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Down syndrome

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.

References

  1. Down, J. L. H. Observations on an ethnic classification of idiots. Lond. Hosp. Rep. 3, 259–262 (1866).

    Google Scholar 

  2. Hasle, H., Clemmensen, I. H. & Mikkelsen, M. Risks of leukaemia and solid tumours in individuals with Down’s syndrome. Lancet 355, 165–169 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. LeJeune, J., Gautier, M. & Turpin, R. Study of somatic chromosomes from 9 mongoloid children [French]. C. R. Hebd. Seances. Acad. Sci. 248, 1721–1722 (1959). This study is the first description of the chromosomal abnormality in DS.

    CAS  PubMed  Google Scholar 

  4. Davisson, M. T., Schmidt, C. & Akeson, E. C. Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome. Prog. Clin. Biol. Res. 360, 263–280 (1990).

    CAS  PubMed  Google Scholar 

  5. Hattori, M. et al. The DNA sequence of human chromosome 21. Nature 405, 311–319 (2000). A landmark paper on the sequencing of the long arm of HSA21.

    Article  CAS  PubMed  Google Scholar 

  6. Antonarakis, S. E. Down syndrome and the complexity of genome dosage imbalance. Nat. Rev. Genet. 18, 147–163 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Herault, Y. et al. Rodent models in Down syndrome research: impact and future opportunities. Dis. Model. Mech. 10, 1165–1186 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen, X. Q. & Mobley, W. C. Exploring the pathogenesis of Alzheimer disease in basal forebrain cholinergic neurons: converging insights from alternative hypotheses. Front. Neurosci. 13, 446 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Reeves, R. H. et al. Paving the way for therapy: the Second International Conference of the Trisomy 21 Research Society. Mol. Syndromol. 9, 279–286 (2019).

    Article  PubMed  Google Scholar 

  10. de Graaf, G., Buckley, F. & Skotko, B. People living with Down syndrome in the USA: births and population. Down Syndrome Education International https://dsuri.net/us-population-factsheet (2019).

  11. de Graaf, G., Buckley, F. & Skotko, B. G. Estimation of the number of people with Down syndrome in the United States. Genet. Med. 19, 439–447 (2017).

    Article  PubMed  Google Scholar 

  12. de Graaf, G., Buckley, F. & Skotko, B. G. Birth and population prevalence of Down syndrome in European countries. (Poster presented at the World Down Syndrome Congress 2018).

  13. Bray, I., Wright, D. E., Davies, C. & Hook, E. B. Joint estimation of Down syndrome risk and ascertainment rates: a meta-analysis of nine published data sets. Prenat. Diagn. 18, 9–20 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Hecht, C. A. & Hook, E. B. Rates of Down syndrome at livebirth by one-year maternal age intervals in studies with apparent close to complete ascertainment in populations of European origin: a proposed revised rate schedule for use in genetic and prenatal screening. Am. J. Med. Genet. 62, 376–385 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Morris, J. K., Wald, N. J., Mutton, D. E. & Alberman, E. Comparison of models of maternal age-specific risk for Down syndrome live births. Prenat. Diagn. 23, 252–258 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. de Graaf, G., Buckley, F. & Skotko, B. G. Estimates of the live births, natural losses, and elective terminations with Down syndrome in the United States. Am. J. Med. Genet. A 167, 756–767 (2015).

    Article  Google Scholar 

  18. Savva, G. M., Morris, J. K., Mutton, D. E. & Alberman, E. Maternal age-specific fetal loss rates in Down syndrome pregnancies. Prenat. Diagn. 26, 499–504 (2006).

    Article  PubMed  Google Scholar 

  19. Bittles, A. H., Bower, C., Hussain, R. & Glasson, E. J. The four ages of Down syndrome. Eur. J. Public Health 17, 221–225 (2007).

    Article  PubMed  Google Scholar 

  20. Deng, C. et al. Recent trends in the birth prevalence of Down syndrome in China: impact of prenatal diagnosis and subsequent terminations. Prenat. Diagn. 35, 311–318 (2015).

    Article  PubMed  Google Scholar 

  21. Morris, J. K. & Alberman, E. Trends in Down’s syndrome live births and antenatal diagnoses in England and Wales from 1989 to 2008: analysis of data from the National Down Syndrome cytogenetic register. BMJ 339, b3794 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Tul, N., Verdenik, I., Srsen, T. P. & Antolic, Z. N. P31.05: incidence of Down syndrome in Slovenia in the last 15 years. Ultrasound Obstet. Gynecol. 30, 569–570 (2007).

    Article  Google Scholar 

  23. Collins, V. R., Muggli, E. E., Riley, M., Palma, S. & Halliday, J. L. Is Down syndrome a disappearing birth defect? J. Pediatr. 152, 20–24.e1 (2008).

    Article  PubMed  Google Scholar 

  24. Dolk, H. et al. Trends and geographic inequalities in the prevalence of Down syndrome in Europe, 1980-1999. Rev. Epidemiol Sante Publique 53, 2S87–2S95 (2005).

    Article  PubMed  Google Scholar 

  25. de Graaf, G. et al. Estimates of live birth prevalence of children with Down syndrome in the period 1991–2015 in the Netherlands. J. Intellect. Disabil. Res. 61, 461–470 (2017).

    Article  PubMed  Google Scholar 

  26. Nagaoka, S. I., Hassold, T. J. & Hunt, P. A. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat. Rev. Genet. 13, 493–504 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gruhn, J. R. et al. Chromosome errors in human eggs shape natural fertility over reproductive life span. Science 365, 1466–1469 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Antonarakis, S. E. et al. The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms. Am. J. Hum. Genet. 50, 544–550 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Allen, E. G. et al. Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects. Hum. Genet. 125, 41–52 (2009).

    Article  PubMed  Google Scholar 

  30. Yoon, P. W. et al. Advanced maternal age and the risk of Down syndrome characterized by the meiotic stage of chromosomal error: a population-based study. Am. J. Hum. Genet. 58, 628–633 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Freeman, S. B. et al. The National Down Syndrome Project: design and implementation. Public Health Rep. 122, 62–72 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ghosh, S., Feingold, E. & Dey, S. K. Etiology of Down syndrome: evidence for consistent association among altered meiotic recombination, nondisjunction, and maternal age across populations. Am. J. Med. Genet. A 149, 1415–1420 (2009).

    Article  CAS  Google Scholar 

  33. Oliver, T. R. et al. New insights into human nondisjunction of chromosome 21 in oocytes. PLoS Genet. 4, e1000033 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Chernus, J. M. et al. A candidate gene analysis and GWAS for genes associated with maternal nondisjunction of chromosome 21. PLoS Genet. 15, e1008414 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Coppede, F. Risk factors for Down syndrome. Arch. Toxicol. 90, 2917–2929 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. Hunter, J. E. et al. The association of low socioeconomic status and the risk of having a child with Down syndrome: a report from the National Down Syndrome Project. Genet. Med. 15, 698–705 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Torfs, C. P. & Christianson, R. E. Socioeconomic effects on the risk of having a recognized pregnancy with Down syndrome. Birth Defects Res. A Clin. Mol. Teratol. 67, 522–528 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Christianson, R. E., Sherman, S. L. & Torfs, C. P. Maternal meiosis II nondisjunction in trisomy 21 is associated with maternal low socioeconomic status. Genet. Med. 6, 487–494 (2004).

    Article  PubMed  Google Scholar 

  39. Ghosh, S., Ghosh, P. & Dey, S. K. Altered incidence of meiotic errors and Down syndrome birth under extreme low socioeconomic exposure in the Sundarban area of India. J. Community Genet. 5, 119–124 (2014).

    Article  PubMed  Google Scholar 

  40. Keen, C. et al. The association between maternal occupation and Down syndrome: a report from the national Down syndrome project. Int. J. Hyg. Environ. Health 223, 207–213 (2020).

    Article  CAS  PubMed  Google Scholar 

  41. Sartain, C. V. & Hunt, P. A. An old culprit but a new story: bisphenol A and "NextGen" bisphenols. Fertil. Steril. 106, 820–826 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Horan, T. S. et al. Replacement bisphenols adversely affect mouse gametogenesis with consequences for subsequent generations. Curr. Biol. 28, 2948–2954.e3 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Grandjean, P. et al. Timescales of developmental toxicity impacting on research and needs for intervention. Basic Clin. Pharmacol. Toxicol. 125, 70–80 (2019).

    Article  CAS  PubMed  Google Scholar 

  44. Antonarakis, S. E., Avramopoulos, D., Blouin, J. L., Talbot, C. C. Jr. & Schinzel, A. A. Mitotic errors in somatic cells cause trisomy 21 in about 4.5% of cases and are not associated with advanced maternal age. Nat. Genet. 3, 146–150 (1993).

    Article  CAS  PubMed  Google Scholar 

  45. Antonarakis, S. E. Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. Down Syndrome Collaborative Group. N. Engl. J. Med. 324, 872–876 (1991). This paper reports the use of DNA polymorphic markers to determine the parental origin of the supernumerary HSA21 in DS.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Morris, J. K., Alberman, E., Mutton, D. & Jacobs, P. Cytogenetic and epidemiological findings in Down syndrome: England and Wales 1989-2009. Am. J. Med. Genet. A 158, 1151–1157 (2012).

    Article  Google Scholar 

  48. Lyle, R. et al. Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21. Eur. J. Hum. Genet. 17, 454–466 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  50. Gupta, M., Dhanasekaran, A. R. & Gardiner, K. J. Mouse models of Down syndrome: gene content and consequences. Mamm. Genome 27, 538–555 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Epstein, C. J. et al. Protocols to establish genotype-phenotype correlations in Down syndrome. Am. J. Hum. Genet. 49, 207–235 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Bray, I. C. & Wright, D. E. Estimating the spontaneous loss of Down syndrome fetuses between the times of chorionic villus sampling, amniocentesis and livebirth. Prenat. Diagn. 18, 1045–1054 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Hassold, T. J. & Jacobs, P. A. Trisomy in man. Ann.Rev.Genet. 18, 69–97 (1984).

    Article  CAS  PubMed  Google Scholar 

  54. Shapiro, B. L. Down syndrome – a disruption of homeostasis. Am. J. Med. Genet. 14, 241–269 (1983).

    Article  CAS  PubMed  Google Scholar 

  55. Pritchard, M. & Kola, I. The ‘gene dosage effect’ hypothesis versus the ‘amplified developmental instability’ hypothesis in Down syndrome. J. Neural Transm. 57, 293–303 (1999).

    CAS  Google Scholar 

  56. Stamoulis, G. et al. Single cell transcriptome in aneuploidies reveals mechanisms of gene dosage imbalance. Nat. Commun. 10, 4495 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Salehi, A. et al. Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51, 29–42 (2006). A study that provided support for the hypothesis that neuronal degeneration in DS is due to increased APP expression.

    Article  CAS  PubMed  Google Scholar 

  58. Pelleri, M. C. et al. Integrated quantitative transcriptome maps of human trisomy 21 tissues and cells. Front. Genet. 9, 125 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Sullivan, K. D. et al. Trisomy 21 consistently activates the interferon response. eLife 5, e16220 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Gonzales, P. K. et al. Transcriptome analysis of genetically matched human induced pluripotent stem cells disomic or trisomic for chromosome 21. PLoS One 13, e0194581 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Letourneau, A. et al. Domains of genome-wide gene expression dysregulation in Down’s syndrome. Nature 508, 345–350 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Do, C., Xing, Z., Yu, Y. E. & Tycko, B. Trans-acting epigenetic effects of chromosomal aneuploidies: lessons from Down syndrome and mouse models. Epigenomics 9, 189–207 (2017).

    Article  CAS  PubMed  Google Scholar 

  63. Do, L. H., Mobley, W. C. & Singhal, N. Questioned validity of gene expression dysregulated domains in Down’s syndrome. F1000Res. 4, 269 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Ahlfors, H. et al. Gene expression dysregulation domains are not a specific feature of Down syndrome. Nat. Commun. 10, 2489 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Umlauf, D. & Mourad, R. The 3D genome: from fundamental principles to disease and cancer. Semin. Cell Dev. Biol. 90, 128–137 (2019).

