Human Molecular Genetics

Human Molecular Genetics 2006 15(Review Issue 1):R57-R66; doi:10.1093/hmg/ddl057

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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Structural variants: changing the landscape of chromosomes and design of disease studies

Lars Feuk, Christian R. Marshall, Richard F. Wintle and Stephen W. Scherer^*

The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, Department of Molecular and Medical Genetics, University of Toronto, Ontario, Canada

^* To whom correspondence should be addressed at: The Centre for Applied Genomics, The Hospital for Sick Children, MaRS Centre—East Tower, 101 College Street, Room 14-701, Toronto, Ontario, Canada M5G 1L7. Tel: +1 4168137613; Fax: +1 4168138319; Email: swscherer{at}sickkids.ca

Received February 23, 2006; Accepted March 9, 2006

	ABSTRACT

TOP ABSTRACT INTRODUCTION STRUCTURAL VARIATION INFLUENCING... POTENTIAL LONG-RANGE (POSITION)... MEDICAL AND BIOLOGICAL... CONCLUSIONS AND FUTURE STUDIES SUPPLEMENTARY MATERIAL REFERENCES

 
The near completeness of human chromosome sequences is facilitating accurate characterization and assessment of all classes of genomic variation. Particularly, using the DNA reference sequence as a guide, genome scanning technologies, such as microarray-based comparative genomic hybridization (array CGH) and genome-wide single nucleotide polymorphism (SNP) platforms, have now enabled the detection of a previously unrecognized degree of larger-sized (non-SNP) variability in all genomes. This heterogeneity can include copy number variations (CNVs), inversions, insertions, deletions and other complex rearrangements, most of which are not detected by standard cytogenetics or DNA sequencing. Although these genomic alterations (collectively termed structural variants or polymorphisms) have been described previously, mainly through locus-specific studies, they are now known to be more global in occurrence. Moreover, as just one example, CNVs can contain entire genes and their number can correlate with the level of gene expression. It is also plausible that structural variants may commonly influence nearby genes through chromosomal positional or domain effects. Here, we discuss what is known of the prevalence of structural variants in the human genome and how they might influence phenotype, including the continuum of etiologic events underlying monogenic to complex diseases. Particularly, we highlight the newest studies and some classic examples of how structural variants might have adverse genetic consequences. We also discuss why analysis of structural variants should become a vital step in any genetic study going forward. All these progresses have set the stage for a golden era of combined microscopic and sub-microscopic (cytogenomic)-based research of chromosomes leading to a more complete understanding of the human genome.

	INTRODUCTION

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In the past few years, several studies have identified a previously uncharacterized prevalence of structural variants of DNA along chromosomes in the size range of 1 kb or greater, adding to the catalog of variants in the human genome (Table 1). Namely, sub-microscopic (usually less than 3 Mb) copy number variations (CNVs) and inversions have been found to occur in every genome studied at high frequencies when compared with the equivalent classes of cytogenetically detectable rearrangements (1–8). Similar findings are also now being made more readily in disease gene studies.

View this table: [in this window] [in a new window]   Table 1. Genetic variation in the human genome

 
These discoveries have come somewhat later than the description (and generation of comprehensive maps) of single nucleotide polymorphisms (SNPs) (9,10), microsatellites (11,12) and minisatellites (13), as well as catalogs of cytogenetically detectable heteromorphisms and rearrangements, because of limits of resolution in the technology at that time. However, new developments in genome-wide scanning methodologies using genomic clone and oligonucleotide-based arrays occurring in parallel with the availability of a reference human genome sequence now provide opportunity to generate advanced maps of structural variation in worldwide populations. Moreover, next generation sequencing technologies and computational comparisons of sequences from different sources will yield a vast number of variants primarily in the <1 kb size range that have not been described previously. Comprehensive reviews describing the discovery and properties of, in particular, CNVs, but also other structural variants, have been published recently (14–19). Here, we highlight the latest findings, with a particular emphasis on the new sub-microscopic variants being increasingly described in the 1 kb to 3 Mb size range and how they may influence phenotype or be involved in disease.

	STRUCTURAL VARIATION INFLUENCING PHENOTYPE

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Changes in DNA that affect gene function (often through affecting dosage) can have a deleterious effect on the reproductive fitness of an organism, and in some cases represent lethal mutations. In these circumstances, the variants would eventually be destined to disappear, but they can often exist in a heterozygous form for many generations. In between these extremes of selectively neutral variants and lethal mutations lie variants that can influence physiological, biochemical, morphological and pathological variation in the human population. Recent descriptions of numerous ‘gene-sized’ (the average size of a gene being 70 kb) sub-microscopic structural variants in all genomes have generated significant excitement in the field (20–25), because (i) it was presumed they probably should exist for the same reasons as SNPs and microscopic variants; (ii) their sheer size (often affecting hundreds to thousands of nucleotides of DNA) increases the likelihood that the alteration is, in fact, a genomic lesion explaining disease outcomes; (iii) as such, some will also be shown to predispose to disease either directly or in combination with other variants and factors and (iv) some will provide substrate for evolutionary change. The description of all variants will be important for many wide-ranging reasons, better resolving a more completely annotated reference genome sequence to understanding implications in pharmacogenomics and clinical diagnostic testing.

It has been well established in many classic (26–33) as well as in more recent studies of monogenic disease (34), oligogenetic disease (35–41), and most recently in complex disease that the study of such chromosome rearrangements can be the most rapid approach to identify candidate susceptibility loci and genes (that then need to be confirmed in other samples). For complex diseases (note that in some cases, these were the Mendelian sub-forms of complex disease demonstrating the same phenotypic endpoint), examples include: in autism, X-chromosome deletions led to the identification of the neuroligin NLGN3 and NLGN4 genes (42); in schizophrenia, a familial chromosome 1 translocation led to the discovery of the DISC1 and DISC2 genes (43); in dyslexia, distinct chromosomes 3 and 15 translocations led to the discovery of ROBO1 and DYXC1, respectively (44,45); in severe speech and language disorder, a chromosome 7q31 translocation pinpointed the FOXP2 gene (46); in Tourette syndrome, a de novo inversion led to SLITRK1 involvement (47); in severe expressive language delay, microduplication of the Williams–Beuren syndrome locus on chromosome 7q11.23 (48) and in early onset Parkinson and Alzheimer's disease, duplications of SNCA and APP on chromosomes 4 and 21, respectively, have been shown to be causative (49,50).

Indeed, the primary message of this review is to increase the awareness of the necessity for including steps for screening for structural variants in genetic experiments. This was exquisitely demonstrated in a recent study showing that copy number polymorphism in the FCGR3 gene predisposes to glomerulonephritis in humans and rats (51). Preliminary data suggest that dozens of CNVs alone will be found in a given genome when assessed using comprehensive scanning methodologies. The sub-microscopic variants will be intermediate in size and frequency in comparison to occurrence of cytogenetically detectable and smaller (<1 kb) polymorphisms. These aberrations can be hundreds of kilobases long, having important implications for the potential effect they may exert on genes and transcriptional regulation (Fig. 1). Moreover, a large number of CNVs have been shown to contain one or more entire coding transcripts (1,2,52,53). In studies where these genes have been characterized, there seems to be a direct correlation between increases in gene copy number and increased levels of mRNA (53–56). Polymorphic deletions containing entire genes have also been described, where a fraction of the population are homozygous for the deletion allele and, therefore, do not have the gene present in their genome (6,8,57). Most of the genes in this category belong to gene families or are recently duplicated in evolutionary history, and this may increase the tolerance for null alleles.

