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Chromosome 21 and Down syndrome: from genomics to pathophysiology



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.

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.

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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.

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Competing interests

The authors declare no competing financial interests.

Correspondence to Stylianos E. Antonarakis.

Supplementary information

  1. 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)

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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.


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


Limb malformations characterized by digit loss.


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


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


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


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


Chromosome banding pattern produced by Giemsa staining.


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


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


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).


The perception of pain.


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.


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.


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


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


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


Percentage of red blood cells in blood.

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Further reading

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.