Key Points
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Trisomy 21 is probably a disorder of altered gene expression.
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The dysregulation of gene expression in trisomy 21 is not confined to genes on chromosome 21, but is instead a genome-wide effect. This dysregulation may be linked to chromatin domains.
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The development of many mouse models for partial or full trisomy provides the opportunity to understand the molecular pathophysiology of Down syndrome; these models are extremely useful in the preclinical development of therapeutic interventions.
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Considerable progress has been made in the understanding of some of the phenotypic consequences of trisomy 21.
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The idea of a Down Syndrome Genomes Project is proposed for the understanding of the genomic variation that causes or predisposes individuals to the various phenotypic characteristics of Down syndrome.
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Recent pharmaceutical treatment efforts are discussed.
Abstract
Down syndrome (also known as trisomy 21) is the model human phenotype for all genomic gain dosage imbalances, including microduplications. The functional genomic exploration of the post-sequencing years of chromosome 21, and the generation of numerous cellular and mouse models, have provided an unprecedented opportunity to decipher the molecular consequences of genome dosage imbalance. Studies of Down syndrome could provide knowledge far beyond the well-known characteristics of intellectual disability and dysmorphic features, as several other important features, including congenital heart defects, early ageing, Alzheimer disease and childhood leukaemia, are also part of the Down syndrome phenotypic spectrum. The elucidation of the molecular mechanisms that cause or modify the risk for different Down syndrome phenotypes could lead to the introduction of previously unimaginable therapeutic options.
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Acknowledgements
The author thanks A. Fort, Y. Hibaoui, S. Nikolaev, M. Garieri, C. Borel, F. Santoni, Y. Herault, E. Yu, V. Tybulewicz, X. L. d'Ardhuy for information and assistance in the preparation of this manuscript. The author also thanks the GTEx investigators for data access, and the funding agencies SNF, EU, ERC, Lejeune, and ChildCare for the support of research in our laboratory. Furthermore, the author thanks all past and present members of the laboratory, collaborators, and the patients and their families for their inspiration and support.
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Supplementary information
Supplementary information S1 (figure)
Number of papers in the scientific literature related to the different human autosomes. (PDF 73 kb)
Supplementary information S3 (figure)
The pie chart shows the different gene types with number of genes indicated in parentheses of HSA21. (PDF 159 kb)
Glossary
- Expression quantitative trait loci
-
(eQTLs). Genetic variation that is associated with gene expression variation.
- Copy number variants
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(CNVs). One form of genetic variation in which sections of the genome are repeated and the number of repeats varies between individuals.
- Indels
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A short name for insertions and deletions in the genome.
- Acrocentric
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Mammalian chromosomes in which the centromere is close to one end. Chromosomes 13, 14, 15, 21 and 22 are acrocentric in humans.
- Lamina-associated domains
-
(LADs). Regions of the chromatin that interact with the nuclear lamina.
- Replication domains
-
Regions of the genome that are copied (replicated) at the same time during the S phase of cell division.
- Partial T21
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A genomic alteration in which a portion of chromosome 21 is triplicated.
- Driver mutations
-
A mutation in a gene or other functional genomic element that provides a selective advantage to a clone of cells.
- Variant allele frequency
-
The frequency of a variant (not reference) allele in each human population.
- Megakaryoblasts
-
Precursor cell to a promegakaryocyte, which in turn becomes a megakaryocyte during haematopoiesis.
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Antonarakis, S. Down syndrome and the complexity of genome dosage imbalance. Nat Rev Genet 18, 147–163 (2017). https://doi.org/10.1038/nrg.2016.154
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DOI: https://doi.org/10.1038/nrg.2016.154
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