View larger version (41K): [in this window] [in a new window]   Figure 1. CNV influencing gene dosage and expression and disease. There are a number of mechanisms by which CNVs potentially could have an effect on gene expression and phenotypic traits. Well-documented examples involve regions with multiple genes deleted in microdeletion syndromes and microduplication syndromes (A), where there is a direct correlation between genotype and phenotype. Copy number polymorphisms where a gene is located entirely within a region that varies in copy number (B) have also been described to show a direct correlation between gene copy number and gene expression. Another mechanism by which CNVs may have an influence on disease phenotype is if the remaining copy harbors a risk allele that becomes apparent only in the hemizygous state (C). The opposite scenario may also occur, with an increased number of copies harboring a risk allele, causing a concurrent increase in disease susceptibility. It can also be hypothesized that CNVs may affect gene expression without directly changing the gene copy number. Gains or losses affecting the regulatory elements or promoter regions can also be important contributors to differences in gene expression. This could involve either loss of an element of transcriptional regulation (D and F) or a loss/gain changing the structural properties of DNA inhibiting enhancer interaction, chromatin structure or access of transcription factors to their binding sites (E). Interaction and additive models with any of these scenarios combined or in combination with any type of variation at other loci can be expected to be the cause of more complex genetic traits.

 
Specific categories of genes seem over-represented in CNVs including those important for interaction with the surrounding environment, such as olfaction and response to external stimuli (19,58). Examples of such polymorphic genes include glutathione S-transferase genes (59,60), cytochrome P450 genes (61–65) and the complement component C4 (66). In each case, changes to gene copy number have been shown to give rise to concomitant changes in the level of enzyme activity, with phenotypic consequences. Another example is the CCL3L1 gene, where the increased copy number has been shown to be protective against HIV infection (56).

Inversions represent another class of structural variation (Table 1), but knowledge of their prevalence in the human genome is more limited. This is partly due to a lack of technologies for robust and inexpensive discovery of such balanced rearrangements. In addition, preliminary data indicate that inversion variants are less abundant than CNVs in the human genome (4). However, there are a number of well-documented cases where inversion variants can be associated with disease predisposition, primarily in microdeletion syndromes. In these instances, the inversion variant need not be a direct cause of the disease, but instead it can act as a risk factor for microdeletion to occur in the offspring, as appears to be the case in Williams–Beuren (67), Angelman (68) and Sotos syndromes (69).

	POTENTIAL LONG-RANGE (POSITION) EFFECTS OF STRUCTURAL VARIANTS ON GENES

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As discussed, structural variants can affect dosage by directly interrupting genes, but it is important to appreciate that they can have an equivalent effect at a distance (in an indirect manner) (Fig. 1). Although genes only represent a small portion (<3%) of the human genome and there are hundreds of putative ‘gene deserts’, sometimes millions of base pairs in size (70–72), there is now substantial evidence that regulatory elements of genes can reside up to a million base pairs or more away (Fig. 1; Table 2) (Supplementary Material, Table S1). Thus, structural variants cannot be presumed to be selectively neutral because they encompass only non-coding segments, but instead a careful assessment of nearby genes that may be affected via a ‘position effect’ mechanism also needs to be considered.

View this table: [in this window] [in a new window]   Table 2. Selected recently published examples of potential position effects caused by structural variants

 
Position effect refers to the alteration of a gene's expression pattern as a result of a change in its genomic location or chromatin environment. This phenomenon has been most extensively studied in Drosophila (73) and yeast (74), but an increasing number of examples in humans have been reported, including a variety of developmental disorders such as aniridia (75–78), holoprosencephaly (79–81), campomelic dysplasia (82–90), thalassemias (91–94), X–Y sex reversal (95,96) and others (Supplementary Material, Table S1). Position effects can be caused by a variety of mechanisms. These include translocation of a gene into a heterochromatic region resulting in the methylation of promoter regions and consequent down-regulation of expression, chromosome breakage (translocations, inversions, deletions and duplications) that separates a gene from some or all of its transcriptional control elements or otherwise alters gene expression (94), or genomic rearrangements that bring a gene into close proximity to a positive regulatory element (97). In recent reviews (80,97), several additional examples of congenital abnormalities resulting in either obvious or postulated position effects in humans have been reported. Here, we call attention to some studies from the past few years, highlighting how the structural variants can be involved in disease through different mechanisms of action (Table 2) (additional historical studies are summarized in Supplementary Material, Table S1).

In most cases, the effect of genomic rearrangement on gene expression has been inferred, rather than observed directly. This is often due to the unavailability of appropriate tissue or developmental timing of expression that would render gene expression analysis impossible. As an example, a translocation that disrupts the HDAC9 gene at 7p21.1 has its reciprocal breakpoint on chromosome 1, 500 kb from the TGFB2 gene. The patient carrying this translocation has Peter's anomaly, a defect of the anterior chamber of the eye, and as Tgfb2 null mice have very similar developmental eye defects, and therefore, the authors consider a position effect at TGFB2, rather than HDAC9 disruption, to be the most likely underlying pathology (98). A more complex example is a 23–25 kb deletion and 340 kb insertion at the deletion point, 67 kb 3' to the SOX3 gene, found in a patient with X-linked recessive hypoparathyroidism (99). It is presumed that down-regulation of SOX3 results in the phenotype, as SOX3 has been observed to be expressed in the developing parathyroid of mouse embryos.

In other recent examples, Wakui et al. (100) report a patient with a large deletion located just 3' of the ALX4 gene having atypical manifestation of Potocki–Shaffer syndrome. Beysen et al. (101) describe a number of patients with Blepharophimosis syndrome (one of the syndromes most frequently reported to be associated with position effects in humans), each having a microdeletion near the FOXL2 gene. Lee et al. (102) describe a patient with an atypical phenotype (spastic paraplegia type II with axonal neuropathy) because of a duplication near the PLP1 gene, deletions and duplications of which usually result in Pelizaeus–Merzbacher syndrome (103). Mild forms of campomelic dysplasia, a skeletal malformation syndrome, have also been reported, as a result of balanced translocations near the SOX9 gene in three different patients [two with simple reciprocal translocations and one with a complex translocation (82,83)]. Ellison et al. (104) report a patient with a ring (X) chromosome that is presumed to cause a down-regulation of the SHOX gene, resulting in short stature in that patient, although a significant amount of Xp and Xq material is also deleted, including several other genes. Finally, in an extreme case carrying a de novo t(6;7) (p21.1;q36) reciprocal translocation exhibiting both holoprosencephaly and cleidocranial dysplasia, there are two apparent position effect mutations in the same individual: the 7q36 breakpoint mapping 15 kb telomeric to the 5' end of Sonic Hedgehog causes holoprosencephaly and the 6p21.1 breakpoint mapping 800 kb upstream of CBFA1 (RUNX2) causes cleidocranial dysplasia (80).

