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:

Chromosome 21 and Down syndrome: from genomics to pathophysiology

Nature Reviews Genetics volume 5, pages 725–738 (2004)Cite this article

Key Points

  • The completion of the high-quality nucleotide sequence of chromosome 21 now provides the basis for the molecular analysis of trisomy 21.

  • Trisomy 21 is the prototype of all syndromes with triplicated genomic material, and provides ample opportunities to study gene dosage imbalance.

  • Comparative and functional genomics will uncover most of the functional genomic regions of the human genome, which in turn provides the basis for understanding the molecular pathophysiology of trisomies.

  • Genomic variability might contribute to the phenotypic variability of trisomy 21.

  • Mouse models with partial trisomy are now providing fundamental knowledge for trisomy 21 and will be useful for developing potential treatments.

  • There are numerous (non-mutually exclusive) molecular mechanisms for phenotypic consequences of protein dosage imbalance. Therefore, a considerable number of genes could contribute directly or indirectly to the Down syndrome phenotypes.

  • Functional genomic elements other than protein coding genes might be involved in the molecular pathogenesis of the phenotypic features of trisomy 21.

Abstract

The sequence of chromosome 21 was a turning point for the understanding of Down syndrome. Comparative genomics is beginning to identify the functional components of the chromosome and that in turn will set the stage for the functional characterization of the sequences. Animal models combined with genome-wide analytical methods have proved indispensable for unravelling the mysteries of gene dosage imbalance.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Features of human chromosome 21 (HSA21).
Figure 2: Regions of synteny between human chromosome 21 (HSA21) and mouse chromosomes (MMUs) 16, 17 and 10.
Figure 3: Gene expression levels of trisomic genes in the Ts65Dn mouse model of Down syndrome.
Figure 4: Trisomy 21 diagnostic methods: old and new.

Similar content being viewed by others

References

  1. Hsu, L. Y. in Genetic Disorders and the Fetus (ed. Milunsky, A.) 179–248 (Johns Hopkins Univ. Press, Baltimore, 1998).

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Pentao, L., Wise, C. A., Chinault, A. C., Patel, P. I. & Lupski, J. R. Charcot–Marie–Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nature Genet. 2, 292–300 (1992).

    CAS  PubMed  Google Scholar 

  4. de Mollerat, X. J. et al. A genomic rearrangement resulting in a tandem duplication is associated with split hand-split foot malformation 3 (SHFM3) at 10q24. Hum. Mol. Genet. 12, 1959–1971 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Ellis, D. & Malcolm, S. Proteolipid protein gene dosage effect in Pelizaeus–Merzbacher disease. Nature Genet. 6, 333–4 (1994).

    CAS  PubMed  Google Scholar 

  7. Inoue, K. & Lupski, J. R. Molecular mechanisms for genomic disorders. Annu. Rev. Genomics Hum. Genet. 3, 199–242 (2002).

    CAS  PubMed  Google Scholar 

  8. Readhead, C., Schneider, A., Griffiths, I. & Nave, K. A. Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage. Neuron 12, 583–595 (1994).

    CAS  PubMed  Google Scholar 

  9. Magyar, J. P. et al. Impaired differentiation of Schwann cells in transgenic mice with increased PMP22 gene dosage. J. Neurosci. 16, 5351–5360 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lettice, L. A. et al. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum. Mol. Genet. 12, 1725–1735 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  12. Hassold, T. & Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nature Rev. Genet. 2, 280–291 (2001).

    CAS  PubMed  Google Scholar 

  13. Antonarakis, S. E. 10 years of genomics, chromosome 21, and Down syndrome. Genomics 51, 1–16 (1998).

    CAS  PubMed  Google Scholar 

  14. Bandyopadhyay, R. et al. Parental origin and timing of de novo Robertsonian translocation formation. Am. J. Hum. Genet. 71, 1456–1462 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Epstein, C. J. in The Metabolic and Molecular Bases of Inherited Diseases (eds Scriver, C. R., Beaudet, A. L., Sly, W. S. & Valle, D.) 1223–1256 (McGraw-Hill, New York, 2001).

    Google Scholar 

  16. Roizen, N. J. & Patterson, D. Down's syndrome. Lancet 361, 1281–1289 (2003).

    PubMed  Google Scholar 

  17. Pennington, B. F., Moon, J., Edgin, J., Stedron, J. & Nadel, L. The neuropsychology of Down syndrome: evidence for hippocampal dysfunction. Child Dev. 74, 75–93 (2003).

