Skip to main content

Thank you for visiting 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.

Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome


Genomic disorders are characterized by the presence of flanking segmental duplications that predispose these regions to recurrent rearrangement. Based on the duplication architecture of the genome, we investigated 130 regions that we hypothesized as candidates for previously undescribed genomic disorders1. We tested 290 individuals with mental retardation by BAC array comparative genomic hybridization and identified 16 pathogenic rearrangements, including de novo microdeletions of 17q21.31 found in four individuals. Using oligonucleotide arrays, we refined the breakpoints of this microdeletion, defining a 478-kb critical region containing six genes that were deleted in all four individuals. We mapped the breakpoints of this deletion and of four other pathogenic rearrangements in 1q21.1, 15q13, 15q24 and 17q12 to flanking segmental duplications, suggesting that these are also sites of recurrent rearrangement. In common with the 17q21.31 deletion, these breakpoint regions are sites of copy number polymorphism in controls, indicating that these may be inherently unstable genomic regions.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Detection of a previously unidentified recurrent microdeletion in 17q21.31 by targeted array CGH.
Figure 2: Structural resolution of a 1.5-Mb region of 17q21.31 (human genome May 2004 assembly (hg17), chr17:40,750,000–42,250,000) using high-density oligonucleotide arrays.
Figure 3: Photographs of individual 338H5 (del 17q21.31), age 4 years.
Figure 4: Structural resolution of five pathogenic rearrangements using high-density oligonucleotide arrays.

Accession codes


Gene Expression Omnibus


  1. Bailey, J.A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002).

    Article  CAS  Google Scholar 

  2. Cheung, V.G. et al. Integration of cytogenetic landmarks into the draft sequence of the human genome. Nature 409, 953–958 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Fredman, D. et al. Complex SNP-related sequence variation in segmental genome duplications. Nat. Genet. 36, 861–866 (2004).

    Article  CAS  Google Scholar 

  7. Sharp, A.J. et al. Segmental duplications and copy-number variation in the human genome. Am. J. Hum. Genet. 77, 78–88 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Lupski, J.R. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 14, 417–422 (1998).

    Article  CAS  Google Scholar 

  10. Locke, D.P. et al. Linkage disequilibrium and heritability of CNPs within duplicated regions of the human genome. Am. J. Hum. Genet. 79, 275–290 (2006).

    Article  CAS  Google Scholar 

  11. Knight, S.J. et al. Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet 354, 1676–1681 (1999).

    Article  CAS  Google Scholar 

  12. Edelmann, L. et al. A common molecular basis for rearrangement disorders on chromosome 22q11. Hum. Mol. Genet. 8, 1157–1167 (1999).

    Article  CAS  Google Scholar 

  13. Potocki, L. et al. Molecular mechanism for duplication 17p11.2 – the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat. Genet. 24, 84–87 (2000).

    Article  CAS  Google Scholar 

  14. Heilstedt, H.A. et al. Physical map of 1p36, placement of breakpoints in monosomy 1p36, and clinical characterization of the syndrome. Am. J. Hum. Genet. 72, 1200–1212 (2003).

    Article  CAS  Google Scholar 

  15. Stefansson, H. et al. A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. 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  Google Scholar 

  18. Gimelli, G. et al. 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 (2003).

    Article  CAS  Google Scholar 

  19. Osborne, L.R. et al. A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nat. Genet. 29, 321–325 (2001).

    Article  CAS  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. 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  Google Scholar 

  22. Zhou, Y. & Mishra, B. Quantifying the mechanisms for segmental duplications in mammalian genomes by statistical analysis and modeling. Proc. Natl. Acad. Sci. USA 102, 4051–4056 (2005).

    Article  CAS  Google Scholar 

  23. Kato, T. et al. Genetic variation affects de novo translocation frequency. Science 311, 971 (2006).

    Article  CAS  Google Scholar 

  24. Evans, W. et al. The tau H2 haplotype is almost exclusively Caucasian in origin. Neurosci. Lett. 369, 183–185 (2004).

    Article  CAS  Google Scholar 

  25. International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  26. Selzer, R.R. et al. Analysis of chromosome breakpoints in neuroblastoma at sub-kilobase resolution using fine-tiling oligonucleotide array CGH. Genes Chromosom. Cancer 44, 305–319 (2005).

    Article  CAS  Google Scholar 

  27. Liehr, T. et al. Mosaicism for the Charcot-Marie-Tooth disease type 1A duplication suggests somatic reversion. Hum. Genet. 98, 22–28 (1996).

    Article  CAS  Google Scholar 

  28. Juyal, R.C. et al. Mosaicism for del(17)(p11.2p11.2) underlying the Smith-Magenis syndrome. Am. J. Med. Genet. 66, 193–196 (1996).

    Article  CAS  Google Scholar 

Download references


The authors would like to thank all participating families and clinicians, particularly J. Flint, P. Bolton, A. Clarke, C. Fairhurst, T. Wolff, S. Mansour, S. Holder, R. Gibbons, L. Brueton, P. Day, F. Stewart, S. Keane, N. Meston, A. Seller, P. Clouston and K. Smith. This work was supported by grants from the US National Institutes of Health (NIH) (HD043569; E.E.E.), Merck Research Laboratories (A.J.S.), The Health Foundation (S.J.L.K.) and the Oxford Genetics Knowledge Park (S.J.L.K., R.R., C.G.). E.E.E. is an Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations



This study was coordinated by A.J.S., P.S.E., S.S., S.J.L. and E.E.E.; the manuscript was written by A.J.S. and E.E.E.; experimental work was performed by A.J.S., S.H., R.R.S., R.R., C.A.F., R.S. and C.G.; clinical work was performed by J.A.H., H.S., S.M.P., E.B. and R.C.H.; computational analysis was performed by Z.C.; and array production was performed by T.A.R., D.G.A. and D.P.

Corresponding author

Correspondence to Evan E Eichler.

Ethics declarations

Competing interests

P.S.E., R.R.S. and T.A.R. are employees of NimbleGen Systems, Inc. and have stock options in the company.

Supplementary information

Supplementary Fig. 1

FISH validation of 13 rearrangements detected using the SD BAC array. (PDF 1361 kb)

Supplementary Fig. 2

Parental origin and inversion analysis of the 17q21.31 deletion in the family of IMR103. (PDF 1588 kb)

Supplementary Table 1

A non-redundant set of 130 potential rearrangement hotspots in the human genome. (PDF 46 kb)

Supplementary Table 2

Copy number variations detected in 269 HapMap samples and in 290 patients with mental retardation using the SD BAC array. (PDF 3016 kb)

Supplementary Table 3

Nine additional rearrangements, including seven of uncertain significance, detected using the SD BAC array in 290 patients with mental retardation. (PDF 16 kb)

Supplementary Table 4

Comparison of phenotypes between four of the five cases of del 17q21.31 ascertained using the SD BAC array and three previously reported overlapping deletions, plus phenotype details of six further pathogenic rearrangements ascertained using the SD BAC array. (PDF 16 kb)

Supplementary Table 5

Segmental duplication clusters at five rearragement breakpoints as defined by high-density oligonucleotide array analysis. (PDF 21 kb)

Supplementary Table 6

PCR primers used in this study. (PDF 8 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sharp, A., Hansen, S., Selzer, R. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 38, 1038–1042 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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