It is striking that a majority of genes reported to be affected by apparent position effects in humans are involved in developmental syndromes. This could be due to ascertainment bias, as phenotypes in these patients tend to be either atypical or unusually mild. Alternatively, it could be that other classes of genes, e.g. those encoding enzymes, are much more tolerant to positional silencing or down-regulation and that individuals with such rearrangements thus escape clinical notice. It has also been suggested that large ‘gene deserts’ often found around the developmental genes (71) may serve as enhanced targets for chromosomal rearrangements (105). Notwithstanding, the take home message from these studies and others is that the structural variant need not only affect what we usually define as the classical gene unit to have an effect; proximal and distal genes also need to be considered.

	MEDICAL AND BIOLOGICAL SIGNIFICANCE

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With the ability to recognize dozens of sub-microscopic variants in all genomes, a hierarchical paradigm of how to differentiate the manifestation of disease- (or phenotype-) associated changes needs to be considered (Fig. 2). For example, in some cases, a structural variant correlates directly with the disease, such as the case in dosage-related microdeletions and duplications that cause genomic disorders and in other cases described earlier (106). Family-based studies can demonstrate whether a change is de novo or has been inherited and, in the latter case, whether there are likely to be associated phenotypic consequences. However, there are numerous examples of lack of penetrance or variable expression of phenotype in inherited chromosomal rearrangements (107), requiring analysis be extended to a larger population of controls. Other factors such as the genomic context (e.g. types of genes and likelihood to be affected by position effect), the heritable stability of the variant (it could predispose to other mitotic or meiotic rearrangements), influence of other variants and possible parent-of-origin effects (e.g. imprinted regions) all need to be considered when evaluating the effect at the genic level.

View larger version (19K): [in this window] [in a new window]   Figure 2. Genetic and genomic considerations of assessing the influence of structural variants on gene expression and phenotype/disease manifestation.

 
Databases cataloging large-scale genotype and phenotype correlations (17,70,108) will be increasingly important to help discern how these changes might cause phenotypic or functional outcomes (Table 3 provides web links). For example, the genome-wide initiatives including the Database of Chromosomal Imbalance and Phenotypes in Humans using Ensembl Resources (DECIPHER) and the Developmental Genome Anatomy Project (DGAP) promise to bridge the gap from DNA sequence to medical genetic outcomes, but the databases are still sparsely populated. Other efforts, including the Mendelian Cytogenetics Network Online Database, the Chromosome Abnormality Database, the European Collection of Cell Cultures, Coriell Cell Repositories, NIGMS Human Genetic Cell Repository and the Mitelman Database of chromosome aberrations in cancer, among others, provide catalogs of samples with karyotypes and phenotypes. The Database of Genomic Variants and the Human Structural Variation Database house information on structural variants that are generally not known to cause disease. It is also worth noting that there are large data sets of SNPs and microsatellites from disease mapping studies (Supplementary Material, Tables S2 and S3) that could be analyzed for their putative CNV content in a manner similar to what has been done in autism (109) and HapMap samples (6,8).

View this table: [in this window] [in a new window]   Table 3. Examples of databases and resources for studies of structural variation

 

	CONCLUSIONS AND FUTURE STUDIES

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The complexity of variation in the human genome continues to be unraveled, providing opportunity to explain genetic contributions to disease in a more comprehensive manner. Going forward into the next few years, studies examining the role of sub-microscopic structural variation will become a predominant theme because of significant advances in technology allowing for the scanning of genomes at relatively high resolution. In fact, on the basis of the numbers of discoveries and impact alone in the past 2 years, it could be argued that we have entered a ‘cytogenomic’ era for discovery in human genetics. In large-scale population-based whole genome association studies (Supplementary Material, Table S3), and in any disease gene study, a component of assessing structural variation content should be incorporated. However, comprehending the contribution of these variants will require the understanding of wide-ranging data from simple presence or absence (in cases and controls) to the position and context in the genome (Fig. 2). It will be important to determine the new mutation rate (25,110) of these variants across the genome, including the heterochromatic regions. The next frontier will be to fully catalog all the structural variants in the 1 kb to 3 Mb size range discussed here, but also all other variations in the 1 bp to 1 kb size range (Table 1), which will probably be best discerned through personalized genome (re-)sequencing (111). Coupling all of this information to large cohorts of meticulously phenotyped sample collections and corresponding databases would provide insight toward understanding the etiology of many unresolved diseases.

	SUPPLEMENTARY MATERIAL

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Supplementary Material is available at HMG Online.

	ACKNOWLEDGEMENTS

 
The work was supported by funds from The Centre for Applied Genomics, Hospital for Sick Children, Genome Canada/Ontario Genomics Institute, the Canadian Institutes of Health Research (CIHR) and the McLaughlin Centre for Molecular Medicine. L.F. is supported by the Swedish Medical Research Council, C.R.M. by The Hospital for Sick Children Research Training Centre and S.W.S. is an Investigator of CIHR and International Scholar of the Howard Hughes Medical Institute.

Conflict of Interest statement. None declared.

	REFERENCES

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1. Iafrate, A.J., Feuk, L., Rivera, M.N., Listewnik, M.L., Donahoe, P.K., Qi, Y., Scherer, S.W. and Lee, C. (2004) Detection of large-scale variation in the human genome. Nat. Genet., 36, 949–951.[CrossRef][Web of Science][Medline]

2. Sebat, J., Lakshmi, B., Troge, J., Alexander, J., Young, J., Lundin, P., Maner, S., Massa, H., Walker, M., Chi, M. et al. (2004) Large-scale copy number polymorphism in the human genome. Science, 305, 525–528.[Abstract/Free Full Text]

3. Sharp, A.J., Locke, D.P., McGrath, S.D., Cheng, Z., Bailey, J.A., Vallente, R.U., Pertz, L.M., Clark, R.A., Schwartz, S., Segraves, R. et al. (2005) Segmental duplications and copy-number variation in the human genome. Am. J. Hum. Genet., 77, 78–88.[CrossRef][Web of Science][Medline]

4. Tuzun, E., Sharp, A.J., Bailey, J.A., Kaul, R., Morrison, V.A., Pertz, L.M., Haugen, E., Hayden, H., Albertson, D., Pinkel, D. et al. (2005) Fine-scale structural variation of the human genome. Nat. Genet., 37, 727–732.[CrossRef][Web of Science][Medline]

5. Feuk, L., Macdonald, J.R., Tang, T., Carson, A.R., Li, M., Rao, G., Khaja, R. and Scherer, S.W. (2005) Discovery of human inversion polymorphisms by comparative analysis of human and chimpanzee DNA sequence assemblies. PLoS Genet., 1, e56.