    Article  CAS  PubMed  Google Scholar 

  66. Kemeny, S. et al. Spatial organization of chromosome territories in the interphase nucleus of trisomy 21 cells. Chromosoma 127, 247–259 (2018).

    Article  CAS  PubMed  Google Scholar 

  67. Mendioroz, M. et al. Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models. Genome Biol. 16, 263 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. El Hajj, N. et al. Epigenetic dysregulation in the developing Down syndrome cortex. Epigenetics 11, 563–578 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Horvath, S. et al. Accelerated epigenetic aging in Down syndrome. Aging Cell 14, 491–495 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Scott, H. S. et al. Identification and characterization of two putative human arginine methyltransferases (HRMT1L1 and HRMT1L2). Genomics 48, 330–340 (1998).

    Article  CAS  PubMed  Google Scholar 

  71. Xiao, C. L. et al. N6-methyladenine DNA modification in the human genome. Mol. Cell 71, 306–318.e7 (2018).

    Article  CAS  PubMed  Google Scholar 

  72. Kim, I. S. et al. Roles of Mis18α in epigenetic regulation of centromeric chromatin and CENP-A loading. Mol. Cell 46, 260–273 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Veland, N. et al. DNMT3L facilitates DNA methylation partly by maintaining DNMT3A stability in mouse embryonic stem cells. Nucleic Acids Res. 47, 152–167 (2019).

    Article  CAS  PubMed  Google Scholar 

  74. Lu, J. et al. Global hypermethylation in fetal cortex of Down syndrome due to DNMT3L overexpression. Hum. Mol. Genet. 25, 1714–1727 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sailani, M. R. et al. DNA-methylation patterns in trisomy 21 using cells from monozygotic twins. PLoS One 10, e0135555 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Guo, X., Williams, J. G., Schug, T. T. & Li, X. DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1. J. Biol. Chem. 285, 13223–13232 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lepagnol-Bestel, A. M. et al. DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome. Hum. Mol. Genet. 18, 1405–1414 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Liu, Y. et al. Systematic proteome and proteostasis profiling in human trisomy 21 fibroblast cells. Nat. Commun. 8, 1212 (2017). First quantitative study of the trisomy 21 proteome, using fibroblasts from individuals with DS.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Gillet, L. C. et al. Targeted data extraction of the MS/MS spectra generated by data-independent acquisition: a new concept for consistent and accurate proteome analysis. Mol. Cell Proteom. 11, O111.016717 (2012).

    Article  CAS  Google Scholar 

  80. Sullivan, K. D. et al. Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation. Sci. Rep. 7, 14818 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Gold, L. et al. Aptamer-based multiplexed proteomic technology for biomarker discovery. PLoS One 5, e15004 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Izzo, A. et al. Mitochondrial dysfunction in Down syndrome: molecular mechanisms and therapeutic targets. Mol. Med. 24, 2 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Zamponi, E. & Helguera, P. R. The shape of mitochondrial dysfunction in Down syndrome. Dev. Neurobiol. 79, 613–621 (2019).

    Article  CAS  PubMed  Google Scholar 

  84. Valenti, D. et al. Mitochondria as pharmacological targets in Down syndrome. Free. Radic. Biol. Med. 114, 69–83 (2018).

    Article  CAS  PubMed  Google Scholar 

  85. Vilardell, M. et al. Meta-analysis of heterogeneous Down syndrome data reveals consistent genome-wide dosage effects related to neurological processes. BMC Genomics 12, 229 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Reeves, R. et al. A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat. Genet. 11, 177–183 (1995). This paper describes the first complex model of trisomy 21, Ts65Dn, and lays out characterizations for comparing the effects of aneuploidy in mice and humans.

    Article  CAS  PubMed  Google Scholar 

  87. Sussan, T., Yang, A., Li, F., Ostrowski, M. & Reeves, R. H. Trisomy protects against ApcMin-mediated tumors in mouse models of Down syndrome. Nature 451, 73–75 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Garcia-Cerro, S., Rueda, N., Vidal, V., Lantigua, S. & Martinez-Cue, C. Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer’s disease phenotypes. Neurobiol. Dis. 106, 76–88 (2017).

    Article  CAS  PubMed  Google Scholar 

  89. Aziz, N. M. et al. Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome. Disease Models Mech 11, dmm031013 (2018).

    Article  CAS  Google Scholar 

  90. Gribble, S. M. et al. Massively parallel sequencing reveals the complex structure of an irradiated human chromosome on a mouse background in the Tc1 model of Down syndrome. PLoS One 8, e60482 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kazuki, Y. et al. A non-mosaic humanized mouse model of Down syndrome, trisomy of a nearly complete long arm of human chromosome 21 in mouse chromosome background. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/862433v1 (2019).

  92. Ramirez-Solis, R., Liu, P. & Bradley, A. Chromosome engineering in mice. Nature 378, 720–724 (1995).

    Article  CAS  PubMed  Google Scholar 

  93. Olson, L. E., Richtsmeier, J. T., Leszl, J. & Reeves, R. H. A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science 306, 687–690 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Yu, T. et al. A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions. Hum. Mol. Genet. 19, 2780–2791 (2010). This paper reports a mouse model that is trisomic for all mouse chromosomal regions syntenic with HSA21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Stefanidis, K. et al. Causes of infertility in men with Down syndrome. Andrologia 43, 353–357 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Williams, B. R. et al. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 322, 703–709 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Contestabile, A. et al. Cell cycle alteration and decreased cell proliferation in the hippocampal dentate gyrus and in the neocortical germinal matrix of fetuses with Down syndrome and in Ts65Dn mice. Hippocampus 17, 665–678 (2007).

    Article  PubMed  Google Scholar 

  98. Kleschevnikov, A. M. et al. Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J. Neurosci. 24, 8153–8160 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Siarey, R. J., Stoll, J., Rapoport, S. I. & Galdzicki, Z. Altered long-term potentiation in the young and old Ts65Dn mouse, a model for Down syndrome. Neuropharmacology 36, 1549–1554 (1997).

    Article  CAS  PubMed  Google Scholar 

  100. Ferencz, C. et al. Congenital cardiovascular malformations associated with chromosome abnormalities: an epidemiologic study. J. Pediatr. 114, 79–86 (1989).