    PubMed  Google Scholar 

  18. Hattori, M. et al. The DNA sequence of human chromosome 21. Nature 405, 311–319 (2000). Landmark study that reports the high-quality nearly-complete nucleotide sequence of HSA21. Important for molecular studies on HSA21.

    CAS  PubMed  Google Scholar 

  19. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    CAS  PubMed  Google Scholar 

  20. Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

    CAS  PubMed  Google Scholar 

  21. Reymond, A. et al. From PREDs and open reading frames to cDNA isolation: revisiting the human chromosome 21 transcription map. Genomics 78, 46–54 (2001).

    CAS  PubMed  Google Scholar 

  22. Reymond, A. et al. Nineteen additional unpredicted transcripts from human chromosome 21. Genomics 79, 824–832 (2002).

    CAS  PubMed  Google Scholar 

  23. Davisson, M. et al. Evolutionary breakpoints on human chromosome 21. 78, 99–106 (2001).

  24. Gardiner, K. & Davisson, M. The sequence of human chromosome 21 and implications for research into Down syndrome. Genome Biol. 1, 1–9 (2000).

    Google Scholar 

  25. Gardiner, K., Fortna, A., Bechtel, L. & Davisson, M. T. Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions. Gene 318, 137–147 (2003).

    CAS  PubMed  Google Scholar 

  26. Pletcher, M. T., Wiltshire, T., Cabin, D. E., Villanueva, M. & Reeves, R. H. Use of comparative physical and sequence mapping to annotate mouse chromosome 16 and human chromosome 21. Genomics 74, 45–54 (2001).

    CAS  PubMed  Google Scholar 

  27. Rogers, M. A. et al. Hair keratin associated proteins: characterization of a second high sulfur KAP gene domain on human chromosome 21. J. Invest. Dermatol. 122, 147–158 (2004).

    CAS  PubMed  Google Scholar 

  28. Shibuya, K. et al. A cluster of 21 keratin-associated protein genes within introns of another gene on human chromosome 21q22. 3. Genomics 83, 679–693 (2004).

    CAS  PubMed  Google Scholar 

  29. Mural, R. J. et al. A comparison of whole-genome shotgun-derived mouse chromosome 16 and the human genome. Science 296, 1661–1671 (2002).

    CAS  PubMed  Google Scholar 

  30. Watanabe, H. et al. DNA sequence and comparative analysis of chimpanzee chromosome 22. Nature 429, 382–388 (2004).

    CAS  PubMed  Google Scholar 

  31. Kapranov, P. et al. Large-scale transcriptional activity in chromosomes 21 and 22. Science 296, 916–919 (2002). DNA chip technology used to study the transcriptional potential of the genome.

    CAS  PubMed  Google Scholar 

  32. Kampa, D. et al. Novel RNAs identified from an in-depth analysis of the transcriptome of human chromosomes 21 and 22. Genome Res. 14, 331–342 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Cawley, S. et al. Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell 116, 499–509 (2004). DNA chip technology used to identify functional elements of the genome.

    CAS  PubMed  Google Scholar 

  34. Waterston, R. H. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002). The sequence of the mouse genome provided the opportunity for comparative analysis to identify human functional genomic elements.

    CAS  PubMed  Google Scholar 

  35. Dermitzakis, E. T. et al. Numerous potentially functional but non-genic conserved sequences on human chromosome 21. Nature 420, 578–582 (2002).

    CAS  PubMed  Google Scholar 

  36. Dermitzakis, E. T. et al. Comparison of human chromosome 21 conserved nongenic sequences (CNGs) with the mouse and dog genomes shows that their selective constraint is independent of their genic environment. Genome Res. 14, 852–859 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Dermitzakis, E. T. et al. Evolutionary discrimination of mammalian conserved non-genic sequences (CNGs). Science 302, 1033–1035 (2003).

    CAS  PubMed  Google Scholar 

  38. Kirkness, E. F. et al. The dog genome: survey sequencing and comparative analysis. Science 301, 1898–1903 (2003).

    PubMed  Google Scholar 

  39. Frazer, K. A. et al. Noncoding sequences conserved in a limited number of mammals in the SIM2 interval are frequently functional. Genome Res. 14, 367–372 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Thomas, J. W. et al. Comparative analyses of multi-species sequences from targeted genomic regions. Nature 424, 788–793 (2003).