6. Conrad, D.F., Andrews, T.D., Carter, N.P., Hurles, M.E. and Pritchard, J.K. (2006) A high-resolution survey of deletion polymorphism in the human genome. Nat. Genet., 38, 75–81.[CrossRef][Web of Science][Medline]

7. Hinds, D.A., Kloek, A.P., Jen, M., Chen, X. and Frazer, K.A. (2006) Common deletions and SNPs are in linkage disequilibrium in the human genome. Nat. Genet., 38, 82–85.[Web of Science][Medline]

8. McCarroll, S.A., Hadnott, T.N., Perry, G.H., Sabeti, P.C., Zody, M.C., Barrett, J.C., Dallaire, S., Gabriel, S.B., Lee, C., Daly, M.J. et al. (2006) Common deletion polymorphisms in the human genome. Nat. Genet., 38, 86–92.[Web of Science][Medline]

9. Altshuler, D., Brooks, L.D., Chakravarti, A., Collins, F.S., Daly, M.J. and Donnelly, P. (2005) A haplotype map of the human genome. Nature, 437, 1299–1320.[CrossRef][Medline]

10. The International HapMap Consortium (2003) The International HapMap Project. Nature, 426, 789–796.[CrossRef][Medline]

11. Murray, J.C., Buetow, K.H., Weber, J.L., Ludwigsen, S., Scherpbier-Heddema, T., Manion, F., Quillen, J., Sheffield, V.C., Sunden, S., Duyk, G.M. et al. (1994) A comprehensive human linkage map with centimorgan density. Cooperative Human Linkage Center (CHLC). Science, 265, 2049–2054.[Abstract/Free Full Text]

12. Kong, A., Gudbjartsson, D.F., Sainz, J., Jonsdottir, G.M., Gudjonsson, S.A., Richardsson, B., Sigurdardottir, S., Barnard, J., Hallbeck, B., Masson, G. et al. (2002) A high-resolution recombination map of the human genome. Nat. Genet., 31, 241–247.[CrossRef][Web of Science][Medline]

13. Nakamura, Y., Leppert, M., O'Connell, P., Wolff, R., Holm, T., Culver, M., Martin, C., Fujimoto, E., Hoff, M., Kumlin, E. et al. (1987) Variable number of tandem repeat (VNTR) markers for human gene mapping. Science, 235, 1616–1622.[Abstract/Free Full Text]

14. Buckley, P.G., Mantripragada, K.K., Piotrowski, A., Diaz de Stahl, T. and Dumanski, J.P. (2005) Copy-number polymorphisms: mining the tip of an iceberg. Trends Genet., 21, 315–317.[CrossRef][Web of Science][Medline]

15. Freeman, J.L., Perry, G.H., Feuk, L., Redon, R., McCarroll, S.A., Althshuler, D.M., Aburatani, H., Jones, K., Tyler-Smith, C., Hurles, M.E. et al.(2006) Copy number variation: new insights in genome diversity. Genome Res., submitted.

16. Stankiewicz, P. and Lupski, J.R. (2002) Genome architecture, rearrangements and genomic disorders. Trends Genet., 18, 74–82.[CrossRef][Web of Science][Medline]

17. Bugge, M., Bruun-Petersen, G., Brondum-Nielsen, K., Friedrich, U., Hansen, J., Jensen, G., Jensen, P.K., Kristoffersson, U., Lundsteen, C., Niebuhr, E. et al. (2000) Disease associated balanced chromosome rearrangements: a resource for large scale genotype–phenotype delineation in man. J. Med. Genet., 37, 858–865.[Abstract/Free Full Text]

18. Lupski, J.R. and Stankiewicz, P. (2005) Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet., 1, e49.[CrossRef][Medline]

19. Feuk, L., Carson, A.R. and Scherer, S.W. (2006) Structural variation in the human genome. Nat. Rev. Genet., 7, 85–97.[Web of Science][Medline]

20. Carter, N.P. (2004) As normal as normal can be? Nat. Genet., 36, 931–932.[CrossRef][Web of Science][Medline]

21. Eichler, E.E. (2006) Widening the spectrum of human genetic variation. Nat. Genet., 38, 9–11.[Web of Science][Medline]

22. Lee, C. (2005) Vive la difference! Nat. Genet., 37, 660–661.[CrossRef][Web of Science][Medline]

23. Nadeau, J.H. and Lee, C. (2006) Genetics: copies count. Nature, 439, 798–799.[CrossRef][Medline]

24. Check, E. (2005) Human genome: patchwork people. Nature, 437, 1084–1086.[CrossRef][Medline]

25. van Ommen, G.J. (2005) Frequency of new copy number variation in humans. Nat. Genet., 37, 333–334.[CrossRef][Web of Science][Medline]

26. Cawthon, R.M., Weiss, R., Xu, G.F., Viskochil, D., Culver, M., Stevens, J., Robertson, M., Dunn, D., Gesteland, R., O'Connell, P. et al. (1990) A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell, 62, 193–201.[CrossRef][Web of Science][Medline]

27. Call, K.M., Glaser, T., Ito, C.Y., Buckler, A.J., Pelletier, J., Haber, D.A., Rose, E.A., Kral, A., Yeger, H., Lewis, W.H. et al. (1990) Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell, 60, 509–520.[CrossRef][Web of Science][Medline]

28. Royer-Pokora, B., Kunkel, L.M., Monaco, A.P., Goff, S.C., Newburger, P.E., Baehner, R.L., Cole, F.S., Curnutte, J.T. and Orkin, S.H. (1986) Cloning the gene for an inherited human disorder—chronic granulomatous disease—on the basis of its chromosomal location. Nature, 322, 32–38.[CrossRef][Medline]

29. Monaco, A.P., Neve, R.L., Colletti-Feener, C., Bertelson, C.J., Kurnit, D.M. and Kunkel, L.M. (1986) Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene. Nature, 323, 646–650.[CrossRef][Medline]

30. Burghes, A.H., Logan, C., Hu, X., Belfall, B., Worton, R.G. and Ray, P.N. (1987) A cDNA clone from the Duchenne/Becker muscular dystrophy gene. Nature, 328, 434–437.[CrossRef][Medline]

31. Friend, S.H., Bernards, R., Rogelj, S., Weinberg, R.A., Rapaport, J.M., Albert, D.M. and Dryja, T.P. (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature, 323, 643–646.[CrossRef][Medline]

32. Gessler, M., Poustka, A., Cavenee, W., Neve, R.L., Orkin, S.H. and Bruns, G.A. (1990) Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature, 343, 774–778.[CrossRef][Medline]

33. Wallace, M.R., Marchuk, D.A., Andersen, L.B., Letcher, R., Odeh, H.M., Saulino, A.M., Fountain, J.W., Brereton, A., Nicholson, J., Mitchell, A.L. et al. (1990) Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science, 249, 181–186.[Abstract/Free Full Text]

34. Vissers, L.E., Veltman, J.A., van Kessel, A.G. and Brunner, H.G. (2005) Identification of disease genes by whole genome CGH arrays. Hum. Mol. Genet., 14 (Spec no. 2), R215–R223.[Abstract/Free Full Text]