    Article  CAS  PubMed  Google Scholar 

  101. Lana-Elola, E. et al. Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel. eLife 5, e11614 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Li, H. et al. Penetrance of congenital heart disease in a mouse model of Down syndrome depends on a trisomic potentiator of a disomic modifier. Genetics 203, 763–770 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Edie, S. et al. Survey of human chromosome 21 gene expression effects on early development in Danio rerio. G3 8, 2215–2223 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Yang, Q., Rasmussen, S. A. & Friedman, J. M. Mortality associated with Down’s syndrome in the USA from 1983 to 1997: a population-based study. Lancet 359, 1019–1025 (2002).

    Article  PubMed  Google Scholar 

  105. Escorihuela, R. M. et al. A behavioral assessment of Ts65Dn mice: a putative Down syndrome model. Neurosci. Lett. 199, 143–146 (1995).

    Article  CAS  PubMed  Google Scholar 

  106. Holtzman, D. M. et al. Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proc. Natl Acad. Sci. USA 93, 13333–13338 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Hanson, J. E., Blank, M., Valenzuela, R. A., Garner, C. C. & Madison, D. V. The functional nature of synaptic circuitry is altered in area CA3 of the hippocampus in a mouse model of Down’s syndrome. J. Physiol. 579, 53–67 (2007). This study establishes the imbalance between excitatory and inhibitory inputs in the hippocampus, which has been the focus of efforts to antagonize signalling through GABA-A receptors, including a trial to improve cognitive ability in individuals with DS (NCT01436955).

    Article  CAS  PubMed  Google Scholar 

  108. Fernandez, F. et al. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat. Neurosci. 10, 411–413 (2007). One of the first mouse studies that raised the possibility of pharmacotherapy for the cognitive impairment in DS.

    Article  CAS  PubMed  Google Scholar 

  109. Braudeau, J. et al. Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice. J Psychopharmacol (2011).

  110. Duchon, A. et al. Long-lasting correction of in vivo LTP and cognitive deficits of mice modelling Down syndrome with an α5-selective GABAA inverse agonist. Br. J. Pharmacol. https://doi.org/10.1111/bph.14903 (2019).

  111. Hart, S. J. et al. Pharmacological interventions to improve cognition and adaptive functioning in Down syndrome: strides to date. Am. J. Med. Genet. A 173, 3029–3041 (2017).

    Article  PubMed  Google Scholar 

  112. de la Torre, R. et al. Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down’s syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 15, 801–810 (2016). A successful randomized trial to improve cognitive functioning in young adults with DS.

    Article  PubMed  CAS  Google Scholar 

  113. Jack, C. R. Jr. et al. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology 87, 539–547 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Esparza, T. J. et al. Amyloid-β oligomerization in Alzheimer dementia versus high-pathology controls. Ann. Neurol. 73, 104–119 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Strydom, A. et al. Alzheimer’s disease in Down syndrome: an overlooked population for prevention trials. Alzheimers Dement. 4, 703–713 (2018).

    Google Scholar 

  116. Thonberg, H. et al. Mutation screening of patients with Alzheimer disease identifies APP locus duplication in a Swedish patient. BMC Res. Notes 4, 476 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Wallon, D. et al. The French series of autosomal dominant early onset Alzheimer’s disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J. Alzheimers Dis. 30, 847–856 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Rovelet-Lecrux, A. et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet. 38, 24–26 (2006). This study provides strong evidence for a link between the triplication of APP in trisomy 21 and early-onset AD in individuals with DS.

    Article  CAS  PubMed  Google Scholar 

  119. Sleegers, K. et al. APP duplication is sufficient to cause early onset Alzheimer’s dementia with cerebral amyloid angiopathy. Brain 129, 2977–2983 (2006).

    Article  PubMed  Google Scholar 

  120. Wiseman, F. K. et al. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nat. Rev. Neurosci. 16, 564–574 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Doran, E. et al. Down syndrome, partial trisomy 21, and absence of Alzheimer’s disease: the role of APP. J. Alzheimers Dis. 56, 459–470 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ryoo, S. R. et al. Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer’s disease. J. Neurochem. 104, 1333–1344 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Wegiel, J. et al. Intraneuronal Aβ immunoreactivity is not a predictor of brain amyloidosis-β or neurofibrillary degeneration. Acta Neuropathol. 113, 389–402 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Vingtdeux, V. et al. Phosphorylation of amyloid precursor carboxy-terminal fragments enhances their processing by a gamma-secretase-dependent mechanism. Neurobiol. Dis. 20, 625–637 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. Woods, Y. L. et al. The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bε at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem. J. 355, 609–615 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lindwall, G. & Cole, R. D. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J. Biol. Chem. 259, 5301–5305 (1984).

    CAS  PubMed  Google Scholar 

  127. LaPointe, N. E. et al. The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity. J. Neurosci. Res. 87, 440–451 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Goedert, M. & Jakes, R. Mutations causing neurodegenerative tauopathies. Biochim. Biophys. Acta 1739, 240–250 (2005).

    Article  CAS  PubMed  Google Scholar 

  129. Liu, F. et al. Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome. FASEB J. 22, 3224–3233 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Yin, X. et al. Dyrk1A overexpression leads to increase of 3R-tau expression and cognitive deficits in Ts65Dn Down syndrome mice. Sci. Rep. 7, 619 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Chen, X. Q., Sawa, M. & Mobley, W. C. Dysregulation of neurotrophin signaling in the pathogenesis of Alzheimer disease and of Alzheimer disease in Down syndrome. Free Radic. Biol. Med. 114, 52–61 (2018).