    CAS  PubMed  Google Scholar 

  41. Patil, N. et al. Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science 294, 1719–1723 (2001). A whole chromosome linkage disequilibrium mapping that provides tools for association studies of human complex phenotypes.

    CAS  PubMed  Google Scholar 

  42. Davisson, M. T. et al. Segmental trisomy as a mouse model for Down syndrome. Prog. Clin. Biol. Res. 384, 117–133 (1993).

    CAS  PubMed  Google Scholar 

  43. Kahlem, P. et al. Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of down syndrome. Genome Res. 14, 1258–1267 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Reeves, R. H. et al. A mouse model for Down syndrome exhibits learning and behavioural deficits. Nature Genet. 11, 177–184 (1995). First phenotypic analysis of the most-used mouse model with partial trisomy 16.

    CAS  PubMed  Google Scholar 

  45. Baxter, L. L., Moran, T. H., Richtsmeier, J. T., Troncoso, J. & Reeves, R. H. Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse. Hum. Mol. Genet. 9, 195–202 (2000).

    CAS  PubMed  Google Scholar 

  46. Costa, A. C., Walsh, K. & Davisson, M. T. Motor dysfunction in a mouse model for Down syndrome. Physiol. Behav. 68, 211–220 (1999).

    CAS  PubMed  Google Scholar 

  47. Escorihuela, R. M. et al. Impaired short- and long-term memory in Ts65Dn mice, a model for Down syndrome. Neurosci. Lett. 247, 171–174 (1998).

    CAS  PubMed  Google Scholar 

  48. Dierssen, M. et al. Murine models for Down syndrome. Physiol. Behav. 73, 859–871 (2001).

    CAS  PubMed  Google Scholar 

  49. Richtsmeier, J. T., Baxter, L. L. & Reeves, R. H. Parallels of craniofacial maldevelopment in Down syndrome and Ts65Dn mice. Dev. Dyn. 217, 137–145 (2000).

    CAS  PubMed  Google Scholar 

  50. Delcroix, J. D. et al. Trafficking the NGF signal: implications for normal and degenerating neurons. Prog. Brain Res. 146, 3–23 (2004).

    CAS  PubMed  Google Scholar 

  51. Cooper, J. D. et al. Failed retrograde transport of NGF in a mouse model of Down's syndrome: reversal of cholinergic neurodegenerative phenotypes following NGF infusion. Proc. Natl Acad. Sci. USA 98, 10439–10444 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Sago, H. et al. Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. Proc. Natl Acad. Sci. USA 95, 6256–6261 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Sago, H. et al. Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome. Pediatr. Res. 48, 606–613 (2000).

    CAS  PubMed  Google Scholar 

  54. Shinohara, T. et al. Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down's syndrome. Hum. Mol. Genet. 10, 1163–1175 (2001).

    CAS  PubMed  Google Scholar 

  55. Maroun, L. E., Heffernan, T. N. & Hallam, D. M. Partial IFN-α/β and IFN-γ receptor knockout trisomy 16 mouse fetuses show improved growth and cultured neuron viability. J. Interferon Cytokine Res. 20, 197–203 ( 2000).

    CAS  PubMed  Google Scholar 

  56. Epstein, C. J. et al. Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome. Proc. Natl Acad. Sci. USA 84, 8044–8048 (1987). First description of single-gene transgenic mouse model to study the overexpression consequences of a HSA21 gene.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Chrast, R. et al. Mice trisomic for a bacterial artificial chromosome with the single-minded 2 gene (Sim2) show phenotypes similar to some of those present in the partial trisomy 16 mouse models of Down syndrome. Hum. Mol. Genet. 9, 1853–1864 (2000).

    CAS  PubMed  Google Scholar 

  58. Sumarsono, S. H. et al. Down's syndrome-like skeletal abnormalities in Ets2 transgenic mice. Nature 379, 534–537 (1996).

    CAS  PubMed  Google Scholar 

  59. Lejeune, J., Gautier, M. & Turpin, R. Études des chromosomes somatiques de neuf enfants mongoliens. C. R. Acad. Sci. 248, 1721–1722 (1959). A classic paper. The first description of trisomy 21.

