taybi syndrome and Alagille syndrome. In other
monogenic diseases, however, large deletions or duplications
involving a dosage-sensitive gene are responsible for the majority
of the cases (Table
2). A more complex situation is encountered
in Sotos syndrome. This syndrome is caused predominantly by
heterozygous
NSD1 point mutations in the Caucasian population
(25
), whereas microdeletions containing the
NSD1 gene prevail
in the Japanese population (26
). This difference in mutation
spectrum may reflect differences in genomic architecture between
Japanese and Caucasians, but this remains to be resolved. Thus,
microdeletions and microduplications occur at various frequencies
in many monogenic diseases with a known genetic cause (Table
2), and the difference between a microdeletion syndrome with
rare mutations and a single gene mutation syndrome with occasional
large deletions may be gradual rather than absolute. The availability
of novel, highly sensitive methods for detecting small chromosomal
deletions and duplications further enhances our possibilities
for a straightforward mapping of the genes underlying these
diseases.
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MOLECULAR KARYOTYPING BY ARRAY CGH
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Conceptual and technological developments in molecular cytogenetics
are now enhancing the resolving power of conventional chromosome
analysis techniques from the megabase to the kilobase level
(currently
100 kb resolution). Tools that have mediated
these developments include (a) the generation of genome-wide
clone resources integrated into the finished human genome sequence,
(b) the development of high-throughput microarray platforms
and (c) the optimization of comparative genomic hybridization
(CGH) protocols and data analysis systems. Together, these developments
have accumulated into a ‘molecular karyotyping’
technology that allows a sensitive and specific detection of
single copy number changes at the submicroscopic level throughout
the entire human genome. Array-based CGH (array CGH), the application
of CGH to an array of genomic fragments with known physical
locations immobilized on glass slides, is at present the most
widely used method for high-resolution screening of genomic
copy number changes (27
,28
). Examples of other methods for high-resolution,
genome-wide detection of genomic copy number changes include
representational oligonucleotide microarray analysis (29
,30
)
and single nucleotide polymorphism oligonucleotide arrays (SNP
arrays) (31
).
When compared with conventional karyotyping, array CGH provides a higher resolution, a higher dynamic range and better possibilities for automation. In addition, it allows for direct linking of copy number alterations to known genomic sequences. Examples of substrates used for hybridization are bacterial artificial chromosomes (BACs) (32), cDNAs (33), oligonucleotides (34) and exon-specific PCR products (35). Many laboratories have started their array CGH studies using BAC clones representing selected genomic regions. Examples of these are arrays targeting all subtelomeric regions (36,37), regions known to be involved in microdeletion or microduplication syndromes (38–42) or other chromosomal regions of interest (43–47). High-density BAC arrays have recently been constructed with the aim to perform genome-wide copy number analyses, initially with a resolution of one clone per megabase (48,49) and now with a tiling resolution of approximately one clone per 100 kb (50). The increase in data obtained through these high-density arrays requires standardized storage systems as well as thorough statistical tools for normalization and automated detection of genomic copy number alterations (51,52). Pilot studies using 1 Mb resolution genome-wide BAC arrays (49,53) have recently indicated that causative microdeletions and/or duplications are present in 10% of patients with unexplained mental retardation and congenital malformations. These pilot studies have provided insight into the quality and reproducibility aspects of the array CGH procedure, and the need for validation of microarray findings by independent technologies such as fluorescent in situ hybridization (FISH) and/or multiplex ligation-dependent probe amplification (MLPA) (54). It is important to note that these studies also identified submicroscopic copy number alterations that have no direct phenotypic consequences, as identical alterations were found in either one of the normal parents as well as in independent normal controls (Fig. 1). This notion has been substantiated by recent systematic studies revealing the presence of large copy number variations in apparently normal individuals (30,55–57). These alterations represent a novel class of polymorphisms within the human genome, termed large-scale copy number variations or copy number polymorphisms, whose exact frequency in different ethnic groups remains to be established. It is essential to rule out such submicroscopic variation by studying parental samples and/or independent normal controls before drawing any firm conclusion on whether an aneusomic segment is causative for the disease under investigation.