35. Rosenberg, C., Knijnenburg, J., Bakker, E., Vianna-Morgante, A.M., Sloos, W., Otto, P.A., Kriek, M., Hansson, K., Krepischi-Santos, A.C., Fiegler, H. et al. (2006) Array-CGH detection of micro rearrangements in mentally retarded individuals: clinical significance of imbalances present both in affected children and normal parents. J. Med. Genet., 43, 180–186.[Abstract/Free Full Text]

36. Schoumans, J., Ruivenkamp, C., Holmberg, E., Kyllerman, M., Anderlid, B.M. and Nordenskjold, M. (2005) Detection of chromosomal imbalances in children with idiopathic mental retardation by array based comparative genomic hybridisation (array-CGH). J. Med. Genet., 42, 699–705.[Abstract/Free Full Text]

37. de Vries, B.B., Pfundt, R., Leisink, M., Koolen, D.A., Vissers, L.E., Janssen, I.M., Reijmersdal, S., Nillesen, W.M., Huys, E.H., Leeuw, N. et al. (2005) Diagnostic genome profiling in mental retardation. Am. J. Hum. Genet., 77, 606–616.[CrossRef][Web of Science][Medline]

38. Shaw-Smith, C., Redon, R., Rickman, L., Rio, M., Willatt, L., Fiegler, H., Firth, H., Sanlaville, D., Winter, R., Colleaux, L. et al. (2004) Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features. J. Med. Genet., 41, 241–248.[Abstract/Free Full Text]

39. Miyake, N., Shimokawa, O., Harada, N., Sosonkina, N., Okubo, A., Kawara, H., Okamoto, N., Kurosawa, K., Kawame, H., Iwakoshi, M. et al. (2006) BAC array CGH reveals genomic aberrations in idiopathic mental retardation. Am. J. Med. Genet. A, 140, 205–211.[Medline]

40. Bauters, M., Van Esch, H., Marynen, P. and Froyen, G. (2005) X chromosome array-CGH for the identification of novel X-linked mental retardation genes. Eur. J. Med. Genet., 48, 263–275.[CrossRef][Web of Science][Medline]

41. Lugtenberg, D., de Brouwer, A.P., Kleefstra, T., Oudakker, A.R., Frints, S.G., Schrander-Stumpel, C.T., Fryns, J.P., Jensen, L.R., Chelly, J., Moraine, C. et al. (2005) Chromosomal copy number changes in patients with non-syndromic X-linked mental retardation detected by array CGH. J. Med. Genet., doi:10.1136/jmg.2005.036178.

42. Jamain, S., Quach, H., Betancur, C., Rastam, M., Colineaux, C., Gillberg, I.C., Soderstrom, H., Giros, B., Leboyer, M., Gillberg, C. et al. (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet., 34, 27–29.[CrossRef][Web of Science][Medline]

43. Millar, J.K., Wilson-Annan, J.C., Anderson, S., Christie, S., Taylor, M.S., Semple, C.A., Devon, R.S., Clair, D.M., Muir, W.J., Blackwood, D.H. et al. (2000) Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum. Mol. Genet., 9, 1415–1423.[Abstract/Free Full Text]

44. Taipale, M., Kaminen, N., Nopola-Hemmi, J., Haltia, T., Myllyluoma, B., Lyytinen, H., Muller, K., Kaaranen, M., Lindsberg, P.J., Hannula-Jouppi, K. et al. (2003) A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain. Proc. Natl Acad. Sci. USA, 100, 11553–11558.[Abstract/Free Full Text]

45. Hannula-Jouppi, K., Kaminen-Ahola, N., Taipale, M., Eklund, R., Nopola-Hemmi, J., Kaariainen, H. and Kere, J. (2005) The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia. PLoS Genet., 1, e50.

46. Lai, C.S., Fisher, S.E., Hurst, J.A., Vargha-Khadem, F. and Monaco, A.P. (2001) A forkhead-domain gene is mutated in a severe speech and language disorder. Nature, 413, 519–523.[CrossRef][Medline]

47. Abelson, J.F., Kwan, K.Y., O'Roak, B.J., Baek, D.Y., Stillman, A.A., Morgan, T.M., Mathews, C.A., Pauls, D.L., Rasin, M.R., Gunel, M. et al. (2005) Sequence variants in SLITRK1 are associated with Tourette's syndrome. Science, 310, 317–320.[Abstract/Free Full Text]

48. Somerville, M.J., Mervis, C.B., Young, E.J., Seo, E.J., del Campo, M., Bamforth, S., Peregrine, E., Loo, W., Lilley, M., Perez-Jurado, L.A. et al. (2005) Severe expressive-language delay related to duplication of the Williams–Beuren locus. N. Engl. J. Med., 353, 1694–1701.[Abstract/Free Full Text]

49. Singleton, A.B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., Hulihan, M., Peuralinna, T., Dutra, A., Nussbaum, R. et al. (2003) alpha-Synuclein locus triplication causes Parkinson's disease. Science, 302, 841.[Free Full Text]

50. Rovelet-Lecrux, A., Hannequin, D., Raux, G., Le Meur, N., Laquerriere, A., Vital, A., Dumanchin, C., Feuillette, S., Brice, A., Vercelletto, M. et al. (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet., 38, 24–26.[Web of Science][Medline]

51. Aitman, T.J., Dong, R., Vyse, T.J., Norsworthy, P.J., Johnson, M.D., Smith, J., Mangion, J., Roberton-Lowe, C., Marshall, A.J., Petretto, E. et al. (2006) Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature, 439, 851–855.[CrossRef][Medline]

52. Groot, P.C., Mager, W.H. and Frants, R.R. (1991) Interpretation of polymorphic DNA patterns in the human alpha-amylase multigene family. Genomics, 10, 779–785.[CrossRef][Web of Science][Medline]

53. Hollox, E.J., Armour, J.A. and Barber, J.C. (2003) Extensive normal copy number variation of a beta-defensin antimicrobial-gene cluster. Am. J. Hum. Genet., 73, 591–600.[CrossRef][Web of Science][Medline]

54. Aldred, P.M., Hollox, E.J. and Armour, J.A. (2005) Copy number polymorphism and expression level variation of the human {alpha}-defensin genes DEFA1 and DEFA3. Hum. Mol. Genet., 14, 2045–2052.[Abstract/Free Full Text]

55. Linzmeier, R.M. and Ganz, T. (2005) Human defensin gene copy number polymorphisms: comprehensive analysis of independent variation in alpha- and beta-defensin regions at 8p22–p23. Genomics, 86, 423–430.[CrossRef][Web of Science][Medline]

56. Gonzalez, E., Kulkarni, H., Bolivar, H., Mangano, A., Sanchez, R., Catano, G., Nibbs, R.J., Freedman, B.I., Quinones, M.P., Bamshad, M.J. et al. (2005) The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science, 307, 1434–1440.[Abstract/Free Full Text]