    CAS  Google Scholar 

  60. Lyle, R., Gehrig, C., Neergaard-Henrichsen, C., Deutsch, S. & Antonarakis, S. E. Gene expression from the aneuploid chromosome in a trisomy mouse model of Down syndrome. Genome Res. 14, 1268–1274 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Reymond, A. et al. Human chromosome 21 gene expression atlas in the mouse. Nature 420, 582–586 (2002). HSA21 gene expression atlas in the mouse.

    CAS  PubMed  Google Scholar 

  62. Gitton, Y. et al. A gene expression map of human chromosome 21 orthologues in the mouse. Nature 420, 586–590 (2002). A gene expression map of HSA21 orthologues in the mouse.

    CAS  PubMed  Google Scholar 

  63. FitzPatrick, D. R. et al. Transcriptome analysis of human autosomal trisomy. Hum. Mol. Genet. 11, 3249–3256 (2002).

    CAS  PubMed  Google Scholar 

  64. Mao, R., Zielke, C. L., Zielke, H. R. & Pevsner, J. Global up-regulation of chromosome 21 gene expression in the developing Down syndrome brain. Genomics 81, 457–467 (2003).

    CAS  PubMed  Google Scholar 

  65. Saran, N. G., Pletcher, M. T., Natale, J. E., Cheng, Y. & Reeves, R. H. Global disruption of the cerebellar transcriptome in a Down syndrome mouse model. Hum. Mol. Genet. 12, 2013–2019 (2003).

    CAS  PubMed  Google Scholar 

  66. Chrast, R. et al. The mouse brain transcriptome by SAGE: differences in gene expression between P30 brains of the partial trisomy 16 mouse model of Down syndrome (Ts65Dn) and normals. Genome Res. 10, 2006–2021 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Barlow, G. M. et al. Down syndrome congenital heart disease: a narrowed region and a candidate gene. Genet. Med. 3, 91–101 (2001).

    CAS  PubMed  Google Scholar 

  68. Korenberg, J. R. et al. Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc. Natl Acad. Sci. USA 91, 4997–5001 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Delabar, J. M. et al. Molecular mapping of twenty-four features of Down syndrome on chromosome 21. Eur. J. Hum. Genet. 1, 114–124 (1993). Systematic attempt to define chromosomal trisomic regions resulting in Down syndrome phenotypes.

    CAS  PubMed  Google Scholar 

  70. Kuo, W. L. et al. Detection of aneuploidy involving chromosomes 13, 18, or 21, by fluorescence in situ hybridization (FISH) to interphase and metaphase amniocytes. Am. J. Hum. Genet. 49, 112–119 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Slater, H. R. et al. Rapid, high throughput prenatal detection of aneuploidy using a novel quantitative method (MLPA). J. Med. Genet. 40, 907–912 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Deutsch, S., Choudhury, U. & Antonarakis, S. E. Detection of trisomy 21 and other aneuploidies by paralogous gene quantification. J. Med. Genet. (in the press).

  74. Ishkanian, A. S. et al. A tiling resolution DNA microarray with complete coverage of the human genome. Nature Genet. 36, 299–303 (2004).

    CAS  PubMed  Google Scholar 

  75. Epstein, C. J., Epstein, L. B., Weil, J. & Cox, D. R. Trisomy 21: mechanisms and models. Ann. NY Acad. Sci. 396, 107–118 (1982).

    CAS  PubMed  Google Scholar 

  76. Epstein, C. J. Mechanisms of the effects of aneuploidy in mammals. Annu. Rev. Genet. 22, 51–75 (1988).

    CAS  PubMed  Google Scholar 

  77. Epstein, C. J. Consequences of Chromosome Imbalance: Principles, Mechanisms, and Models, (Cambridge Univ. Press, New York, 1986).

    Google Scholar 

  78. Meeks-Wagner, D. & Hartwell, L. H. Normal stoichiometry of histone dimer sets is necessary for high fidelity of mitotic chromosome transmission. Cell 44, 43–52 (1986).

    CAS  PubMed  Google Scholar 

  79. Zwart, R. & Vijverberg, H. P. Four pharmacologically distinct subtypes of α4β2 nicotinic acetylcholine receptor expressed in Xenopus laevis oocytes. Mol. Pharmacol. 54, 1124–1131 (1998).