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Figure 1. From genome profile to disease gene identification. Example of a genome profile obtained by array CGH in a patient with mental retardation and additional congenital malformations. The 32 447 human BAC clones (indicated by small circles representing the log 2-transformed and normalized test-over-reference intensity ratios) are ordered from 1pter to Yqter in the genome profile, and for individual chromosomes (B) from pter to qter, on the basis of the physical mapping positions obtained from May 2004 freeze of the UCSC genome browser. The male patient is hybridized versus a female reference pool. (A) Two deletions, one on chromosome 1 and another on chromosome 15 are identified. (B) Testing for de novo occurrence by analyzing parental DNA samples showed that the deletion on chromosome 1 was de novo, whereas the deletion on chromosome 15 was inherited. (C) FISH and MLPA analysis were performed for validation of the de novo chromosome 1 deletion after which the target genes for the disease under investigation can be identified (D) using publicly available genome browsers such as the UCSC genome browser (http://genome.ucsc.edu).
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DISEASE GENE IDENTIFICATION BY ARRAY CGH
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We localized the gene for CHARGE syndrome by identifying and
characterizing microdeletions by array CGH (58
). CHARGE syndrome
(OMIM no. 214800
[OMIM]
) is a pleiotropic disorder comprising of coloboma,
heart defects, choanal atresia, retarded growth and development,
genital hypoplasia, ear anomalies and deafness (59
,60
). Until
recently, the cause of this sporadic malformation syndrome was
unknown. We tested 18 patients with CHARGE syndrome on a 1 Mb
resolution genome-wide BAC array. One
de novo microdeletion
of 4.8 Mb was identified on 8q12. Another CHARGE patient
originally reported with a balanced chromosome 8 translocation
(61
) revealed a complex microdeletion partially overlapping
with the one encountered in our index patient. No microdeletions
were identified in 17 additional CHARGE patients tested on a
tiling resolution chromosome 8 BAC array. Sequence analysis
of nine genes located within the minimal region of deletion
overlap revealed causative mutations in
CHD7, a novel member
of the chromodomain helicase DNA-binding gene family, in the
majority of CHARGE patients without microdeletions. From these
results, we concluded that CHARGE syndrome is caused by haploinsufficiency
of the
CHD7 gene, either by a microdeletion encompassing the
CHD7 gene or by single base changes within this gene.
CHD7 encodes
a protein of the chromodomain (chromatin organization modifier)
family, which shares a unique combination of functional domains
consisting of two N-terminal chromodomains, followed by a SWI2/SNF2-like
ATPase/helicase domain and a DNA binding domain (62
,63
). It
is assumed that CHD protein complexes can affect chromatin structure
and gene expression, and thereby play an important role in regulating
embryonic development. This study showed that array CGH can
indeed serve as an effective new approach to localize disease-causing
genes.
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CONSIDERATIONS FOR THE USE OF ARRAY CGH IN DISEASE GENE DISCOVERY
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Molecular karyotyping is most suited to the discovery of those
single gene diseases that involve haploinsufficiency as the
pathogenic mechanism. Whether this is the case may be impossible
to predict from the phenotype alone. For example, much effort
went into a strategy that aimed at the identification of the
gene that causes Noonan syndrome by detecting deletions in individual
patients with a Noonan-like phenotype (64
–67
). This strategy
failed because all causative mutations of the
PTPN11 gene are
missense mutations (68
). Other syndromes that could have been
never found by analyzing the genome for deletions or duplications
by array CGH are achondroplasia, EEC syndrome, brachydactyly
B and multiple endocrine neoplasia Type II, which all involve
similar missense mutations with a presumed or proven gain-of-function
(69
–72
). A further constraint on the use of deletion and
duplication searches for disease gene identification concerns
the local genome composition. Deletions need to be of sufficient
size and to be detectable with current techniques (50–100 kb
for array CGH). The frequency of patients with such large rearrangements
depends on the sequence characteristics of the region involved,
which may contain repeats that predispose to deletion or duplication
(18
). Another relevant consideration is the presence of further
genes in the region that are subject to gene dosage effects.