57. Sprenger, R., Schlagenhaufer, R., Kerb, R., Bruhn, C., Brockmoller, J., Roots, I. and Brinkmann, U. (2000) Characterization of the glutathione S-transferase GSTT1 deletion: discrimination of all genotypes by polymerase chain reaction indicates a trimodular genotype–phenotype correlation. Pharmacogenetics, 10, 557–565.[CrossRef][Web of Science][Medline]

58. Nguyen, D.Q., Webber, C. and Ponting, C.P. (2006) Bias of selection on human copy-number variants. PLoS Genet., 2, e20.[CrossRef][Medline]

59. Hayes, J.D. and Strange, R.C. (2000) Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology, 61, 154–166.[CrossRef][Web of Science][Medline]

60. McLellan, R.A., Oscarson, M., Alexandrie, A.K., Seidegard, J., Evans, D.A., Rannug, A. and Ingelman-Sundberg, M. (1997) Characterization of a human glutathione S-transferase mu cluster containing a duplicated GSTM1 gene that causes ultrarapid enzyme activity. Mol. Pharmacol., 52, 958–965.[Abstract/Free Full Text]

61. Rao, Y., Hoffmann, E., Zia, M., Bodin, L., Zeman, M., Sellers, E.M. and Tyndale, R.F. (2000) Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking. Mol. Pharmacol., 58, 747–755.[Abstract/Free Full Text]

62. Koppens, P.F., Hoogenboezem, T. and Degenhart, H.J. (2002) Duplication of the CYP21A2 gene complicates mutation analysis of steroid 21-hydroxylase deficiency: characteristics of three unusual haplotypes. Hum. Genet., 111, 405–410.[CrossRef][Web of Science][Medline]

63. Dalen, P., Dahl, M.L., Ruiz, M.L., Nordin, J. and Bertilsson, L. (1998) 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin. Pharmacol. Ther., 63, 444–452.[CrossRef][Web of Science][Medline]

64. Mitsunaga, Y., Kubota, T., Ishiguro, A., Yamada, Y., Sasaki, H., Chiba, K. and Iga, T. (2002) Frequent occurrence of CYP2D6*10 duplication allele in a Japanese population. Mutat. Res., 505, 83–85.[Web of Science][Medline]

65. Ingelman-Sundberg, M. (2002) Polymorphism of cytochrome P450 and xenobiotic toxicity. Toxicology, 181–182, 447–452.

66. Chung, E.K., Yang, Y., Rennebohm, R.M., Lokki, M.L., Higgins, G.C., Jones, K.N., Zhou, B., Blanchong, C.A. and Yu, C.Y. (2002) Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex. Am. J. Hum. Genet., 71, 823–837.[CrossRef][Web of Science][Medline]

67. Osborne, L.R., Li, M., Pober, B., Chitayat, D., Bodurtha, J., Mandel, A., Costa, T., Grebe, T., Cox, S., Tsui, L.C. et al. (2001) A 1.5 million-base pair inversion polymorphism in families with Williams–Beuren syndrome. Nat. Genet., 29, 321–325.[CrossRef][Web of Science][Medline]

68. Gimelli, G., Pujana, M.A., Patricelli, M.G., Russo, S., Giardino, D., Larizza, L., Cheung, J., Armengol, L., Schinzel, A., Estivill, X. et al. (2003) Genomic inversions of human chromosome 15q11–q13 in mothers of Angelman syndrome patients with class II (BP2/3) deletions. Hum. Mol. Genet., 12, 849–858.[Abstract/Free Full Text]

69. Visser, R., Shimokawa, O., Harada, N., Kinoshita, A., Ohta, T., Niikawa, N. and Matsumoto, N. (2005) Identification of a 3.0-kb major recombination hotspot in patients with Sotos syndrome who carry a common 1.9-Mb microdeletion. Am. J. Hum. Genet., 76, 52–67.[CrossRef][Web of Science][Medline]

70. Scherer, S.W., Cheung, J., MacDonald, J.R., Osborne, L.R., Nakabayashi, K., Herbrick, J.A., Carson, A.R., Parker-Katiraee, L., Skaug, J., Khaja, R. et al. (2003) Human chromosome 7: DNA sequence and biology. Science, 300, 767–772.[Abstract/Free Full Text]

71. Ovcharenko, I., Loots, G.G., Nobrega, M.A., Hardison, R.C., Miller, W. and Stubbs, L. (2005) Evolution and functional classification of vertebrate gene deserts. Genome Res., 15, 137–145.[Abstract/Free Full Text]

72. Hillier, L.W., Graves, T.A., Fulton, R.S., Fulton, L.A., Pepin, K.H., Minx, P., Wagner-McPherson, C., Layman, D., Wylie, K., Sekhon, M. et al. (2005) Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Nature, 434, 724–731.[CrossRef][Medline]

73. Schotta, G., Ebert, A., Dorn, R. and Reuter, G. (2003) Position-effect variegation and the genetic dissection of chromatin regulation in Drosophila. Semin. Cell Dev. Biol., 14, 67–75.[CrossRef][Web of Science][Medline]

74. Tham, W.H. and Zakian, V.A. (2002) Transcriptional silencing at Saccharomyces telomeres: implications for other organisms. Oncogene, 21, 512–521.[CrossRef][Web of Science][Medline]

75. Crolla, J.A. and van Heyningen, V. (2002) Frequent chromosome aberrations revealed by molecular cytogenetic studies in patients with aniridia. Am. J. Hum. Genet., 71, 1138–1149.[CrossRef][Web of Science][Medline]

76. Lauderdale, J.D., Wilensky, J.S., Oliver, E.R., Walton, D.S. and Glaser, T. (2000) 3' deletions cause aniridia by preventing PAX6 gene expression. Proc. Natl Acad. Sci. USA, 97, 13755–13759.[Abstract/Free Full Text]

77. Fantes, J., Redeker, B., Breen, M., Boyle, S., Brown, J., Fletcher, J., Jones, S., Bickmore, W., Fukushima, Y., Mannens, M. et al. (1995) Aniridia-associated cytogenetic rearrangements suggest that a position effect may cause the mutant phenotype. Hum. Mol. Genet., 4, 415–422.[Abstract/Free Full Text]

78. Crolla, J.A., Cross, I., Atkey, N., Wright, M. and Oley, C.A. (1996) FISH studies in a patient with sporadic aniridia and t(7;11) (q31.2;p13). J. Med. Genet., 33, 66–68.[Abstract/Free Full Text]

79. Belloni, E., Muenke, M., Roessler, E., Traverso, G., Siegel-Bartelt, J., Frumkin, A., Mitchell, H.F., Donis-Keller, H., Helms, C., Hing, A.V. et al. (1996) Identification of sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nat. Genet., 14, 353–356.[CrossRef][Web of Science][Medline]

80. Fernandez, B.A., Siegel-Bartelt, J., Herbrick, J.A., Teshima, I. and Scherer, S.W. (2005) Holoprosencephaly and cleidocranial dysplasia in a patient due to two position-effect mutations: case report and review of the literature. Clin. Genet., 68, 349–359.[CrossRef][Web of Science][Medline]

81. Wallis, D.E., Roessler, E., Hehr, U., Nanni, L., Wiltshire, T., Richieri-Costa, A., Gillessen-Kaesbach, G., Zackai, E.H., Rommens, J. and Muenke, M. (1999) Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat. Genet., 22, 196–198.[CrossRef][Web of Science][Medline]

82. Velagaleti, G.V., Bien-Willner, G.A., Northup, J.K., Lockhart, L.H., Hawkins, J.C., Jalal, S.M., Withers, M., Lupski, J.R. and Stankiewicz, P. (2005) Position effects due to chromosome breakpoints that map approximately 900 kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia. Am. J. Hum. Genet., 76, 652–662.[CrossRef][Web of Science][Medline]

83. Erdel, M., Lane, A.H., Fresser, F., Probst, P., Utermann, G. and Scherer, G. (2004) A new campomelic dysplasia translocation breakpoint maps 400 kb from SOX9. Eur. J. Hum. Genet., Suppl. 12, 136.

