Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

From microscopes to microarrays: dissecting recurrent chromosomal rearrangements

Nature Reviews Genetics volume 8, pages 869–883 (2007)Cite this article

Key Points

  • Recurrent chromosomal rearrangements include cytogenetically detectable and submicroscopic deletions, duplications, inversions and translocations. Many lead to pathological copy-number differences.

  • New developments in genomic analysis methodologies, including PCR- and array-based platforms, coupled with the availability of a reference genomic sequence, have made possible the discovery of clinically relevant recurrent rearrangements.

  • These recurrent rearrangements are frequently associated with segmental duplications and often produce clinically recognizable syndromes.

  • The segmental duplications contain highly related sequences, which are predisposed to engage in non-allelic homologous recombination leading to copy-number differences.

  • Thus, high-resolution sequence-based genome analysis tools will surpass the microscope as the diagnostic tool of choice in the identification of clinically relevant genomic disorders.

Abstract

Submicroscopic chromosomal rearrangements that lead to copy-number changes have been shown to underlie distinctive and recognizable clinical phenotypes. The sensitivity to detect copy-number variation has escalated with the advent of array comparative genomic hybridization (CGH), including BAC and oligonucleotide-based platforms. Coupled with improved assemblies and annotation of genome sequence data, these technologies are facilitating the identification of new syndromes that are associated with submicroscopic genomic changes. Their characterization reveals the role of genome architecture in the aetiology of many clinical disorders. We review a group of genomic disorders that are mediated by segmental duplications, emphasizing the impact that high-throughput detection methods and the availability of the human genome sequence have had on their dissection and diagnosis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Chromosomal rearrangements mediated by segmental duplications.
Figure 2: The multiplex ligation-dependent probe amplification (MLPA) reaction.
Figure 3: Model for interchromosomal recombination leading to formation of a deletion and a duplication.
Figure 4: Intrachromosomal recombination between segmental duplications on a single chromosome.
Figure 5: Models for formation of the inv dup(15) or the cat eye syndrome marker chromosomes.
Figure 6: Model for the translocation between 11q23 and 22q11.
Figure 7: Ideograms and partial karyotypes of chromosome 22 abnormalities.

Similar content being viewed by others

References

  1. Klein, R. J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Frayling, T. M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nature Genet. 39, 724–726 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Helgadottir, A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316, 1491–1493 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Tishkoff, S. A. et al. Convergent adaptation of human lactase persistence in Africa and Europe. Nature Genet. 39, 31–40 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Conrad, D. F. & Hurles, M. E. The population genetics of structural variation. Nature Genet. 39, S30–S36 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Iafrate, A. J. et al. Detection of large-scale variation in the human genome. Nature Genet. 36, 949–951 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004). A landmark study demonstrating genome-wide analysis of copy-number polymorphisms or variants in normal individuals. It provided an initial glimpse of the surprising amount of large-scale variation and its implications for human diversity.

    Article  CAS  PubMed  Google Scholar 

  9. Tuzun, E. et al. Fine-scale structural variation of the human genome. Nature Genet. 37, 727–732 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. McCarroll, S. A. et al. Common deletion polymorphisms in the human genome. Nature Genet. 38, 86–92 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006). The first CNV map of the human genome. This study utilized oligonucleotide arrays and hundreds of reference samples from several different human populations to show a remarkable number of variable regions in 'normal' individuals, underscoring the need to catalogue CNVs comprehensively.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Scherer, S. W. et al. Challenges and standards in integrating surveys of structural variation. Nature Genet. 39, S7–S15 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Bailey, J. A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002). This work analysed public sequence databases to detect large intervals of high sequence identity that were localized to regions of genomic instability associated with human disease and primate evolution.

    Article  CAS  PubMed  Google Scholar 

  14. Cooper, G. M., Nickerson, D. A. & Eichler, E. E. Mutational and selective effects on copy-number variants in the human genome. Nature Genet. 39, S22–S29 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Feuk, L., Carson, A. R. & Scherer, S. W. Structural variation in the human genome. Nature Rev. Genet. 7, 85–97 (2006). A comprehensive review of genome-scanning technologies and the discovery of large-scale genomic variation. Provides an excellent overview of structural variants and their contribution to genomic diversity and disease.

    Article  CAS  PubMed  Google Scholar 

  16. Stankiewicz, P. & Lupski, J. R. Genome architecture, rearrangements, and genomic disorders. Trends Genet. 18, 74–82 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Shaffer, L. G. & Lupski, J. R. Molecular mechanisms for constitutional chromosomal rearrangements in humans. Annu. Rev. Genet. 34, 297–329 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Lupski, J. R. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 14, 415–420 (1998). The paper that coined the phrase 'genomic disorders' based on the concept that structural features of the genome can lead to DNA rearrangements and human disease traits.

    Article  Google Scholar 

  19. Sharp, A. J. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nature Genet. 38, 1038–1042 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Koolen, D. A. et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nature Genet. 38, 999–1001 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Shaw-Smith, C. et al. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nature Genet. 38, 1032–1037 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Sharp, A. J. et al. Characterization of a recurrent 15q24 microdeletion syndrome. Hum. Mol. Genet., 16, 567–572 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Ballif, B. C. et al. Discovery of a novel microdeletion syndrome on 16p11.2p12.2. Nature Genet. 39, 1071–1073 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Ledbetter, D. H. & Ballabio, A. in The metabolic and molecular bases of inherited disease Vol. 1 (eds Scriver, C.R., Beaudet, A. L., Sly, W. S. & Valle, D.) 811–839 (McGraw–Hill, New York, 1995).

    Google Scholar 

  25. Levy, B., Dunn, T. M., Kaffe, S., Kardon, N. & Hirschhorn, K. Clinical applications of comparative genomic hybridization. Genet. Med. 1, 4–12 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Feenstra, I., Brunner, H. G. & van Ravenswaaij, C. M. Cytogenetic genotype–phenotype studies: improving genotyping, phenotyping and data storage. Cytogenet. Genome Res. 115, 231–239 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Knight, S. J. et al. An optimized set of human telomere clones for studying telomere integrity and architecture. Am. J. Hum. Genet. 67, 320–332 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. de Vries, B. B. et al. Clinical studies on submicroscopic subtelomeric rearrangements: a checklist. J. Med. Genet. 38, 145–150 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Knight, S. J. & Flint, J. The use of subtelomeric probes to study mental retardation. Methods Cell Biol. 75, 799–831 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Kallioniemi, A. et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258, 818–821 (1992).

    Article  CAS  PubMed  Google Scholar 

  31. Pinkel, D. et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nature Genet. 20, 207–211 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Snijders, A. M. et al. Assembly of microarrays for genome-wide measurement of DNA copy number. Nature Genet. 29, 263–264 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Shaffer, L. G. & Bejjani, B. A. Medical applications of array CGH and the transformation of clinical cytogenetics. Cytogenet. Genome Res. 115, 303–309 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Fritz, B. et al. Microarray-based copy number and expression profiling in dedifferentiated and pleomorphic liposarcoma. Cancer Res. 62, 2993–2998 (2002).

    CAS  PubMed  Google Scholar 

  35. Wilhelm, M. et al. Array-based comparative genomic hybridization for the differential diagnosis of renal cell cancer. Cancer Res. 62, 957–960 (2002).

    CAS  PubMed  Google Scholar 

  36. Snijders, A. N. et al. Genome-wide array based comparative genomic hybridization reveals genetic homogeneity and frequent copy number increases encompassing CCNE1 in Fallopian tube carcinoma. Oncogene 22, 4281–4286 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Squire, J. A. et al. High-resolution mapping of amplifications and deletions in pediatric osteosarcoma by use of CGH analysis of cDNA microarrays. Genes Chromosomes Cancer 38, 215–225 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Albertson, D. G., Collins, C., McCormick, F. & Gray, J. W. Chromosome aberrations in solid tumors. Nature Genet. 34, 369–376 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Vissers, L. E. et al. Array-based comparative genomic hybridization for the genomewide detection of submicroscopic chromosomal abnormalities. Am. J. Hum. Genet. 73, 1261–1270 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Menten, B. et al. Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of published reports. J. Med. Genet. 43, 625–633 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. De Vries, B. B. et al. Diagnostic genome profiling in mental retardation. Am. J. Hum. Genet. 77, 606–616 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Veltman, J. A. et al. High-throughput analysis of subtelomeric chromosome rearrangements by use of array-based comparative genomic hybridization. Am. J. Hum. Genet. 70, 1269–1276 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yu, W. et al. Development of a comparative genomic hybridization microarray and demonstration of its utility with 25 well-characterized 1p36 deletions. Hum. Mol. Genet. 12, 2145–2152 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Ballif, B. C. et al. The clinical utility of enhanced subtelomeric coverage in array CGH. Am. J. Med. Genet. A 143, 1850–1857 (2007).

    Article  Google Scholar 

  45. Rauen, K. A., Albertson, D. G., Pinkel, D. & Cotter, P. D. Additional patient with del(12)(q21.2q22): further evidence for a candidate region for cardio-facio-cutaneous syndrome? Am. J. Med. Genet. 110, 51–56 (2002).

    Article  PubMed  Google Scholar 

  46. Veltman, J. A. et al. Definition of a critical region on chromosome 18 for congenital aural atresia by arrayCGH. Am. J. Hum. Genet. 72, 1578–1584 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gunn, S. R. et al. Molecular characterization of a patient with central nervous system dysmyelination and cryptic unbalanced translocation between chromosomes 4q and 18q. Am. J. Med. Genet. 120, 127–135 (2003).

    Article  Google Scholar 

  48. Hoffman, J. D. et al. Array based CGH and FISH fail to confirm duplication of 8p22–p23.1 in association with Kabuki syndrome. J. Med. Genet. 42, 49–53 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Prescott, K. et al. A novel 5q11.2 deletion detected by microarray comparative genomic hybridisation in a child referred as a case of suspected 22q11 deletion syndrome. Hum. Genet. 116, 83–90 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Lu, X. et al. Clinical implementation of chromosomal microarray analysis: summary of 2513 postnatal cases. PLoS ONE 2, e327 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Friedman, J. et al. Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation. Am. J. Hum. Genet. 79, 500–513 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ming, J. E. et al. Rapid detection of submicroscopic chromosomal rearrangements in children with multiple congenital anomalies using high density oligonucleotide arrays. Hum. Mutat. 27, 467–473 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Shaikh, T. H. et al. Oligonucleotide arrays for high-resolution analysis of copy number alteration in mental retardation/multiple congenital anomalies. Genet. Med. 9, 617–625 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Wagenstaller, J. et al. Copy-number variations measured by single-nucleotide-polymorphism oligonucleotide arrays in patients with mental retardation. Am. J. Hum. Genet. 81, 768–779 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sharp, A. J. et al. Optimal design of oligonucleotide microarrays for measurement of DNA copy number. Hum. Mol. Genet. 28 August 2007 (doi:10.1093/hmg/ddm234).

    Article  CAS  PubMed  Google Scholar 

  56. Armour, J. A., Sismani, C., Patsalis, P. C. & Cross, G. Measurement of locus copy number by hybridisation with amplifiable probes. Nucleic Acids Res. 28, 605–609 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Schouten, J. P. et al. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 30, e57 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Vorstman, J. A. et al. MLPA: a rapid, reliable, and sensitive method for detection and analysis of abnormalities of 22q. Hum. Mutat. 27, 814–821 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Deininger, P. L. & Batzer, M. A. Alu repeats and human disease. Mol. Genet. Metab. 67, 183–193 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Babushok, D. V. & Kazazian, H. H. Jr. Progress in understanding the biology of the human mutagen LINE-1. Hum. Mutat. 28, 527–539 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Shaikh, T. H. et al. Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms. Genome Res. 17, 482–491 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Schmickel, R. D. Contiguous gene syndromes: a component of recognizable syndromes. J. Pediatr. 109, 231–241 (1986). The paper that introduced the concept of a non-traditional pattern of inheritance involving duplication or deletion of contiguous genes.

    Article  CAS  PubMed  Google Scholar 

  63. Kurotaki, N. et al. Haploinsufficiency of NSD1 causes Sotos syndrome. Nature Genet. 30, 365–366 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Kurotaki, N., Stankiewicz, P., Wakui, K., Niikawa, N. & Lupski, J. R. Sotos syndrome common deletion is mediated by directly oriented subunits within inverted Sos-REP low-copy repeats. Hum. Mol. Genet. 14, 535–542 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Tatton-Brown, K. et al. Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome. J. Med. Genet. 42, 307–313 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Visser, R. et al. 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 (2005). A detailed analysis of breakpoint junctions within segmental duplications for Sotos syndrome. This paper identified the influence of both sequence and orientation on hotspots for mediating aberrant recombination.