Obviously, if two prenatally lethal genes flank the disease
gene, no live-born patients with large deletions will exist.
Some patients are more likely to have deletions (or duplications)
that are within the detection limits of array CGH or other current
molecular karyotyping methods. Significant mental retardation,
for instance, predicts the presence of microdeletions for a
number of single gene conditions (Table
3). In addition, combinations
of clinical features may occur through contiguous gene deletion
syndromes, which continue to be defined (Table
4). Therefore,
selection of individual cases with monogenic diseases presenting
with additional features such as mental retardation will increase
the chance of disease gene discovery. In the case of CHARGE
syndrome, the index patient with the 4.8 Mb deletion presented
with relatively severe mental retardation, which may be due
to the deletion of genes adjacent to the dosage-sensitive
CHD7 gene. Subsequent testing of over 40 patients with typical CHARGE
characteristics revealed no further large deletions of the
CHD7 gene and confirmed point mutations of
CHD7 as the major cause
for CHARGE syndrome (Jongmans
et al., manuscript in preparation).
This observation is in conformity with attempts by other groups
to detect microdeletions in CHARGE syndrome that have all been
unsuccessful (73
–75
). Therefore, the low frequency of
microdeletions in CHARGE syndrome might argue against deletion
screening as a general strategy for malformation syndromes.
In contrast, we identified a 4 Mb microdeletion in one
out of five families with the Feingold syndrome that were studied
for linkage on chromosome 2 (76
). Haploinsufficient point mutations
of the
NMYC gene were subsequently identified in several additional
families but also a second 1.2 Mb microdeletion, thus yielding
a provisional estimate of 10% occurrence for microdeletions
in this syndrome (77
).
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CONCLUSIONS AND FUTURE PROSPECTS
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Microdeletions and/or microduplications may comprise up to 15%
of all mutations underlying monogenic diseases. Array CGH is
a powerful disease gene identification strategy, especially
when straightforward linkage mapping is impractical or impossible
due to reproductive lethality. This strategy is most likely
to be successful in patients with a monogenic condition in combination
with mental retardation or in rare patients with two or more
unrelated genetic conditions. In addition, the success of this
approach is determined by the resolution of the genome-wide
copy number screening technology used. The current resolution
of tiling resolution array CGH is
100 kb, limited by the
size of the BAC clones used as array elements. With this resolution
rearrangements of individual genes will not be identified, let alone
individual exons. In theory, alternative array elements using
shorter sequences may yield higher genomic resolutions, provided
that measurement precision is maintained. Reliable detection
of single copy number changes has been demonstrated for sequences
of <1000 bases, although not on a genome-wide scale (35
).
In addition, combining data from multiple elements is currently
required for genome profiling using oligonucleotides (78
) or
SNPs (79
,80
), as these provide less intense hybridization signals
and, consequently, a reduction in measurement precision. Nonetheless,
rapid developments in current microarray technologies will lead
to a significant increase in the numbers of elements to be tested,
which will soon surpass a million. Thus, reliable genomic copy
number screening of most if not all exons present within the
human genome will soon become possible (Fig.
2). On the
basis of published data for X-linked diseases and for some comprehensively
studied inherited cancer genes like
APC,
VHL and
BRCA1, the
overall percentage of gross deletions involving one or more
whole exons may account for up to 15% of all mutations. Assuming
an average of 10% whole exon deletions or duplications in monogenic
diseases, one would have a 65% chance of identifying any disease
gene among 10 unrelated patients, and nearly 90% chance of identifying
the causative gene if 20 such patients were available. This
suggests that a further development of methods for gene dosage
measurement will result in a general strategy for disease gene
identification that is applicable to individual patients.
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Figure 2. The impact of increasing resolution of genome profiling methods on disease gene identification.
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Conflict of Interest statement. None declared.
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ABSTRACT
INTRODUCTION