Download Identification of disease genes by whole genome

Human Molecular Genetics, 2005, Vol. 14, Review Issue 2
doi:10.1093/hmg/ddi268
R215–R223
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
Received June 30, 2005; Revised and Accepted July 14, 2005
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 microarraybased 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.
INTRODUCTION
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.
DELETIONS AND DUPLICATIONS IN
MONOGENIC DISEASES
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
*To whom correspondence should be addressed. Tel: þ31 243614941; Fax: þ31 243668752; Email: [email protected]
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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.
MOLECULAR KARYOTYPING BY ARRAY CGH
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 highthroughput 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.
DISEASE GENE IDENTIFICATION BY ARRAY CGH
We localized the gene for CHARGE syndrome by identifying
and characterizing microdeletions by array CGH (58).
CHARGE syndrome (OMIM no. 214800) 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.
Human Molecular Genetics, 2005, Vol. 14, Review Issue 2
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Table 1. Frequency of gross deletions in X-linked diseases
Syndrome
Chromosome location
Gene involved
Frequency of
deletion (%)
Androgen insensitivity syndrome
X-linked Alport syndrome
Mucopolysaccharidosis Type II
X-linked juvenile retinoschisis
Hemophilia A
Menkes disease
Lesch–Nyhan syndrome
Duchenne muscular dystrophy
X-linked lymphoproliferative syndrome
Xq11– q12
Xq22.3
Xq28
Xp22.2–p22.1
Xq28
Xq12– q13
Xq26– q27.2
Xp21.2
Xq25
AR
COL4A5
IDS
RS1
Coagulation factor VIII
ATP7A
HPRT1
DMD
SH2D1A
7
8
9
11
12
15
21
23
38
Data from: Human Gene Mutation database (23,24).
Table 2. Monogenic diseases with frequent occurrence of deletions or duplications .50 kb
Syndrome
Chromosome location
Dosage-sensitive gene
Frequency of deletion/
duplication (%)
Reference
Sotos syndrome
Neurofibromatosis Type 1
Alagille syndrome
Rubinstein–Taybi syndrome
Congenital 21-alpha
hydroxylase deficiency
Transient neonatal diabetes
Cystinosis syndrome
Pelizaeus–Merzbacher
Smith–Magenis syndrome
5q35
17q11.2
20p12
16p13.3
6p21.3
NSD1
NF1
JAG1
CREBBP
CYP21A2
6–49a
7
7
10
28
(25,26,81)
(82,83)
(84– 87)
(88,89)
(90)
6q24
17p13
Xq22
17p11.2
tbd
CTNS
PLP1
RAI1
36
44
62
.90
(91,92)
(93)
(94,95)
(96)
Only single gene disorders without mental retardation are listed. tbd, to be determined.
a
Mutation/deletion detection dependent on ethnic background.
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 diseasecausing genes.
CONSIDERATIONS FOR THE USE OF ARRAY
CGH IN DISEASE GENE DISCOVERY
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
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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-overreference 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).
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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Table 3. Monogenic diseases with mental retardation due to a genomic deletion
Syndrome
Chromosome
Gene involved
Deletion size
Reference
Hereditary non-polyposis
colorectal carcinoma
BPES (blepharophimosis)
Rieger syndrome
Greig cephalopolysyndactyly
Saethre–Chotzen syndrome
Aniridia Type II
Alport syndrome
2p22–p21
MSH2
5 kb to .150 kb
(97,98)
3q23
4q25–q26
7p13
7p21
11p13
Xq22.3
FOXL2
PITX2
GLI3
TWIST
PAX6
COL4A5
.200 kb
445 kb
150 kb to 10.6 Mb
3 Mb to .11.6 Mb
75 kb to ,1500 kb
10 kb to 1.4 Mb
(99,100)
(101)
(102)
(103)
(104,105)
(106)
Table 4. Recently defined contiguous gene syndromes
Syndrome
Chromosome
Gene(s) involved
Deletion
size (kb)
Detectable by tiling
resolution BAC arraya
Reference
Cystinuria with mitochondrial disease
Adrenal hyperplasia with hypermobility
Otofacialcervical syndrome
Potocki–Shaffer
Infantile hyperinsulinism, enteropathy
and deafness
Tuberous sclerosis, polycystic
kidney disease
Alport-leiomyomatosis
del(2p16)
del(6)(p21)
del(8)(q13.3)
del(11)(p11.2)
del(11)(p15p14)
SLC3A1; PPM1B; KIAA0436
TNXB; CYP21A
EYA1
EXT2; ALX4
USH1C; ABCC8; KCNJ11
179
33
316
2100
122
þþ
2
þþ
þþþ
þ
(107)
(108)
(109)
(110)
(111)
del(16)(p13)
TSC2; PKD1
þ/2
(112)
del(X)(q22.3)
COL4A5; COL4A6
þ
(113)
87
133
a
Detection indicated by ‘þ’ and ‘2’ for detectable and undetectable, respectively.
CONCLUSIONS AND FUTURE PROSPECTS
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
Figure 2. The impact of increasing resolution of genome profiling methods on
disease gene identification.
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
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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.
Conflict of Interest statement. None declared.
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