    Article  CAS  PubMed  Google Scholar 

  67. Kirchhoff, M., Bisgaard, A. M., Bryndorf, T. & Gerdes, T. MLPA analysis for a panel of syndromes with mental retardation reveals imbalances in 5.8% of patients with mental retardation and dysmorphic features, including duplications of the Sotos syndrome and Williams–Beuren syndrome regions. Eur. J. Med. Genet. 50, 33–42 (2007).

    Article  PubMed  Google Scholar 

  68. Chen, C. P. et al. Molecular cytogenetic analysis of de novo dup(5)(q35.2q35.3) and review of the literature of pure partial trisomy 5q. Am. J. Med. Genet. A 140, 1594–1600 (2006).

    Article  PubMed  Google Scholar 

  69. Tassabehji, M. & Urban, Z. Congenital heart disease: molecular diagnostics of supravalvular aortic stenosis. Methods Mol. Med. 126, 129–156 (2006).

    CAS  PubMed  Google Scholar 

  70. Merla, G. et al. Submicroscopic deletion in patients with Williams–Beuren syndrome influences expression levels of the nonhemizygous flanking genes. Am. J. Hum. Genet. 79, 332–341 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Osborne, L. R. et al. A 1.5 million-base pair inversion polymorphism in families with Williams–Beuren syndrome. Nature Genet. 29, 321–325 (2001). The first study to demonstrate the presence of inversion polymorphisms in regions flanked by segmental duplications. This suggested that genomic polymorphism is an important contributor to disease-associated chromosomal rearrangements, which were previously thought to be random.

    Article  CAS  PubMed  Google Scholar 

  72. Scherer, S. W. et al. Observation of a parental inversion variant in a rare Williams–Beuren syndrome family with two affected children. Hum. Genet. 117, 383–388 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. DePienne, C. et al. Autism, language delay and mental retardation in a patient with 7q11 duplication. J. Med. Genet. 44, 452–458 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Somerville, M. J. et al. Severe expressive-language delay related to duplication of the Williams–Beuren locus. N. Engl. J. Med. 353, 1694–1701 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mombaerts, P. Odorant receptor genes in humans. Curr. Opin. Genet. Dev. 9, 315–320 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Niimura, Y. & Nei, M. Evolution of olfactory receptor genes in the human genome. Proc. Natl Acad. Sci. USA 100, 12235–12240 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Floridia, G. et al. The same molecular mechanism at the maternal meiosis I produces mono- and dicentric 8p duplications. Am. J. Hum. Genet. 58, 785–796 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Devriendt, K. et al. Delineation of the critical deletion region for congenital heart defects, on chromosome 8p23.1. Am. J. Hum. Genet. 64, 1119–1126 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pehlivan, T. et al. GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease. Am. J. Med. Genet. 83, 201–206 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Giglio, S. et al. Deletion of a 5-cM region at chromosome 8p23 is associated with a spectrum of congenital heart defects. Circulation 102, 432–437 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Ohashi, H. et al. A stable acentric marker chromosome: possible existence of an intercalary ancient centromere at distal 8p. Am. J. Hum. Genet. 55, 1202–1208 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Giglio, S. et al. Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am. J. Hum. Genet. 68, 874–883 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Giglio, S. et al. Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation. Am. J. Hum. Genet. 71, 276–285 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Faivre, L. et al. Prenatal diagnosis of an 8p23.1 deletion in a fetus with a diaphragmatic hernia and review of the literature. Prenat. Diagn. 18, 1055–1060 (1998).

    Article  CAS  PubMed  Google Scholar 

  85. Lopez, I. et al. Prenatal diagnosis of de novo deletions of 8p23.1 or 15q26.1 in two fetuses with diaphragmatic hernia and congenital heart defects. Prenat. Diagn. 26, 577–580 (2006).

    Article  PubMed  Google Scholar 

  86. Zollino, M. et al. Mapping the Wolf–Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am. J. Hum. Genet. 72, 590–597 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Rodríguez, L. et al. The new Wolf–Hirschhorn syndrome critical region (WHSCR-2): a description of a second case. Am. J. Med. Genet. 136, 175–178 (2005).