84. Wagner, T., Wirth, J., Meyer, J., Zabel, B., Held, M., Zimmer, J., Pasantes, J., Bricarelli, F.D., Keutel, J., Hustert, E. et al. (1994) Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell, 79, 1111–1120.[CrossRef][Web of Science][Medline]

85. Ninomiya, S., Isomura, M., Narahara, K., Seino, Y. and Nakamura, Y. (1996) Isolation of a testis-specific cDNA on chromosome 17q from a region adjacent to the breakpoint of t(12;17) observed in a patient with acampomelic campomelic dysplasia and sex reversal. Hum. Mol. Genet., 5, 69–72.[Abstract/Free Full Text]

86. Foster, J.W., Dominguez-Steglich, M.A., Guioli, S., Kowk, G., Weller, P.A., Stevanovic, M., Weissenbach, J., Mansour, S., Young, I.D., Goodfellow, P.N. et al. (1994) Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature, 372, 525–530.[CrossRef][Medline]

87. Pop, R., Conz, C., Lindenberg, K.S., Blesson, S., Schmalenberger, B., Briault, S., Pfeifer, D. and Scherer, G. (2004) Screening of the 1 Mb SOX9 5' control region by array CGH identifies a large deletion in a case of campomelic dysplasia with XY sex reversal. J. Med. Genet., 41, e47.[Free Full Text]

88. Wirth, J., Wagner, T., Meyer, J., Pfeiffer, R.A., Tietze, H.U., Schempp, W. and Scherer, G. (1996) Translocation breakpoints in three patients with campomelic dysplasia and autosomal sex reversal map more than 130 kb from SOX9. Hum. Genet., 97, 186–193.[CrossRef][Web of Science][Medline]

89. Wunderle, V.M., Critcher, R., Hastie, N., Goodfellow, P.N. and Schedl, A. (1998) Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia. Proc. Natl Acad. Sci. USA, 95, 10649–10654.[Abstract/Free Full Text]

90. Pfeifer, D., Kist, R., Dewar, K., Devon, K., Lander, E.S., Birren, B., Korniszewski, L., Back, E. and Scherer, G. (1999) Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region. Am. J. Hum. Genet., 65, 111–124.[CrossRef][Web of Science][Medline]

91. Romao, L., Osorio-Almeida, L., Higgs, D.R., Lavinha, J. and Liebhaber, S.A. (1991) Alpha-thalassemia resulting from deletion of regulatory sequences far upstream of the alpha-globin structural genes. Blood, 78, 1589–1595.[Abstract/Free Full Text]

92. Higgs, D.R., Wood, W.G., Jarman, A.P., Sharpe, J., Lida, J., Pretorius, I.M. and Ayyub, H. (1990) A major positive regulatory region located far upstream of the human alpha-globin gene locus. Genes Dev., 4, 1588–1601.[Abstract/Free Full Text]

93. Driscoll, M.C., Dobkin, C.S. and Alter, B.P. (1989) Gamma delta beta-thalassemia due to a de novo mutation deleting the 5' beta-globin gene activation-region hypersensitive sites. Proc. Natl Acad. Sci. USA, 86, 7470–7474.[Abstract/Free Full Text]

94. Barbour, V.M., Tufarelli, C., Sharpe, J.A., Smith, Z.E., Ayyub, H., Heinlein, C.A., Sloane-Stanley, J., Indrak, K., Wood, W.G. and Higgs, D.R. (2000) Alpha-thalassemia resulting from a negative chromosomal position effect. Blood, 96, 800–807.[Abstract/Free Full Text]

95. McElreavey, K., Vilain, E., Barbaux, S., Fuqua, J.S., Fechner, P.Y., Souleyreau, N., Doco-Fenzy, M., Gabriel, R., Quereux, C., Fellous, M. et al. (1996) Loss of sequences 3' to the testis-determining gene, SRY, including the Y pseudoautosomal boundary associated with partial testicular determination. Proc. Natl Acad. Sci. USA, 93, 8590–8594.[Abstract/Free Full Text]

96. McElreavy, K., Vilain, E., Abbas, N., Costa, J.M., Souleyreau, N., Kucheria, K., Boucekkine, C., Thibaud, E., Brauner, R., Flamant, F. et al. (1992) XY sex reversal associated with a deletion 5' to the SRY ‘HMG box’ in the testis-determining region. Proc. Natl Acad. Sci. USA, 89, 11016–11020.[Abstract/Free Full Text]

97. Kleinjan, D.J. and van Heyningen, V. (1998) Position effect in human genetic disease. Hum. Mol. Genet., 7, 1611–1618.[Abstract/Free Full Text]

98. David, D., Cardoso, J., Marques, B., Marques, R., Silva, E.D., Santos, H. and Boavida, M.G. (2003) Molecular characterization of a familial translocation implicates disruption of HDAC9 and possible position effect on TGFbeta2 in the pathogenesis of Peters' anomaly. Genomics, 81, 489–503.[CrossRef][Web of Science][Medline]

99. Bowl, M.R., Nesbit, M.A., Harding, B., Levy, E., Jefferson, A., Volpi, E., Rizzoti, K., Lovell-Badge, R., Schlessinger, D., Whyte, M.P. et al. (2005) An interstitial deletion–insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism. J. Clin. Invest., 115, 2822–2831.[CrossRef][Web of Science][Medline]

100. Wakui, K., Gregato, G., Ballif, B.C., Glotzbach, C.D., Bailey, K.A., Kuo, P.L., Sue, W.C., Sheffield, L.J., Irons, M., Gomez, E.G. et al. (2005) Construction of a natural panel of 11p11.2 deletions and further delineation of the critical region involved in Potocki–Shaffer syndrome. Eur. J. Hum. Genet., 13, 528–540.[CrossRef][Web of Science][Medline]

101. Beysen, D., Raes, J., Leroy, B.P., Lucassen, A., Yates, J.R., Clayton-Smith, J., Ilyina, H., Brooks, S.S., Christin-Maitre, S., Fellous, M. et al. (2005) Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome. Am. J. Hum. Genet., 77, 205–218.[CrossRef][Web of Science][Medline]

