New Imperial-led research maps the genetic drivers of Down Syndrome

Down Syndrome affects approximately one in every 700 live births and is the most common genetic cause of intellectual disability in the world. Yet despite decades of research, no treatment exists that addresses the intellectual disability itself.

A new study published in Nature Medicine, led by scientists from Imperial College London and Duke-NUS Medical School in Singapore, with collaborators across Europe and the United States, may have brought that goal meaningfully closer. The team used tissue samples from the developing brains of foetuses with Down syndrome to create the most detailed molecular map of the Down syndrome brain to date.

“Our study shows how combining advanced technologies for analysing, modelling and modulating gene activity can reveal new biological insights into complex conditions”, says Dr Michael Lattke, Research Associate in the Department of Brain Sciences, Faculty of Medicine at Imperial College London and first author of the study. “By identifying key genetic regulators and demonstrating that their activity can be adjusted in human brain cells, we provide a foundation for future research into Down syndrome.” 

Our study shows how combining advanced technologies for analysing, modelling and modulating gene activity can reveal new biological insights into complex conditions. Dr Michael Lattke Research Associate in the Department of Brain Sciences, Imperial College London

An unfinished success story 

In England and Wales alone, around 42,000 people live with Down syndrome, and globally the population has grown to an estimated 5.8 million¹. In 1983, a child born with Down syndrome had a median life expectancy of just 25 years. Today, that figure stands at 58 years in the UK, with many individuals living into their sixties and seventies. It’s a transformation driven largely by advances in children’s cardiac surgery, antibiotics, vaccinations, improved management of associated health conditions, and an enhanced understanding of the condition² .  

Down syndrome leads to developmental delays that impact everyday functioning. Most people with the condition experience mild to moderate intellectual disability, whilst a smaller proportion face some additional challenges. People with Down syndrome have an increased risk of numerous health conditions, including heart defects, hearing problems and vision problems, sleep apnoea, hypothyroidism, leukaemia and early-onset Alzheimer’s disease³.

A step-by-step approach 

A genetic cause of Down syndrome has been known since 1959: French physician Jérôme Lejeune discovered that it's caused by an extra copy of chromosome 21⁴. But knowing the cause has never meant fully understanding the consequences. Researchers still do not fully understand why the extra chromosome causes such diverse symptoms – from physical characteristics to intellectual disability and an increased risk of specific conditions. 

Previous research using mouse models and stem cells had pointed to several genes as likely drivers of the neurological changes, but could not answer that more fundamental question: what precisely happens in individual cell types of the developing human brain, during the critical window between weeks 10 and 20 after conception, when neurons are being formed? The new study set out to tackle this challenge directly. 

As the authors note, Down syndrome offers a rare scientific advantage – because it is caused by a clearly defined genetic change present from conception, researchers can study brain tissue at the very earliest stages of development. This makes it possible to trace the path from genetic cause to cellular consequence, step by step. 

Using tissue samples from the developing brains of foetuses with Down syndrome, the team built the most detailed molecular map to date of the developing Down syndrome brain. It shows how different cell types form, mature and interact and how these processes are altered by the extra chromosome. 

Towards future treatment?  

The team identified three transcription factors encoded on chromosome 21: BACH1, PKNOX1 and GABPA, none of which had previously been implicated as key drivers of the condition. All three were found to be overactive in human brain cells derived from individuals with Down syndrome, disrupting the normal activity of hundreds of other molecular processes involved in learning and memory.  

To explore whether these effects could be reversed, the team used a technique called antisense oligonucleotides (ASOs), tiny synthetic molecules designed to dial down the activity of specific genes. When applied to laboratory-grown human brain cells, they observed a partial restoration of more normal patterns of gene activity. 

Dr Lattke is careful to contextualise what this might eventually mean for patients. Cognitive function, behaviour and motor skills are all possible areas that may show benefit, he says, “but we still need to investigate this, for example, in mouse models.” 

The findings may also carry implications for Alzheimer’s disease, for which individuals with Down syndrome face a lifetime risk exceeding 90%⁵. At least one of the newly identified transcription factors is already being investigated by others in this context. 

More than a dataset 

Professor Vincenzo De Paola, Visiting Professor at Duke-NUS, Honorary Professor of Translational Neuroscience at Imperial College London and the lead-author of the study, said: “This discovery would have been impossible without the families who contributed to this research, and we are profoundly grateful for their generosity. By analysing individual cells at unprecedented scale and depth, we uncovered previously unresolved molecular mechanisms and moved closer to understanding the root causes of Down syndrome’s neurological features. Benchmarking current in vitro and humanised in vivo models against primary fetal tissue allowed us to define a practical roadmap to help the field choose the most appropriate systems to study specific aspects of the condition.” 

This discovery would have been impossible without the families who contributed to this research, and we are profoundly grateful for their generosity. Professor Vincenzo De Paola Visiting Professor at Duke-NUS, Honorary Professor of Translational Neuroscience at Imperial College London

Professor Lok Sheemei, Duke-NUS’s Interim Vice-Dean for Research, added: “The result is more than a dataset. It is a new framework for understanding how Down syndrome unfolds at the cellular level. The atlas pinpoints specific genes, pathways and cell populations that may drive neurological changes, offering concrete targets for future therapies.” 

The research team’s immediate priority is understanding the functional consequences of adjusting the newly discovered drivers, specifically, whether normalising their activity can influence how brain cells grow and form connections ⁶.  

 More: 

[1] C. Ballard C, et al, Dementia in Down’s syndrome, Lancet Neurol 2016, pubmed.ncbi.nlm.nih.gov; Demography, The Down Syndrome Medical Interest Group, dsmig.org.uk

[2] The Story of Two Syndromes, Global Down Syndrome Foundation, globaldownsyndrome.org; Living with Down Syndrome, cdc.gov; M. Kazemi, et al., Down Syndrome: Current Status, Challenges and Future Perspectives, pmc.ncbi.nlm.nih.gov; Cardiac, The Down Syndrome Medical Interest Group, dsmig.org.uk.

[3] What conditions or disorders are commonly associated with Down syndrome?  nichd.nih.gov; A. Mégarbané et al, The 50th anniversary of the discovery of trisomy 21...,  nature.com

[4] J. Fortea et al, Alzheimer's disease associated with Down syndrome... Lancet Neurology, pubmed.ncbi.nlm.nih.gov

[5] R. Real, et al., In vivo modeling of human neuron dynamics and Down syndrome, science.org

[6] M. Peter, et al., Trisomy 21 impairs synchronized activity and connectivity in developing human Down Syndrome cortical excitatory neuron networks, biorxiv.org;