    Article  PubMed  Google Scholar 

  88. Butler, M. G., Meaney, F. J. & Palmer, C. G. Clinical and cytogenetic survey of 39 individuals with Prader–Labhart–Willi syndrome. Am. J. Med. Genet. 23, 793–809 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Nicholls, R. D., Knoll, J. H., Butler, M. G., Karam, S. & Lalande, M. Genetic imprinting suggested by maternal heterodisomy in nondeletion Prader–Willi syndrome. Nature 342, 281–285 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Robinson, W. P. et al. Molecular, cytogenetic, and clinical investigations of Prader–Willi syndrome patients. Am. J. Hum. Genet. 49, 1219–1234 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Lalande, M. & Calciano, M. A. Molecular epigenetics of Angelman syndrome. Cell. Mol. Life Sci. 64, 947–960 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Sahoo, T. et al. Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: molecular characterization and genotype–phenotype correlations. Eur. J. Hum. Genet. 15, 943–949 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Smeets, D. F. et al. Prader–Willi syndrome and Angelman syndrome in cousins from a family with a translocation between chromosomes 6 and 15. N. Engl. J. Med. 326, 807–811 (1992).

    Article  CAS  PubMed  Google Scholar 

  94. Christian, S. L., Fantes, J. A., Mewborn, S. K., Huang, B. & Ledbetter, D. H. Large genomic duplicons map to sites of instability in the Prader–Willi/Angelman syndrome chromosome region (15q11–q13). Hum. Mol. Genet. 8, 1025–1037 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Amos-Landgraf, J. M. et al. Chromosome breakage in the Prader–Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints. Am. J. Hum. Genet. 65, 370–386 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Emanuel, B. S. & Shaikh, T. H. Segmental duplications: an 'expanding' role in genomic instability and disease. Nature Rev. Genet. 2, 791–800 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Lee, S. & Wevrick, R. Identification of novel imprinted transcripts in the Prader–Willi syndrome and Angelman syndrome deletion region: further evidence for regional imprinting control. Am. J. Hum. Genet. 66, 848–858 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Chai, J. H. et al. Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader–Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons. Am. J. Hum. Genet. 73, 898–925 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Buiting, K. et al. C15orf2 and a novel noncoding transcript from the Prader–Willi/Angelman syndrome region show monoallelic expression in fetal brain. Genomics, 89, 588–595 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Schulze, A. et al. Exclusion of SNRPN as a major determinant of Prader–Willi syndrome by a translocation breakpoint. Nature Genet. 12, 452–454 (1996).

    Article  CAS  PubMed  Google Scholar 

  101. Jiang, Y., Lev-Lehman, E., Bressler, J., Tsai, T. F. & Beaudet, A. L. Genetics of Angelman syndrome. Am. J. Hum. Genet. 65, 1–6 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wang, N. J., Liu, D., Parokonny, A. S. & Schanen, N. C. High-resolution molecular characterization of 15q11–q13 rearrangements by array comparative genomic hybridization (array CGH) with detection of gene dosage. Am. J. Hum. Genet. 75, 267–281 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wandstrat, A. E. & Schwartz, S. Isolation and molecular analysis of inv dup(15) and construction of a physical map of a common breakpoint in order to elucidate their mechanism of formation. Chromosoma 109, 498–505 (2000).

    Article  CAS  PubMed  Google Scholar 

  104. Wandstrat, A. E., Leana-Cox, J., Jenkins, L. & Schwartz, S. Molecular cytogenetic evidence for a common breakpoint in the largest inverted duplications of chromosome 15. Am. J. Hum. Genet. 62, 925–936 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Robinson, W. P. et al. Uniparental disomy explains the occurrence of the Angelman or Prader–Willi syndrome in patients with an additional small inv dup(15) chromosome. J. Med. Genet. 30, 756–760 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Cheng, S. D., Spinner, N. B., Zackai, E. H. & Knoll, J. H. Cytogenetic and molecular characterization of inverted duplicated chromosomes 15 from 11 patients. Am. J. Hum. Genet. 55, 753–759 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Leana-Cox, J. et al. Molecular cytogenetic analysis of inv dup(15) chromosomes, using probes specific for the Prader–Willi/Angelman syndrome region: clinical implications. Am. J. Hum. Genet. 54, 748–755 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Mignon, C. et al. Clinical heterogeneity in 16 patients with inv dup 15 chromosome: cytogenetic and molecular studies, search for an imprinting effect. Eur. J. Hum. Genet. 4, 88–100 (1996).

    Article  CAS  PubMed  Google Scholar 

  109. Lupski, J. R. Genomic rearrangements and sporadic disease. Nature Genet. 39, S43–S47 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Smith, A. C. et al. Interstitial deletion of (17)(p11.2p11.2) in nine patients. Am. J. Med. Genet. 24, 393–414 (1986).