    Article  CAS  PubMed  Google Scholar 

  132. Stenmark, H. Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. Cell Biol. 10, 513–525 (2009).

    Article  CAS  PubMed  Google Scholar 

  133. Roberts, R. L. et al. Endosome fusion in living cells overexpressing GFP-rab5. J. Cell Sci. 112, 3667–3675 (1999).

    CAS  PubMed  Google Scholar 

  134. Cataldo, A. et al. Endocytic disturbances distinguish among subtypes of Alzheimer’s disease and related disorders. Ann. Neurol. 50, 661–665 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Cataldo, A. M., Barnett, J. L., Pieroni, C. & Nixon, R. A. Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer’s disease: neuropathologic evidence for a mechanism of increased β-amyloidogenesis. J. Neurosci. 17, 6142–6151 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Cataldo, A. M. et al. Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer’s disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. Am. J. Pathol. 157, 277–286 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Corlier, F. et al. Modifications of the endosomal compartment in peripheral blood mononuclear cells and fibroblasts from Alzheimer’s disease patients. Transl. Psychiatry 5, e595 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Saunders, A. M. et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43, 1467–1472 (1993).

    Article  CAS  PubMed  Google Scholar 

  139. Rohn, T. T., McCarty, K. L., Love, J. E. & Head, E. Is apolipoprotein E4 an important risk factor for dementia in persons with Down syndrome? J. Parkinsons Dis. Alzheimers Dis. 1, 7 (2014).

    PubMed  PubMed Central  Google Scholar 

  140. Cataldo, A. M. et al. Down syndrome fibroblast model of Alzheimer-related endosome pathology: accelerated endocytosis promotes late endocytic defects. Am. J. Pathol. 173, 370–384 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Cossec, J. C. et al. Trisomy for synaptojanin1 in Down syndrome is functionally linked to the enlargement of early endosomes. Hum. Mol. Genet. 21, 3156–3172 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Nuriel, T. et al. The endosomal-lysosomal pathway is dysregulated by APOE4 expression in vivo. Front. Neurosci. 11, 702 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Xu, W. et al. Amyloid precursor protein-mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration. J. Clin. Invest. 126, 1815–1833 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Jiang, Y. et al. Alzheimer’s-related endosome dysfunction in Down syndrome is Aβ-independent but requires APP and is reversed by BACE-1 inhibition. Proc. Natl Acad. Sci. USA 107, 1630–1635 (2010).

    Article  CAS  PubMed  Google Scholar 

  145. Jiang, Y. et al. Lysosomal dysfunction in Down syndrome is APP-dependent and mediated by APP-βCTF (C99). J. Neurosci. 39, 5255–5268 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Kwart, D. et al. A large panel of isogenic APP and PSEN1 mutant human iPSC neurons reveals shared endosomal abnormalities mediated by APP β-CTFs, not Aβ. Neuron 104, 256–270.e1–e5 (2019).

    Article  CAS  PubMed  Google Scholar 

  147. Cuckle, H. & Maymon, R. Development of prenatal screening – a historical overview. Semin. Perinatol. 40, 12–22 (2016).

    Article  PubMed  Google Scholar 

  148. Bianchi, D. W., Crombleholme, T. M., D’Alton M. E. & Malone, F. D. Fetology: Diagnosis and Management of the Fetal Patient Ch. 131 (McGraw-Hill Medical, 2010).

  149. Bianchi, D. W., Rava, R. P. & Sehnert, A. J. DNA sequencing versus standard prenatal aneuploidy screening. N. Engl. J. Med. 371, 577–578 (2014).

    Article  Google Scholar 

  150. Norton, M. E. & Wapner, R. J. Cell-free DNA analysis for noninvasive examination of trisomy. N. Engl. J. Med. 373, 2581–2582 (2015).

    Article  Google Scholar 

  151. Bianchi, D. W. & Chiu, R. W. K. Sequencing of circulating cell-free DNA during pregnancy. N. Engl. J. Med. 379, 464–473 (2018).

    Article  CAS  PubMed  Google Scholar 

  152. Liu, S. et al. Genomic analyses from non-invasive prenatal testing reveal genetic associations, patterns of viral infections, and Chinese population history. Cell 175, 347–359.e14 (2018).

    Article  CAS  PubMed  Google Scholar 

  153. Taylor-Phillips, S. et al. Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes: a systematic review and meta-analysis. BMJ Open. 6, e010002 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Hill, M. et al. Has noninvasive prenatal testing impacted termination of pregnancy and live birth rates of infants with Down syndrome? Prenat. Diagn. 37, 1281–1290 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Ralston, S. J., Wertz, D., Chelmow, D., Craigo, S. D. & Bianchi, D. W. Pregnancy outcomes after prenatal diagnosis of aneuploidy. Obstet. Gynecol. 97, 729–733 (2001).

    CAS  PubMed  Google Scholar 

  156. Alexander, M. et al. Morbidity and medication in a large population of individuals with Down syndrome compared to the general population. Dev. Med. Child. Neurol. 58, 246–254 (2016).

    Article  PubMed  Google Scholar 

  157. Bull, M. J. & Committee on Genetics,. Health supervision for children with Down syndrome. Pediatrics 128, 393–406 (2011).

    Article  PubMed  Google Scholar 

  158. Jensen, K. M. & Bulova, P. D. Managing the care of adults with Down’s syndrome. BMJ 349, g5596 (2014).

    Article  PubMed  CAS  Google Scholar 

  159. Capone, G. et al. Co-occurring medical conditions in adults with Down syndrome: a systematic review toward the development of health care guidelines. Am. J. Med. Genet. A 176, 116–133 (2018).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  161. Glasson, E. J., Dye, D. E. & Bittles, A. H. The triple challenges associated with age-related comorbidities in Down syndrome. J. Intellect. Disabil. Res. 58, 393–398 (2014).

    Article  CAS  PubMed  Google Scholar 

  162. Bergstrom, S. et al. Trends in congenital heart defects in infants with Down syndrome. Pediatrics 138, e20160123 (2016).

    Article  PubMed  Google Scholar 

  163. Morales-Demori, R. Congenital heart disease and cardiac procedural outcomes in patients with trisomy 21 and Turner syndrome. Congenit. Heart Dis. 12, 820–827 (2017).

    Article  PubMed  Google Scholar 

  164. Russell, M. W., Chung, W. K., Kaltman, J. R. & Miller, T. A. Advances in the understanding of the genetic determinants of congenital heart disease and their impact on clinical outcomes. J. Am. Heart Assoc. 7, e006906 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Churchill, S. S., Kieckhefer, G. M., Landis, C. A. & Ward, T. M. Sleep measurement and monitoring in children with Down syndrome: a review of the literature, 1960–2010. Sleep. Med. Rev. 16, 477–488 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Smith, D. S. Health care management of adults with Down syndrome. Am. Fam. Physician 64, 1031–1039 (2001).

