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Down syndrome

Nature Reviews Disease Primers volume 6, Article number: 9 (2020) Cite this article

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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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Fig. 1: Symptoms and manifestations in Down syndrome.
Fig. 2: Prevalence of DS and pregnancy outcomes in the USA.
Fig. 3: Conserved synteny of human chromosome 21 with mouse chromosomes and mouse models of trisomy 21.
Fig. 4: Mechanisms of Alzheimer disease in Down syndrome.
Fig. 5: Alzheimer disease prevalence and cognitive decline in Down syndrome.

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Acknowledgements

The authors thank the members of the London Down Syndrome (LonDownS) Consortium, G. de Graaf of the Dutch Down Syndrome Foundation and F. Buckley of Down Syndrome Education International for their review of the epidemiology section of this article. Work in the authors’ laboratories and clinics was supported by grants from the SNF, EU, ERC, Jerome Lejeune, and ChildCare Foundations to S.E.A.; a Wellcome Trust Strategic Award (grant number 098330/Z/12/Z) conferred upon the LonDownS Consortium, an MRC project grant (LonDownsPREVENT MR/S011277/1), and grants from the EU Joint Programme - Neurodegenerative Disease Research (MR/R024901/1, as part of the HEROES consortium), Network of Centres of Excellence in Neurodegeneration (COEN) (MR/S005145/1), Lumind Foundation and Jerome Lejeune Foundation to A.S.; the Jerome Lejeune Foundation USA, Anna and John Sie Foundation, US National Institutes of Health (NIH; HD42053-10, UL1TR001064, ZIA HG200399-04) to D.W.B.; NIH and Lumind Foundation to S.L.S.; HD038384-20, HD098540 and the Lumind Foundation to R.H.R.; and the Alzheimer’s Society and BRC to S.P. The authors thank all past and present members of their laboratories, their collaborators and the patients and their families for their inspiration and support.

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Authors and Affiliations

  1. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland

    Stylianos E. Antonarakis

  2. Down Syndrome Program, Division of Medical Genetics, Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA

    Brian G. Skotko

  3. Department of Pediatrics, Harvard Medical School, Boston, MA, USA

    Brian G. Skotko

  4. Keck School of Medicine of University of Southern California, California, CA, USA

    Michael S. Rafii

  5. Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

    Andre Strydom & Sarah E. Pape

  6. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

    Diana W. Bianchi

  7. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Diana W. Bianchi

  8. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA

    Stephanie L. Sherman

  9. Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Roger H. Reeves

  10. McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Roger H. Reeves

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  1. Stylianos E. Antonarakis
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Contributions

Introduction (S.E.A.); Epidemiology (B.G.S.); Mechanisms/pathophysiology (S.E.A., M.S.R., S.L.S. and R.H.R.); Diagnosis, screening and prevention (S.E.A. and D.W.B.); Management (A.S. and S.E.P.); Quality of life (A.S. and S.E.P.); Outlook (S.E.A.).

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Correspondence to Stylianos E. Antonarakis.

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Competing interests

S.E.A. is the co-founder and CEO of MediGenome, a clinical and laboratory diagnostic company. B.G.S. occasionally consults on the topic of Down syndrome through Gerson Lehrman Group. B.G.S. receives remuneration from Down syndrome non-profit organizations for speaking engagements and associated travel expenses. B.G.S. receives annual royalties from Woodbine House, Inc., for the publication of his book, Fasten Your Seatbelt: A Crash Course on Down Syndrome for Brothers and Sisters. Within the past 2 years, B.G.S. has received research funding from F. Hoffmann-La Roche, Inc., and LuMind IDSC Down Syndrome Foundation to conduct clinical trials for people with Down syndrome. B.G.S. is occasionally asked to serve as an expert witness in legal cases where Down syndrome is discussed. B.G.S. serves in a non-paid capacity on the Honorary Board of Directors for the Massachusetts Down Syndrome Congress and the Professional Advisory Committee for the National Center for Prenatal and Postnatal Down Syndrome Resources. B.G.S. has a sister with Down syndrome. M.S.R. is a consultant to AC Immune SA. A.S. has consulted for Roche Pharmaceuticals, ONO Pharma, Aelis Farma and AC Immune, and he serves on the Scientific Advisory Board of ProMIS Neurosciences. A.S. and S.E.P. provide clinical services within the UK National Health Service to individuals with Down syndrome. The remaining authors declare no competing interests.

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Related links

Down’s Syndrome Association and the Down Syndrome Medical Interest Group fact sheet: http://www.perinatalservicesbc.ca/Documents/Guidelines-Standards/Maternal/DownSyndromePracticeResource.pdf

Protein-coding genes on HSA21: https://www.ensembl.org/Homo_sapiens/Location/Chromosome?r=21

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Antonarakis, S.E., Skotko, B.G., Rafii, M.S. et al. Down syndrome. Nat Rev Dis Primers 6, 9 (2020). https://doi.org/10.1038/s41572-019-0143-7

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