    Article  CAS  PubMed  Google Scholar 

  111. Stratton, R. F. et al. Interstitial deletion of (17)(p11.2p11.2): report of six additional patients with a new chromosome deletion syndrome. Am. J. Med. Genet. 24, 421–432 (1986).

    Article  CAS  PubMed  Google Scholar 

  112. Chen, K. S. et al. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nature Genet. 17, 154–163 (1997).

    Article  CAS  PubMed  Google Scholar 

  113. Potocki, L. et al. Characterization of Potocki–Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am. J. Hum. Genet. 80, 633–649 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Shaw, C. J., Withers, M. A. & Lupski, J. R. Uncommon deletions of the Smith–Magenis syndrome region can be recurrent when alternate low-copy repeats act as homologous recombination substrates. Am. J. Hum. Genet. 75, 75–81 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Bi, W. et al. Reciprocal crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome 17p11.2. Am. J. Hum. Genet. 73, 1302–1315 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Shaw, C. J. & Lupski, J. R. Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum. Mol. Genet. 13, R57–R64 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Reiter, L. T. et al. A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element. Nature Genet. 12, 288–297 (1996). Erratum in: Nature Genet. 19, 303 (1998).

    Article  CAS  PubMed  Google Scholar 

  118. Reiter, L. T. et al. Human meiotic recombination products revealed by sequencing a hotspot for homologous strand exchange in multiple HNPP deletion patients. Am. J. Hum. Genet. 62, 1023–1033 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Dorschner, M. O., Sybert, V. P., Weaver, M., Pletcher, B. A. & Stephens, K. NF1 microdeletion breakpoints are clustered at flanking repetitive sequences. Hum. Mol. Genet. 9, 35–46 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Lopez-Correa, C. et al. Recombination hotspot in NF1 microdeletion patients. Hum. Mol. Genet. 10, 1387–1392 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. Stary, A. & Sarasin, A. Molecular analysis of DNA junctions produced by illegitimate recombination in human cells. Nucleic Acids Res. 20, 4269–4274 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hyrien, O. Mechanisms and consequences of replication fork arrest. Biochimie 82, 5–17 (2000).

    Article  CAS  PubMed  Google Scholar 

  123. Badge, R. M., Yardley, J., Jeffreys, A. J. & Armour, J. A. Crossover breakpoint mapping identifies a subtelomeric hotspot for male meiotic recombination. Hum. Mol. Genet. 9, 1239–1244 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. Abeysinghe, S. S., Chuzhanova, N., Krawczak, M., Ball, E. V. & Cooper, D. N. Translocation and gross deletion breakpoints in human inherited disease and cancer I: nucleotide composition and recombination-associated motifs. Hum. Mutat. 22, 229–244 (2003).

    Article  CAS  PubMed  Google Scholar 

  125. Gerdes, M. et al. Cognitive and behavioral profile of preschool children with chromosome 22q11.2. Am. J. Med. Genet. 85, 127–133 (1999).

    Article  CAS  PubMed  Google Scholar 

  126. McDonald-McGinn, D. M. et al. The 22q11.2 deletion: screening for deletion, diagnostic workup, and outcome of results. Report on 181 patients. Genet. Test. 1, 99–108 (1997).

    Article  CAS  PubMed  Google Scholar 

  127. Swillen, A., Vogels, A., Devriendt, K. & Fryns, J. P. Chromosome 22q11 deletion syndrome: update and review of the clinical features, cognitive-behavioral spectrum, and psychiatric complications. Am. J. Med. Genet. 97, 128–135, (2000).

    Article  CAS  PubMed  Google Scholar 

  128. Emanuel, B. S., McDonald-McGinn, D., Saitta, S. C. & Zackai, E. H. The 22q11.2 deletion syndrome. Adv. Pediatr. 48, 39–73 (2001).

    CAS  PubMed  Google Scholar 

  129. Jerome, L. A. & Papaioannou, V. E. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nature Genet. 27, 286–291 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. Lindsay, E. A. et al. Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410, 97–101 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Merscher, S. et al. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104, 619–629 (2001).

    Article  CAS  PubMed  Google Scholar 

  132. Yagi, H. et al. Role of TBX1 in human del22q11.2 syndrome. Lancet 362, 1366–1373 (2003).

    Article  CAS  PubMed  Google Scholar 

  133. Paylor, R. et al. Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome. Proc. Natl Acad. Sci. USA 103, 7729–7734 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Baumer, A. et al. High level of unequal meiotic crossovers at the origin of the 22q11.2 and 7q11.23 deletions. Hum. Mol. Genet. 7, 887–894 (1998).