    CAS  PubMed  Google Scholar 

  80. Nelson, M. E., Kuryatov, A., Choi, C. H., Zhou, Y. & Lindstrom, J. Alternate stoichiometries of α4β2 nicotinic acetylcholine receptors. Mol. Pharmacol. 63, 332–341 (2003).

    CAS  PubMed  Google Scholar 

  81. Antoch, M. P. et al. Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell 89, 655–667 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Alkema, M. J., van der Lugt, N. M., Bobeldijk, R. C., Berns, A. & van Lohuizen, M. Transformation of axial skeleton due to overexpression of bmi-1 in transgenic mice. Nature 374, 724–727 (1995).

    CAS  PubMed  Google Scholar 

  83. Heitzler, P. & Simpson, P. The choice of cell fate in the epidermis of Drosophila. Cell 64, 1083–1092 (1991).

    CAS  PubMed  Google Scholar 

  84. Semenza, G. L., Koury, S. T., Nejfelt, M. K., Gearhart, J. D. & Antonarakis, S. E. Cell-type-specific and hypoxia-inducible expression of the human erythropoietin gene in transgenic mice. Proc. Natl Acad. Sci. USA 88, 8725–8729 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Singaraja, R. R. et al. Human ABCA1 BAC transgenic mice show increased high density lipoprotein cholesterol and ApoAI-dependent efflux stimulated by an internal promoter containing liver X receptor response elements in intron 1. J. Biol. Chem. 276, 33969–33979 (2001).

    CAS  PubMed  Google Scholar 

  86. Hoffman, S. & Edelman, G. M. Kinetics of homophilic binding by embryonic and adult forms of the neural cell adhesion molecule. Proc. Natl Acad. Sci. USA 80, 5762–5766 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Struhl, G., Struhl, K. & Macdonald, P. M. The gradient morphogen bicoid is a concentration-dependent transcriptional activator. Cell 57, 1259–1273 (1989).

    CAS  PubMed  Google Scholar 

  88. MacKay, V. L. et al. Gene expression analyzed by high-resolution state array analysis and quantitative proteomics: response of yeast to mating pheromone. Mol. Cell. Proteomics 3, 478–489 (2004).

    CAS  PubMed  Google Scholar 

  89. Baptista, M. J. et al. Heterotrisomy, a significant contributing factor to ventricular septal defect associated with Down syndrome? Hum. Genet. 107, 476–482 (2000).

    CAS  PubMed  Google Scholar 

  90. Ward, O. C., John Langdon Down (Royal Society of Medicine, London, 1998).

    Google Scholar 

  91. Wang, S. Y. et al. A high-resolution physical map of human chromosome 21p using yeast artificial chromosomes. Genome Res. 9, 1059–1073 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Kong, A. et al. A high-resolution recombination map of the human genome. Nature Genet. 31, 241–247 ( 2002).

    CAS  PubMed  Google Scholar 

  93. Lynn, A. et al. Patterns of meiotic recombination on the long arm of human chromosome 21. Genome Res. 10, 1319–1332 (2000).

    CAS  PubMed  Google Scholar 

  94. Harrison, P. M. et al. Molecular fossils in the human genome: identification and analysis of the pseudogenes in chromosomes 21 and 22. Genome Res. 12, 272–280 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Worton, R. G. et al. Human ribosomal RNA genes: orientation of the tandem array and conservation of the 5′ end. Science 239, 64–68 (1988).

    CAS  PubMed  Google Scholar 

  96. Yamada, Y. et al. A comprehensive analysis of allelic methylation status of CpG islands on human chromosome 21q. Genome Res. 14, 247–266 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Antonarakis, S. E., Lyle, R., Deutsch, S. & Reymond, A. Chromosome 21: a small land of fascinating disorders with unknown pathophysiology. Int. J. Dev. Biol. 46, 89–96 (2002).