102. Lee, J.A., Madrid, R.E., Sperle, K., Ritterson, C.M., Hobson, G.M., Garbern, J., Lupski, J.R. and Inoue, K. (2006) Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann. Neurol., 59, 398–403.[CrossRef][Web of Science][Medline]

103. Muncke, N., Wogatzky, B.S., Breuning, M., Sistermans, E.A., Endris, V., Ross, M., Vetrie, D., Catsman-Berrevoets, C.E. and Rappold, G. (2004) Position effect on PLP1 may cause a subset of Pelizaeus–Merzbacher disease symptoms. J. Med. Genet., 41, e121.[Free Full Text]

104. Ellison, J.W., Tekin, M., Sikes, K.S., Yankowitz, J., Shapiro, L., Rappold, G.A. and Neely, K.E. (2002) Molecular characterization of a ring X chromosome in a male with short stature. Hum. Genet., 110, 322–326.[CrossRef][Web of Science][Medline]

105. Lettice, L.A. and Hill, R.E. (2005) Preaxial polydactyly: a model for defective long-range regulation in congenital abnormalities. Curr. Opin. Genet. Dev., 15, 294–300.[CrossRef][Web of Science][Medline]

106. Inoue, K. and Lupski, J.R. (2002) Molecular mechanisms for genomic disorders. Annu. Rev. Genomics Hum. Genet., 3, 199–242.[CrossRef][Web of Science][Medline]

107. Ravnan, J.B., Tepperberg, J.H., Papenhausen, P., Lamb, A.N., Hedrick, J., Eash, D., Ledbetter, D.H. and Martin, C.L. (2005) Subtelomere FISH analysis of 11 688 cases: an evaluation of the frequency and pattern of subtelomere rearrangements in individuals with developmental disabilities. J. Med. Genet., doi:10.1136/jmg.2005.036350.

108. Ioannidis, J.P., Gwinn, M., Little, J., Higgins, J.P., Bernstein, J.L., Boffetta, P., Bondy, M., Bray, M.S., Brenchley, P.E., Buffler, P.A. et al. (2006) A road map for efficient and reliable human genome epidemiology. Nat. Genet., 38, 3–5.[CrossRef][Web of Science][Medline]

109. Yu, C.E., Dawson, G., Munson, J., D'Souza, I., Osterling, J., Estes, A., Leutenegger, A.L., Flodman, P., Smith, M., Raskind, W.H. et al. (2002) Presence of large deletions in kindreds with autism. Am. J. Hum. Genet., 71, 100–115.[CrossRef][Web of Science][Medline]

110. Repping, S., van Daalen, S.K., Brown, L.G., Korver, C.M., Lange, J., Marszalek, J.D., Pyntikova, T., van der Veen, F., Skaletsky, H., Page, D.C. et al. (2006) High mutation rates have driven extensive structural polymorphism among human Y chromosomes. Nat. Genet., doi:10.1038/ng1754.

111. Shendure, J., Mitra, R.D., Varma, C. and Church, G.M. (2004) Advanced sequencing technologies: methods and goals. Nat. Rev. Genet., 5, 335–344.[Web of Science][Medline]

112. International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature, 431, 931–945.[CrossRef][Medline]

113. Kruglyak, L. and Nickerson, D.A. (2001) Variation is the spice of life. Nat. Genet., 27, 234–236.[CrossRef][Web of Science][Medline]

114. Lander, E.S., Linton, L.M., Birren, B., Nusbaum, C., Zody, M.C., Baldwin, J., Devon, K., Dewar, K., Doyle, M., FitzHugh, W. et al. (2001) Initial sequencing and analysis of the human genome. Nature, 409, 860–921.[CrossRef][Medline]

115. Weber, J.L., David, D., Heil, J., Fan, Y., Zhao, C. and Marth, G. (2002) Human diallelic insertion/deletion polymorphisms. Am. J. Hum. Genet., 71, 854–862.[CrossRef][Web of Science][Medline]

116. Dawson, E., Chen, Y., Hunt, S., Smink, L.J., Hunt, A., Rice, K., Livingston, S., Bumpstead, S., Bruskiewich, R., Sham, P. et al. (2001) A SNP resource for human chromosome 22: extracting dense clusters of SNPs from the genomic sequence. Genome Res., 11, 170–178.[Abstract/Free Full Text]

117. Litt, M. and Luty, J.A. (1989) A hypervariable microsatellite revealed by in vitro amplification of a dinucleotide repeat within the cardiac muscle actin gene. Am. J. Hum. Genet., 44, 397–401.[Web of Science][Medline]

118. Ellegren, H. (2004) Microsatellites: simple sequences with complex evolution. Nat. Rev. Genet., 5, 435–445.[CrossRef][Web of Science][Medline]

119. Jeffreys, A.J., Wilson, V. and Thein, S.L. (1985) Hypervariable ‘minisatellite’ regions in human DNA. Nature, 314, 67–73.[CrossRef][Medline]

120. Naslund, K., Saetre, P., von Salome, J., Bergstrom, T.F., Jareborg, N. and Jazin, E. (2005) Genome-wide prediction of human VNTRs. Genomics, 85, 24–35.[CrossRef][Web of Science][Medline]

121. Fredman, D., White, S.J., Potter, S., Eichler, E.E., Dunnen, J.T. and Brookes, A.J. (2004) Complex SNP-related sequence variation in segmental genome duplications. Nat. Genet., 36, 861–866.[CrossRef][Web of Science][Medline]

122. Van Dyke, D.L., Weiss, L., Roberson, J.R. and Babu, V.R. (1983) The frequency and mutation rate of balanced autosomal rearrangements in man estimated from prenatal genetic studies for advanced maternal age. Am. J. Hum. Genet., 35, 301–308.[Web of Science][Medline]

123. Gardner, R.J.M. and Sunderland, G.R. (2004) Chromosome Abnormalitites and Genetic Counseling, 3rd edn. Oxford University Press, New York.

124. Warburton, D. (1991) De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am. J. Hum. Genet., 49, 995–1013.[Web of Science][Medline]

125. Nussbaum, R.L., McInnes, R.R. and Willard, H.F. (2004) Thompson & Thompson Genetics in Medicine, 6th edn. W.B. Saunders, Philadelphia, PA.

126. Lee, J.A., Cheung, S.W., Ward, P.A., Inoue, K. and Lupski, J.R. (2005) Prenatal diagnosis of PLP1 copy number by array comparative genomic hybridization. Prenat. Diagn., 25, 1188–1191.[CrossRef][Web of Science][Medline]

127. Marlin, S., Blanchard, S., Slim, R., Lacombe, D., Denoyelle, F., Alessandri, J.L., Calzolari, E., Drouin-Garraud, V., Ferraz, F.G., Fourmaintraux, A. et al. (1999) Townes–Brocks syndrome: detection of a SALL1 mutation hot spot and evidence for a position effect in one patient. Hum. Mutat., 14, 377–386.[CrossRef][Web of Science][Medline]

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