    Article  CAS  PubMed  Google Scholar 

  135. Saitta, S. C. et al. Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Hum. Mol. Genet. 13, 417–428 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Ashley, T. et al. Meiotic recombination and spatial proximity in the etiology of the recurrent t(11;22). Am. J. Hum. Genet. 79, 524–38 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Edelmann, L. et al. A common molecular basis for rearrangement disorders on chromosome 22q11. Hum. Mol. Genet. 8, 1157–1167 (1999). A demonstration of the role of segmental duplications in promoting multiple different rearrangements of chromosome 22, including the first 22q11.2 duplications.

    Article  CAS  PubMed  Google Scholar 

  138. Ensenauer, R. E. et al. Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients. Am. J. Hum. Genet. 73, 1027–1040 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Yobb, T. M. et al. Microduplication and triplication of 22q11.2: a highly variable syndrome. Am. J. Hum. Genet. 76, 865–876 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Alberti, A. et al. 1.5 Mb de novo 22q11.21 microduplication in a patient with cognitive deficits and dysmorphic facial features. Clin. Genet. 71, 177–182 (2007).

    Article  CAS  PubMed  Google Scholar 

  141. Fraccaro, M., Lindsten, J., Ford, C. E. & Iselius, L. The 11q;22q translocation: a European collaborative analysis of 43 cases. Hum. Genet. 56, 2l–5l (l980).

  142. Mears, A. J. et al. Molecular characterization of the marker chromosome associated with cat eye syndrome. Am. J. Hum. Genet. 55, 134–142 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Zackai, E. H. & Emanuel, B. S. Site specific reciprocal translocation, t(11;22)(q23;q11) in several unrelated families with 3:l meiotic disjunction. Am. J. Med. Genet. 7, 507–52l (l980).

  144. Martin, R. H. et al. Analysis of human sperm chromosome complements from a male heterozygous for a reciprocal translocation t(11;22)(q23;q11). Clin. Genet. 25, 357–361 (1984).

    Article  CAS  PubMed  Google Scholar 

  145. Armstrong, S. J., Goldman, A. S., Speed, R. M. & Hulten, M. A. Meiotic studies of a human male carrier of the common translocation, t(11;22), suggests postzygotic selection rather than preferential 3:1 MI segregation as the cause of liveborn offspring with an unbalanced translocation. Am. J. Hum. Genet. 67, 601–609 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Kurahashi, H. et al. Regions of genomic instability on 22q11 and 11q23 as the etiology for the recurrent constitutional t(11;22). Hum. Mol. Genet. 9, 1665–1670 (2000).

    Article  CAS  PubMed  Google Scholar 

  147. Kato, T. et al. Genetic variation affects de novo translocation frequency. Science 311, 971 (2006). The first study to demonstrate that genomic sequence variation has an important role in influencing the frequency of chromosomal rearrangements.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Shaikh, T. S. et al. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum. Mol. Genet. 9, 489–501 (2000). This study provides detailed analysis of the complex modular segmental duplication that mediate the most frequently occurring microdeletion syndrome in humans.

    Article  CAS  PubMed  Google Scholar 

  149. Budarf, M., Canaani, E. & Emanuel, B. S. Linear order of the four BCR-related loci in 22q11. Genomics 3, 168–171 (1988).

    Article  CAS  PubMed  Google Scholar 

  150. Bailey, J. A., Liu, G. & Eichler, E. E. An Alu transposition model for the origin and expansion of human segmental duplications. Am. J. Hum. Genet. 73, 823–834 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Thomas, N. S. et al. Parental and chromosomal origins of microdeletion and duplication syndromes involving 7q11.23, 15q11–q13 and 22q11. Eur. J. Hum. Genet. 14, 831–837 (2006).

    Article  CAS  PubMed  Google Scholar 

  152. Bailey, J. A. & Eichler, E. E. Primate segmental duplications: crucibles of evolution, diversity and disease. Nature Rev. Genet. 7, 552–564 (2006). A recent review of the associations among segmental duplications, genomic instability and large-scale variation. The authors discuss evidence for distinct waves of duplication during primate evolution and the creation of novel gene families.

