Human Molecular Genetics

Human Molecular Genetics 2005 14(Review Issue 2):R215-R223; doi:10.1093/hmg/ddi268

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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

	ABSTRACT

TOP ABSTRACT INTRODUCTION DELETIONS AND DUPLICATIONS IN... MOLECULAR KARYOTYPING BY ARRAY... DISEASE GENE IDENTIFICATION BY... CONSIDERATIONS FOR THE USE... CONCLUSIONS AND FUTURE PROSPECTS REFERENCES

 
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.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION DELETIONS AND DUPLICATIONS IN... MOLECULAR KARYOTYPING BY ARRAY... DISEASE GENE IDENTIFICATION BY... CONSIDERATIONS FOR THE USE... CONCLUSIONS AND FUTURE PROSPECTS REFERENCES

 
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

TOP ABSTRACT INTRODUCTION DELETIONS AND DUPLICATIONS IN... MOLECULAR KARYOTYPING BY ARRAY... DISEASE GENE IDENTIFICATION BY... CONSIDERATIONS FOR THE USE... CONCLUSIONS AND FUTURE PROSPECTS REFERENCES

 
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.

View this table: [in this window] [in a new window]   Table 1. Frequency of gross deletions in X-linked diseases

 

View this table: [in this window] [in a new window]   Table 2. Monogenic diseases with frequent occurrence of deletions or duplications >50 kb

 

	MOLECULAR KARYOTYPING BY ARRAY CGH

TOP ABSTRACT INTRODUCTION DELETIONS AND DUPLICATIONS IN... MOLECULAR KARYOTYPING BY ARRAY... DISEASE GENE IDENTIFICATION BY... CONSIDERATIONS FOR THE USE... CONCLUSIONS AND FUTURE PROSPECTS REFERENCES

 
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.

View larger version (40K): [in this window] [in a new window]   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).

 

	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.

	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).

View this table: [in this window] [in a new window]   Table 3. Monogenic diseases with mental retardation due to a genomic deletion

 

View this table: [in this window] [in a new window]   Table 4. Recently defined contiguous gene syndromes

 

	CONCLUSIONS AND FUTURE PROSPECTS

TOP ABSTRACT INTRODUCTION DELETIONS AND DUPLICATIONS IN... MOLECULAR KARYOTYPING BY ARRAY... DISEASE GENE IDENTIFICATION BY... CONSIDERATIONS FOR THE USE... CONCLUSIONS AND FUTURE PROSPECTS REFERENCES

 
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.

View larger version (20K): [in this window] [in a new window]   Figure 2. The impact of increasing resolution of genome profiling methods on disease gene identification.

 
Conflict of Interest statement. None declared.

	REFERENCES

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