    CAS  PubMed  Google Scholar 

  167. Esbensen, A. J., Hoffman, E. K., Stansberry, E. & Shaffer, R. Convergent validity of actigraphy with polysomnography and parent reports when measuring sleep in children with Down syndrome. J. Intellect. Disabil. Res. 62, 281–291 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Hill, C. M. et al. Home oximetry to screen for obstructive sleep apnoea in Down syndrome. Arch. Dis. Child. 103, 962–967 (2018).

    Article  PubMed  Google Scholar 

  169. Venekamp, R. P. et al. Tonsillectomy or adenotonsillectomy versus non-surgical management for obstructive sleep-disordered breathing in children. Cochrane Database Syst. Rev. 10, CD011165 (2015).

    Google Scholar 

  170. Purdy, I. B., Singh, N., Brown, W. L., Vangala, S. & Devaskar, U. P. Revisiting early hypothyroidism screening in infants with Down syndrome. J. Perinatol. 34, 936–940 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Iughetti, L., Lucaccioni, L., Fugetto, F., Mason, A. & Predieri, B. Thyroid function in Down syndrome. Expert Rev. Endocrinol. Metab. 10, 525–532 (2015).

    Article  CAS  PubMed  Google Scholar 

  172. Sarici, D. et al. Thyroid functions of neonates with Down syndrome. Ital. J. Pediatr. 38, 44 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Hardy, O. et al. Hypothyroidism in Down syndrome: screening guidelines and testing methodology. Am. J. Med. Genet. A 124, 436–437 (2004).

    Article  Google Scholar 

  174. Bittles, A. H. & Glasson, E. J. Clinical, social, and ethical implications of changing life expectancy in Down syndrome. Dev. Med. Child. Neurol. 46, 282–286 (2004).

    Article  CAS  PubMed  Google Scholar 

  175. Hithersay, R. et al. Association of dementia with mortality among adults with Down syndrome older than 35 years. JAMA Neurol. 76, 152–160 (2019). This paper identifies AD as the most prominent cause of mortality in adults with DS.

    Article  PubMed  Google Scholar 

  176. Strydom, A. et al. Dementia in older adults with intellectual disabilities—epidemiology, presentation, and diagnosis. J. Policy Pract. Intellect. Disabil. 7, 96–110 (2010).

    Article  Google Scholar 

  177. Ballard, C., Mobley, W., Hardy, J., Williams, G. & Corbett, A. Dementia in Down’s syndrome. Lancet Neurol. 15, 622–636 (2016).

    Article  PubMed  Google Scholar 

  178. Bayen, E., Possin, K. L., Chen, Y., Cleret de Langavant, L. & Yaffe, K. Prevalence of aging, dementia, and multimorbidity in older adults with Down syndrome. JAMA Neurol. 75, 1399–1406 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Lott, I. T. & Head, E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat. Rev. Neurol. 15, 135–147 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Startin, C. M. et al. Cognitive markers of preclinical and prodromal Alzheimer’s disease in Down syndrome. Alzheimers Dement. 15, 245–257 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Firth, N. C. et al. Aging related cognitive changes associated with Alzheimer’s disease in Down syndrome. Ann. Clin. Transl. Neurol. 5, 741–751 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  182. De Simone, R., Puig, X. S., Gelisse, P., Crespel, A. & Genton, P. Senile myoclonic epilepsy: delineation of a common condition associated with Alzheimer’s disease in Down syndrome. Seizure 19, 383–389 (2010).

    Article  PubMed  Google Scholar 

  183. Royal College of Psychiatrists & The British Psychological Society. Dementia and People with Intellectual Disabilities: Guidance on the assessment, diagnosis, interventions and support of people with intellectual disabilities who develop dementia. https://www.dsrf.org/media/REP77%20final%20proof%20(3).pdf (The British Psychological Society, 2015).

  184. Eady, N. et al. Impact of cholinesterase inhibitors or memantine on survival in adults with Down syndrome and dementia: clinical cohort study. Br. J. Psychiatry 212, 155–160 (2018).

    Article  PubMed  Google Scholar 

  185. Livingstone, N., Hanratty, J., McShane, R. & Macdonald, G. Pharmacological interventions for cognitive decline in people with Down syndrome. Cochrane Database Syst. Rev. 10, CD011546 (2015).

    Google Scholar 

  186. Dodd, K. et al. Consensus statement of the international summit on intellectual disability and Dementia related to post-diagnostic support. Aging Mental Health 22, 1406–1415 (2018).

    Article  PubMed  Google Scholar 

  187. Sanmaneechai, O. et al. Treatment outcomes of West syndrome in infants with Down syndrome. Pediatric Neurol. 48, 42–47 (2013).

    Article  Google Scholar 

  188. Gholipour, T., Mitchell, S., Sarkis, R. A. & Chemali, Z. The clinical and neurobehavioral course of Down syndrome and dementia with or without new-onset epilepsy. Epilepsy Behav. 68, 11–16 (2017).

    Article  PubMed  Google Scholar 

  189. Austeng, M. E. et al. Otitis media with effusion in children with in Down syndrome. Int. J. Pediatr Otorhinolaryngol. 77, 1329–1332 (2013).

    Article  PubMed  Google Scholar 

  190. Fisher, P. G. Congenital hearing loss in Down syndrome. J. Pediatr. 166, 1–3 (2015).

    Article  Google Scholar 

  191. Shott, S. R., Joseph, A. & Heithaus, D. Hearing loss in children with Down syndrome. Int. J. Pediatr. Otorhinolaryngol. 61, 199–205 (2001).

    Article  CAS  PubMed  Google Scholar 

  192. Krinsky-McHale, S. J. et al. Vision deficits in adults with Down syndrome. J. Appl. Res. Intellect. Disabil. 27, 247–263 (2014).

    Article  PubMed  Google Scholar 

  193. Li, E. Y., Chan, T. C., Lam, N. M. & Jhanji, V. Cataract surgery outcomes in adult patients with Down’s syndrome. Br. J. Ophthalmol. 98, 1273–1276 (2014).

    Article  PubMed  Google Scholar 

  194. Brockmeyer, D. Down syndrome and craniovertebral instability. Topic review and treatment recommendations. Pediatr. Neurosurg. 31, 71–77 (1999).

    Article  CAS  PubMed  Google Scholar 

  195. Capone, G., Goyal, P., Ares, W. & Lannigan, E. Neurobehavioral disorders in children, adolescents, and young adults with Down syndrome. Am. J. Med. Genet. C 142, 158–172 (2006).

    Article  Google Scholar 

  196. Mantry, D. et al. The prevalence and incidence of mental ill-health in adults with Down syndrome. J. Intellect. Disabil. Res. 52, 141–155 (2008).

    CAS  PubMed  Google Scholar 

  197. Tassé, M. J. et al. Psychiatric conditions prevalent among adults with Down syndrome. J. Policy Pract. Intellect. Disabil. 13, 173–180 (2016).

    Article  Google Scholar 

  198. Mircher, C. et al. Acute regression in young people with Down syndrome. Brain Sci. 7, 57 (2017).

    Article  PubMed Central  Google Scholar 

  199. Spendelow, J. S. Assessment of mental health problems in people with Down syndrome: key considerations. Br. J. Learn. Disabil. 39, 306–313 (2011).

    Article  Google Scholar 

  200. Nevill, R. E. & Benson, B. A. Risk factors for challenging behaviour and psychopathology in adults with Down syndrome. J.Intellect. Disabil. Res. 62, 941–951 (2018).

    Article  CAS  PubMed  Google Scholar 

  201. Liogier d’Ardhuy, X. et al. Assessment of cognitive scales to examine memory, executive function and language in individuals with Down syndrome: implications of a 6-month observational study. Front. Behav. Neurosci. 9, 300 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Dykens, E. M. Psychiatric and behavioral disorders in persons with Down syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 13, 272–278 (2007).

    Article  PubMed  Google Scholar 

  203. Aman, M. G., Buican, B. & Arnold, L. E. Methylphenidate treatment in children with borderline IQ and mental retardation: analysis of three aggregated studies. J. Child. Adolesc. Psychopharmacol. 13, 29–40 (2003).

    Article  PubMed  Google Scholar 

  204. Guedj, F., Bianchi, D. W. & Delabar, J. M. Prenatal treatment of Down syndrome: a reality? Curr. Opin. Obstet. Gynecol. 26, 92–103 (2014).

    Article  PubMed  Google Scholar 

  205. Bianchi, D. W. From prenatal genomic diagnosis to fetal personalized medicine: progress and challenges. Nat. Med. 18, 1041–1051 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Stagni, F., Giacomini, A., Emili, M., Guidi, S. & Bartesaghi, R. Neurogenesis impairment: an early developmental defect in Down syndrome. Free. Radic. Biol. Med. 114, 15–32 (2018).

    Article  CAS  PubMed  Google Scholar 

  207. Guidi, S. et al. Neurogenesis impairment and increased cell death reduce total neuron number in the hippocampal region of fetuses with Down syndrome. Brain Pathol. 18, 180–197 (2008).

    Article  PubMed  Google Scholar 

  208. Guidi, S., Ciani, E., Bonasoni, P., Santini, D. & Bartesaghi, R. Widespread proliferation impairment and hypocellularity in the cerebellum of fetuses with Down syndrome. Brain Pathol. 21, 361–373 (2011).

    Article  PubMed  Google Scholar 

  209. Dierssen, M. & de Lagran, M. M. DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A): a gene with dosage effect during development and neurogenesis. ScientificWorldJournal 6, 1911–1922 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Tarui, T. et al. Quantitative MRI analyses of regional brain growth in living fetuses with Down syndrome. Cereb. Cortex. https://doi.org/10.1093/cercor/bhz094 (2019).

    Article  PubMed Central  Google Scholar 

  211. Stagni, F., Giacomini, A., Guidi, S., Ciani, E. & Bartesaghi, R. Timing of therapies for Down syndrome: the sooner, the better. Front. Behav. Neurosci. 9, 265 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. de Wert, G., Dondorp, W. & Bianchi, D. W. Fetal therapy for Down syndrome: an ethical exploration. Prenat. Diagn. 37, 222–228 (2017).

    Article  PubMed  Google Scholar 

  213. Incerti, M. et al. Prenatal treatment prevents learning deficit in Down syndrome model. PLoS One 7, e50724 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Kelley, C. M. et al. Effects of maternal choline supplementation on the septohippocampal cholinergic system in the Ts65Dn mouse model of Down syndrome. Curr. Alzheimer Res. 13, 84–96 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. McElyea, S. D. et al. Influence of prenatal EGCG treatment and Dyrk1a dosage reduction on craniofacial features associated with Down syndrome. Hum. Mol. Genet. 25, 4856–4869 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Nakano-Kobayashi, A. et al. Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice. Proc. Natl Acad. Sci. USA 114, 10268–10273 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Izzo, A. et al. Metformin restores the mitochondrial network and reverses mitochondrial dysfunction in Down syndrome cells. Hum. Mol. Genet. 26, 1056–1069 (2017).

    CAS  PubMed  Google Scholar 

  218. Guidi, S. et al. Prenatal pharmacotherapy rescues brain development in a Down’s syndrome mouse model. Brain 137, 380–401 (2014).

    Article  PubMed  Google Scholar 

  219. Gao, S. Y. et al. Fluoxetine and congenital malformations: a systematic review and meta-analysis of cohort studies. Br. J. Clin. Pharmacol. 83, 2134–2147 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Chan, M. et al. The burden of respiratory syncytial virus (RSV) associated acute lower respiratory infections in children with Down syndrome: a systematic review and meta-analysis. J. Glob. Health 7, 020413 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  221. Grut, V., Söderström, L. & Naumburg, E. National cohort study showed that infants with Down’s syndrome faced a high risk of hospitalisation for the respiratory syncytial virus. Acta Paediatr. 106, 1519–1524 (2017).

    Article  PubMed  Google Scholar 

  222. Bloemers, B. L. P. et al. Increased risk of respiratory tract infections in children with Down syndrome: the consequence of an altered immune system. Microbes Infect. 12, 799–808 (2010).