    Article  CAS  PubMed  Google Scholar 

  153. Johnson, M. E. et al. Recurrent duplication-driven transposition of DNA during hominoid evolution. Proc. Natl Acad. Sci. USA 103, 17626–17631 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Antonell, A., de Luis, O., Domingo-Roura, X. & Pérez-Jurado, L. A. Evolutionary mechanisms shaping the genomic structure of the Williams–Beuren syndrome chromosomal region at human 7q11.23. Genome Res. 15, 1179–1188 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Nannya et al. A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. Cancer Res. 65, 6071–6079 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Korbel, J. O. et al. Paired-end mapping reveals extensive structural variation in the human genome. Science 27 September 2007 (doi:10.1126/science.1149504).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

These studies were supported in part by HL74731, CA39926, a research grant from the National Organization for Rare Disorders (NORD) and funds from the Charles E.H. Upham chair (B.S.E.). S.C.S. was supported by HL04487 and HL080637. The authors wish to thank T. Shaikh for helpful discussions and assistance with artwork. Additional assistance with the figures was provided by R. Jalali, as well as A. Hacker and R. O'Connor.

Author information

Authors and Affiliations

  1. Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Abramson Research Center, Suite 1002, University of Pennsylvania School of Medicine, Philadelphia, 19104-4318, Philadelphia, USA

    Beverly S. Emanuel & Sulagna C. Saitta

Authors
  1. Beverly S. Emanuel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sulagna C. Saitta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Beverly S. Emanuel.

Related links

Related links

DATABASES

OMIM

Angelman syndrome

cat eye syndrome

Charcot–Marie–Tooth Disease type 1A

conotruncal anomaly face syndrome

DiGeorge syndrome

Emanuel syndrome

hereditary neuropathy and liability to pressure palsies

neurofibromatosis type 1

Potocki–Lupski syndrome

Prader–Willi syndrome

Smith–Magenis syndrome

Sotos syndrome

velocardiofacial syndrome

Williams–Beuren syndrome

Wolf–Hirschhorn syndrome

FURTHER INFORMATION

Gene Reviews

The Sick Kids Centre for Applied Genomics

UCSC Genome Browser

Glossary

Constitutional abnormalities

Chromosomal abnormalities that are present at birth in the somatic cells of an individual.

Uniparental Disomy

A condition whereby both members of a chromosome pair are contributed by one parent rather than one from each parent.

Translocation

The fusion or exchange of material between chromosomes. When there is no gain or loss of material, the translocation is said to be balanced; when there is a gain or loss, resulting in trisomy or monosomy for a particular chromosome segment, it is said to be unbalanced.

Pericentromeric

The region surrounding the centromere, the chromosomal region where two sister chromatids are joined.

Haploinsufficiency

The inactivation or deletion of one of two alleles in diploid cells such that insufficient protein is produced.

Hypercalcaemia

A condition that refers to an elevated calcium level in the blood.

Unbalanced karyotype

A gain or loss of genetic material, resulting in trisomy or monosomy for a particular chromosome or chromosomal segment.

Acrocentric chromosome

A chromosome in which the centromere lies very close to one end. The short (p) arms are very short and usually have small dot-like appendages on stalks, known as satellites. In humans, chromosomes 13,14,15, 21 & 22 are acrocentric.

Imprinting

The differential expression of genes depending on whether they were inherited maternally or paternally.

Supernumerary marker chromosome

A marker chromosome present in a karyotype that consists of more than 46 chromosomes.

Bisatellited marker chromosome

A marker chromosome is usually small, of unknown origin and unidentifiable from its G-banding pattern. Bisatellited markers have small round appendages that are attached by fine stalks to both ends of the marker chromosome.

Non-Robertsonian

A reciprocal translocation of material between two chromosome arms, not at the centromere of an acrocentric chromosome.

Constitutional translocations

Translocations that are present at birth in the somatic cells of an individual.

Palindrome

A DNA sequence that reads the same in both directions.

Synaptonemal complex

The structure seen in electron micrographs of paired chromosomes at the pachytene stage of meiosis. The name is derived from the word synapsis, which has been used to designate chromosome pairing. Originally it referred to the protein structure aggregating the two chromosomes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Emanuel, B., Saitta, S. From microscopes to microarrays: dissecting recurrent chromosomal rearrangements. Nat Rev Genet 8, 869–883 (2007). https://doi.org/10.1038/nrg2136

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg2136

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing