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Cited by 964Down syndrome and intellectual disability researchWilliams Syndrome ResearchGenetics and Neurodevelopmental Disorders

Down syndrome

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Antonarakis, Stylianos E., Skotko, Brian G., Rafii, Michael S., Strydom, Andre, Pape, Sarah E., Bianchi, Diana W., Sherman, Stephanie L., Reeves, Roger H.·2020·Nature Reviews Disease Primers
DOI 10.1038/s41572-019-0143-7PMC PMC8428796
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Abstract

Trisomy 21, the presence of a supernumerary chromosome 21, results in a collection of clinical features commonly known as Down syndrome (DS). DS is among the most genetically complex of the conditions that are compatible with human survival post-term, and the most frequent survivable autosomal aneuploidy. Mouse models of DS, involving trisomy of all or part of human chromosome 21 or orthologous mouse genomic regions, are providing valuable insights into the contribution of triplicated genes or groups of genes to the many clinical manifestations in DS. This endeavour is challenging, as there are >200 protein-coding genes on chromosome 21 and they can have direct and indirect effects on homeostasis in cells, tissues, organs and systems. Although this complexity poses formidable challenges to understanding the underlying molecular basis for each of the many clinical features of DS, it also provides opportunities for improving understanding of genetic mechanisms underlying the development and function of many cell types, tissues, organs and systems. Since the first description of trisomy 21, we have learned much about intellectual disability and genetic risk factors for congenital heart disease. The lower occurrence of solid tumours in individuals with DS supports the identification of chromosome 21 genes that protect against cancer when overexpressed. The universal occurrence of the histopathology of Alzheimer disease and the high prevalence of dementia in DS are providing insights into the pathology and treatment of Alzheimer disease. Clinical trials to ameliorate intellectual disability in DS signal a new era in which therapeutic interventions based on knowledge of the molecular pathophysiology of DS can now be explored; these efforts provide reasonable hope for the future.

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  • Cognitive impairment is a hallmark DS phenotype affecting all individuals with Ts21.

    “Cognitive impairment is a hallmark DS phenotype affecting all individuals with Ts21 (Antonarakis et al., 2020) with regions of disproportionately small brain volume including the cerebrum, cerebellum, and hippocampus (Aylward et al., 1999; Kesslak et al., 1994; Pinter et al., 2001; Raz et al., 1995; Weis et al., 1991).”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Antonarakis et al., 2020

    The Abstract describes intellectual disability as a common feature of Down syndrome, and the Management > Neurodevelopment section describes a cognitive profile with a wide range of functioning (page numbers unavailable). Neither passage establishes that cognitive impairment affects every individual with trisomy 21; the claim’s universal qualifier is unsupported. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Trisomy of genes on human chromosome 21 leads to the ~80 clinical phenotypes associated with DS.

    “Trisomy of genes on human chromosome 21 (Hsa21)—the smallest human chromosome with 46.7 Mbp of DNA that contains 233 protein coding, 423 noncoding, and 188 pseudogenes (ensembl.org)—leads to the ~80 clinical phenotypes associated with DS (Antonarakis et al., 2020).”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Antonarakis et al., 2020

    The Abstract states that trisomy 21 causes Down syndrome and its many clinical manifestations. The Genetics of DS section discusses how triplicated genes may contribute to those manifestations, but our copy does not give a count of approximately 80 clinical phenotypes. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The DS neurodevelopmental phenotype encompasses deficits in executive function, working memory, motor coordination, and linguistic processing that emerge within the first postnatal months and influence academic, occupational, and adaptive functioning trajectories throughout the lifespan.

    “This neurodevelopmental phenotype encompasses deficits in executive function, working memory, motor coordination, and linguistic processing - impairments that emerge within the first postnatal months and profoundly influence academic, occupational, and adaptive functioning trajectories throughout the lifespan (2-5).”

    From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [5]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • DS leads to variable intellectual deficits.

    “leading to variable intellectual deficits 1”

    From Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations (2026) · cites this paper as [1]

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Authors
Antonarakis, S. E., Skotko, B. G., Rafii, M. S., Strydom, A., Pape, S. E., Bianchi, D. W., Sherman, S. L., & Reeves, R. H.
Affiliations
  • University of Geneva (CH)
  • Harvard University (US)
  • University of Southern California (US)
  • King's College London (GB)
  • National Institutes of Health (US)
  • Emory University (US)
  • Johns Hopkins University (US)
Corresponding author
Antonarakis, Stylianos E.
ORCID
Venue
Nature Reviews Disease Primers
Publisher
Springer Science and Business Media LLC
Published
2020-02-06
Volume
6
Issue
1
Pages
9-9
ISSN
2056-676X (ISSN-L)
DOI
10.1038/s41572-019-0143-7
PMC
PMC8428796
OpenAlex
W4210691315
Cited by
964
References
24
Citations by year
2026: 145 · 2025: 225 · 2024: 204 · 2023: 165 · 2022: 112 · 2021: 80 · 2020: 29
FWCI
16.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Disease Primers (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Wellcome Trust (098330/Z/12/Z)
  • Agence Nationale de la Recherche (ANR-18-COEN-0002)
  • National Institutes of Health (UL1TR001064)
  • Medical Research Council (MR/S011277/1, MR/R024901/1, MR/S005145/1)
  • National Human Genome Research Institute (ZIAHG200399)
  • National Center for Advancing Translational Sciences
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD042053, R21HD098540, R01HD038384)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
Down syndrome, chromosome 21, mouse models of Down syndrome, intellectual disability, congenital heart disease, cancer susceptibility, Alzheimer's disease, dementia
MeSH terms
Down Syndrome, Humans, Risk Factors

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