    CAS  PubMed  Google Scholar 

  98. Olson, L. et al. Down syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65Dn exhibit variable severity of cerebellar phenotypes. Dev. Dyn. 230, 581–589 (2004).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank H. Attar, E. Hafen, U. Schibler, K. Basler, A. Estreicher, M. Friedli, K. Casada, L. Curtis, D. Sutter, C. Borel, and C. Attanasio for their contributions in the preparation of the manuscript; S. Dahoun and D. Marelli for figures 4a,b, and F. Bena for figure 4c. We also thank R. Reeves and three anonymous reviewers for critical reading of the manuscript and numerous insightful suggestions; all members (past and present) of the Antonarakis laboratory for discussions, debates and experimental data; the Swiss National Science Foundation, NCCR 'Frontiers in Genetics', European Union/Swiss OFES, Lejeune and 'Childcare' Foundations for support. We also thank the patients and their families for the donation of their samples and the continuous inspiration for research.

Author information

Authors and Affiliations

  1. Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, 1 rue Michel-Servet, Geneva, 1211, Switzerland

    Stylianos E. Antonarakis, Robert Lyle, Alexandre Reymond & Samuel Deutsch

  2. Population and Comparative Genomics, The Wellcome Trust, Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, Cambridge, UK

    Emmanouil T. Dermitzakis

Authors
  1. Stylianos E. Antonarakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Lyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emmanouil T. Dermitzakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexandre Reymond
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Samuel Deutsch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stylianos E. Antonarakis.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1: The origin of supernumerary human chromosome 21 (HSA21) in free trisomy 21

Supplementary Table 2: Frequency of Down syndrome (DS) phenotypes (PDF 41 kb)

Related links

Related links

DATABASES

Entrez Gene

PLP1

PMP22

clock

OMIM

Down syndrome

CMT1A

SHFM3

Hirschsprung disease

Swiss-Prot

FURTHER INFORMATION

Interpro

Gene Ontology Annotation

Single Nucleotide Polymorphism

Glossary

ROBERTSONIAN TRANSLOCATIONS

Occurs when the long arms of two acrocentric chromosomes fuse at the centromere and the two short arms are lost. A non-robertsonian rearrangement is a chromosomal rearrangement other than a Robertsonian translocation.

ACROCENTRIC CHROMOSOMES

A chromosome, the centromere of which is located near one end.

ECTRODACTYLY

Limb malformations characterized by digit loss.

BAC ARRAY CGH

A microarray that contains DNA from bacterial artificial chromosomes, which is used in comparative genomic hybridization to determine copy number differences of DNA sequences.

PREAXIAL POLYDACTYLY

Polydactyly (additional fingers or toes) on the thumb side of the hand and the big-toe side of the foot.

ATRIOVENTRICULAR CANAL

A complex congenital heart defect characterized by atrial septal defect, ventricular septal defect and abnormalities of the tricuspid and mitral valves.

DUODENAL STENOSIS/ATRESIA

Narrowing (stenosis) or complete obliteration of the duodenal lumen.

GIEMSA BANDS

Chromosome banding pattern produced by Giemsa staining.

CPG ISLANDS

A genomic region of about one kilobase that contains close to the theoretical, expected frequency of the CpG dinucleotide.

LINKAGE DISEQUILIBRIUM

Refers to the fact that particular alleles at nearby sites can co-occur on the same haplotype more often than is expected by chance.

HAPLOTYPE BLOCKS

Long stretches (tens of megabases) along a chromosome that have low recombination rates (and relatively few haplotypes). Adjacent blocks are separated by recombination hot spots (short regions with high recombination rates).

NOCICEPTION

The perception of pain.

SAGE

Serial analysis of gene expression: a method for comprehensive analysis of gene expression patterns using a short sequence tag (10–14bp) for each RNA molecule.

PYROSEQUENCING

A method for DNA sequencing, in which the inorganic pyrophosphate (PPi) that is released from a nucleoside triphosphate on DNA chain elongation is detected by a bioluminometric assay.

FISH

Fluorescent in situ hybridization is a method that uses fluorescent molecular DNA probes to visualize specific regions in chromosomes that hybridize to the probe.

CHROMOSOME PAINTING

Fluorescent in situ hybridization to chromosomes using a probe that represents a whole chromosome or a part of a chromosome.

POLYCYTHAEMIA

The increase of the red blood cell count, haemoglobin and the total red blood cell volume, accompanied by an increase in total blood volume.

HAEMATOCRIT

Percentage of red blood cells in blood.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Antonarakis, S., Lyle, R., Dermitzakis, E. et al. Chromosome 21 and Down syndrome: from genomics to pathophysiology. Nat Rev Genet 5, 725–738 (2004). https://doi.org/10.1038/nrg1448

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1448

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