    Article  CAS  PubMed  Google Scholar 

  223. Giménez-Barcons, M. et al. Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens. J. Immunol. 193, 3872–3879 (2014).

    Article  PubMed  CAS  Google Scholar 

  224. Swigonski, N. L., Kuhlenschmidt, H. L., Bull, M. J., Corkins, M. R. & Downs, S. M. Screening for celiac disease in asymptomatic children with Down syndrome: cost-effectiveness of preventing lymphoma. Pediatrics 118, 594–602 (2006).

    Article  PubMed  Google Scholar 

  225. Tunstall, O. et al. Guidelines for the investigation and management of transient leukaemia of Down syndrome. Br. J. Haematol. 182, 200–211 (2018).

    Article  PubMed  Google Scholar 

  226. Mateos, M. K., Barbaric, D., Byatt, S.-A., Sutton, R. & Marshall, G. M. Down syndrome and leukemia: insights into leukemogenesis and translational targets. Transl. Pediatr. 4, 76–92 (2015).

    PubMed  PubMed Central  Google Scholar 

  227. Gamis, A. S. & Smith, F. O. Transient myeloproliferative disorder in children with Down syndrome: clarity to this enigmatic disorder. Br. J. Haematol. 159, 277–287 (2012).

    Article  PubMed  Google Scholar 

  228. Skotko, B. G., Levine, S. P., Macklin, E. A. & Goldstein, R. D. Family perspectives about Down syndrome. Am. J. Med. Genet. A 170, 930–941 (2016).

    Article  Google Scholar 

  229. Van Herwegen, J., Ashworth, M. & Palikara, O. Parental views on special educational needs provision: cross-syndrome comparisons in Williams syndrome, Down syndrome, and autism spectrum disorders. Res. Dev. Disabil. 80, 102–111 (2018).

    Article  PubMed  Google Scholar 

  230. Buckley, S., Bird, G., Sacks, B. & Archer, T. A comparison of mainstream and special education for teenagers with Down syndrome: implications for parents and teachers. Syndrome Res. Pract. 9, 54–67 (2006).

    Article  Google Scholar 

  231. Kumin, L. & Schoenbrodt, L. Employment in adults with Down syndrome in the United States: results from a national survey. Appl. Res. Intellect. Disabil. 29, 330–345 (2015).

    Article  Google Scholar 

  232. Mihaila, I. et al. Leisure activity and caregiver involvement in middle-aged and older adults with Down syndrome. Intellect. Dev. Disabil. 55, 97–109 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  233. Xanthopoulos, M. S. et al. Caregiver-reported quality of life in youth with Down syndrome. J. Pediatr. 189, 98–104.e1 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  234. Diaz, K. M. Physical inactivity among parents of children with and without Down syndrome: the National Health Interview Survey. J. Intellect. Disabil. Res. 64, 38–44 (2020).

    Article  CAS  PubMed  Google Scholar 

  235. Hardee, J. P. & Fetters, L. The effect of exercise intervention on daily life activities and social participation in individuals with Down syndrome: a systematic review. Res. Dev. Disabil. 62, 81–103 (2017).

    Article  CAS  PubMed  Google Scholar 

  236. O’Roak, B. J. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Becker, W., Soppa, U. & Tejedor, F. J. DYRK1A: a potential drug target for multiple Down syndrome neuropathologies. CNS Neurol. Disord. Drug Targets 13, 26–33 (2014).

    Article  CAS  PubMed  Google Scholar 

  238. Mowery, C. T. et al. Trisomy of a Down syndrome critical region globally amplifies transcription via HMGN1 overexpression. Cell Rep. 25, 1898–1911.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Tanay, A. & Regev, A. Scaling single-cell genomics from phenomenology to mechanism. Nature 541, 331–338 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Annus, T. et al. The Down syndrome brain in the presence and absence of fibrillar β-amyloidosis. Neurobiol. Aging 53, 11–19 (2017). Describes the age of onset of amyloid deposition in the brain of individuals with DS using PET imaging.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Rafii, M. S. Tau PET imaging for staging of Alzheimer’s disease in Down syndrome. Dev. Neurobiol. 79, 711–715 (2019).

    Article  PubMed  Google Scholar 

  242. Fortea, J. et al. Plasma and CSF biomarkers for the diagnosis of Alzheimer’s disease in adults with Down syndrome: a cross-sectional study. Lancet Neurol. 17, 860–869 (2018). Explores age-related changes in fluid biomarkers associated with AD in individuals with DS to show similarities with sporadic AD.

    Article  CAS  PubMed  Google Scholar 

  243. Strydom, A. et al. Neurofilament light as a blood biomarker for neurodegeneration in Down syndrome. Alzheimer’s Res. Ther. 10, 39 (2018).

    Article  CAS  Google Scholar 

  244. Xiao, M. F. et al. NPTX2 and cognitive dysfunction in Alzheimer’s disease. eLife 6, e23798 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  245. Rafii, M. S. et al. Plasma neurofilament light and Alzheimer’s disease biomarkers in Down syndrome: results from the Down syndrome biomarker initiative (DSBI). J. Alzheimers Dis. 70, 131–138 (2019).

    Article  CAS  PubMed  Google Scholar 

  246. Das, I. & Reeves, R. H. The use of mouse models to understand and improve cognitive deficits in Down syndrome. Dis. Model.Mech. 4, 596–606 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Duchon, A. et al. Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: relevance for modeling Down syndrome. Mamm. Genome 22, 674–684 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Reinholdt, L. et al. Molecular characterization of the translocation breakpoints in the Down syndrome mouse model Ts65Dn. Mamm. Genome 22, 685–691 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Kanekiyo, T., Xu, H. & Bu, G. ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron 81, 740–754 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Startin, C. M. et al. The LonDownS adult cognitive assessment to study cognitive abilities and decline in Down syndrome. Wellcome Open Res. 1, 11 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  251. Sinai, A. et al. Predictors of age of diagnosis and survival of Alzheimer’s disease in Down syndrome. J. Alzheimers Dis. 61, 717–728 (2018).

    Google Scholar 

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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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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.).

Corresponding author

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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