Mapping the Molecular Effects of Down Syndrome

What is Down Syndrome?

Down Syndrome (DS) is a genetic condition caused by an extra copy of chromosome 21, leading to three types: trisomy 21 (T21), mosaicism, and translocation:

• Trisomy 21 accounts for 95% of DS cases, where each cell has three separate copies of chromosome 21;

• Mosaicism accounts for 1-2% of DS cases, where some cells have the normal number of 46 chromosomes, while some have 47 due to the extra copy of chromosome 21;

• Translocation accounts for 3-4% of DS cases, where a partial part of chromosome 21 breaks off during cell division and is attached to a different chromosome.

This condition results in physical features like a flat face and upward-slanting eyes, and developmental features such as intellectual disabilities. Children with this condition are also at higher risk of health problems, including heart defects, vision loss, infections, hypothyroidism, and Alzheimer’s disease later in life. With an estimated 5.4 million people with DS globally, it’s becoming increasingly essential for scientists to understand the molecular effects that disrupt early developmental events, so that they can be identified and treated.

"Foetuses and infants with DS have thinner cortices and reduced grey matter in the frontal lobe, hippocampus, cerebellum, and cerebral hemispheres, resulting in a smaller total brain volume.

How does DS affect the developing brain?

Whilst it’s still being researched, scientists have established clear neurodevelopmental abnormalities in children with DS during pregnancy and infancy, leading to underdeveloped areas of the brain. For example, DS disrupts learning and memory by causing decreased synaptic plasticity and neuron development in the hippocampus, resulting in learning disabilities. It also directly contributes to changes in the physical structure of the brain. Foetuses and infants with DS have thinner cortices and reduced grey matter in the frontal lobe, hippocampus, cerebellum, and cerebral hemispheres, resulting in a smaller total brain volume. This limits the amount of tissue available for efficient signal transmission across brain networks, affecting information processing, coordination, and often leading to impaired intellectual abilities.

New studies

Scientists have established the ways in which DS impacts brain development, but they’re still trying to understand more about the underlying molecular mechanisms. A new study by Vuong et al. used single-nucleus multi-omic sequencing on 26 foetal DS and control neocortex donors to find key differences in their composition. This type of sequencing was used to simultaneously measure gene expression and chromatin accessibility within individual cell nuclei. They found that the DS neocortices had a reduction in the expression of neural progenitors – multipotent stem cells that can divide a limited number of times into neurons and glial cells. This can result in reduced neurogenesis in adulthood, as the brain’s ability to generate new neurons and glial cells decreases, leading to memory and learning impairments often associated with DS, as well as decreased synaptic plasticity. These findings were consistent with another recent study by Risgaard et al., where the same sequencing technique was used on 220,956 cells from DS and unaffected (control) dorsolateral prefrontal cortices, an area essential for working memory. They also found a decrease in the expression of glial cells, specifically oligodendrocyte progenitors, resulting in decreased axon myelination.

Treatments resulting from molecular mapping

The main purpose of using these molecular mapping techniques is to identify therapeutic targets for possible treatments. Stem cell therapy is currently one of the most promising treatments for DS; a 2024 study suggests that neural stem cell transplantation could be a potential therapy, replacing depleted neural progenitors with healthy stem cells to boost progenitor expression and synaptic plasticity, and thus promoting neurogenesis.

"A new study used single-nucleus multi-omic sequencing on foetal DS and control neocortex donors to find key differences in their composition (...) to simultaneously measure gene expression and chromatin accessibility within individual cell nuclei."  

Furthermore, newborns and children with DS are at higher risk of developing haematological disorders that can lead to blood cancers like leukaemia. This could be addressed with CAR T-cell therapy: a revolutionary immunotherapy that reprograms a patient’s own T cells to fight cancer. Blood is taken from a cancer patient to isolate the T cells, followed by addition of a special gene to create chimeric antigen receptors (CARs) that can target and bind to specific surface proteins on cancer cells. The CAR T-cells are multiplied in a lab and infused back into the patient’s bloodstream to attack the cancer cells. Due to genetic and metabolic differences, children with DS often process drugs differently, making them more susceptible to chemotherapy-related toxicity and infections. This makes targeted treatments like CAR T-cell therapy more effective at treating DS-linked leukaemia, as it reduces the risk of further complications.

To conclude, this groundbreaking research demonstrates how sequencing techniques can be used to map the molecular effects of DS on the brain. We’ve established that DS causes both physical and molecular changes in the brain; now it is time to work on innovative treatments to help reduce the effects of DS and the illnesses that commonly follow.

References

CDC. “Down Syndrome.” 22 May 2024.

Guidi, Sandra, et al. “RESEARCH ARTICLE: Neurogenesis Impairment and Increased Cell Death Reduce Total Neuron Number in the Hippocampal Region of Fetuses With Down Syndrome.” Brain Pathology, vol. 18, no. 2, 18 Dec. 2007, pp. 180–197, 10.1111/j.1750-3639.2007.00113.x.

Huang, Tan, et al. “Chromosomal and Cellular Therapeutic Approaches for Down Syndrome: A Research Update.” Biochemical and Biophysical Research Communications, vol. 735, 4 Sept. 2024, p. 150664, https://www.sciencedirect.com/science/article/pii/S0006291X24012002?utm_source=copilot.com#sec4, 10.1016/j.bbrc.2024.150664. Accessed 6 Aug. 2026.

Lupo, Giuseppe, et al. “Molecular Profiling of Aged Neural Progenitors Identifies Dbx2 as a Candidate Regulator of Age‐Associated Neurogenic Decline.” Aging Cell, vol. 17, no. 3, 5 Mar. 2018, p. e12745, https://pmc.ncbi.nlm.nih.gov/articles/PMC5946077/, 10.1111/acel.12745. Accessed 29 July 2026.

Martínez-Cerdeño, Verónica, and Stephen C. Noctor. “Neural Progenitor Cell Terminology.” Frontiers in Neuroanatomy, vol. 12, 6 Dec. 2018, 10.3389/fnana.2018.00104.

National Cancer Institute. “CAR T Cells: Engineering Immune Cells to Treat Cancer.” Cancer.gov, 26 Feb. 2025.

National Institute of Child Health and Human Development. “What Conditions or Disorders Are Commonly Associated With Down Syndrome?” 2023.

Risgaard, Ryan D., et al. “Molecular and Cellular Processes Disrupted in the Early Postnatal Down Syndrome Prefrontal Cortex.” Science, vol. 392, no. 6796, 23 Apr. 2026, 10.1126/science.aea1549.

Robinson, Joelle, et al. “Neurodevelopmental Abnormalities in Down Syndrome: Assessing Structural and Functional Deficits.” Cureus, 21 Dec. 2024, 10.7759/cureus.76156. Accessed 29 July 2026.

Russo, Matthew L, et al. “Consequences of Trisomy 21 for Brain Development in Down Syndrome.” Nature Reviews. Neuroscience, vol. 25, no. 11, Nov. 2024, pp. 740–755, https://pubmed.ncbi.nlm.nih.gov/39379691/, 10.1038/s41583-024-00866-2. Accessed 1 Aug. 2026.

Sinha, Prashasti, and Anil Kumar Yadav. “miRNAs Mediated Hsa21 Gene Suppression as Potential Therapeutic Agent for Down Syndrome: Molecular Dynamics and MM/PBSA-Based Study.” Journal of Molecular Modeling, vol. 32, no. 2, 28 Jan. 2026, 10.1007/s00894-026-06634-6. Accessed 5 Aug. 2026.

Vuong, Celine K., et al. “A Single-Cell Multiomic Analysis Identifies Molecular and Gene-Regulatory Mechanisms Dysregulated in Developing Down Syndrome Neocortex.” Science, vol. 392, no. 6796, 23 Apr. 2026, 10.1126/science.aea1259.

Whalley, Katherine. “Mapping the Molecular Effects of Down Syndrome in the Developing Brain.” Nature Reviews Neuroscience, vol. 27, no. 7, 12 May 2026, pp. 462–462, https://www.nature.com/articles/s41583-026-01050-4#Bib1, 10.1038/s41583-026-01050-4. Accessed 30 July 2026.

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This article was written by Priya Chaudhuri and edited by Julia Dabrowska, with graphics produced by Ishika Joshi. If you enjoyed this article, be the first to be notified about new posts by signing up to become a WiNUK member (top right of this page)! Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch.