Researchers uncover how changes in a non-coding gene cause multiple neuro-developmental disorders
Researchers using data from the National Genomic Research Library (NGRL) have made major advances in understanding how changes in a single non-coding gene contribute to neurodevelopmental disorders affecting thousands of people worldwide. The findings are reported today in two papers published in Nature and Nature Genetics.
The studies, led by the University of Oxford, Francis Crick Institute, and Garvan Institute of Medical Research, focus on RNU4-2, a non-coding gene. Non-coding genes are DNA sequences that do not provide instructions for making proteins.
A non-coding gene with a major impact on rare conditions
Previous work by multiple research groups in 2024 identified that specific changes in RNU4-2 cause ReNU syndrome, a dominantly inherited neurodevelopmental disorder. Around 20 changes in a small critical region of the gene are now known to cause this condition.
These changes are estimated to account for approximately 100,000 cases of neurodevelopmental disorders globally, making ReNU syndrome one of the most prevalent known neurodevelopmental disorders.
This discovery came from data in Genomics England’s NGRL. The NGRL is one of the world’s largest and most valuable databases of its kind, enabling researchers to uncover new diagnoses and driving the development of innovative treatments.
Systematically testing every possible change
In the new Nature study, the team sought to understand why only certain changes cause ReNU syndrome.
To address this, they applied saturation genome editing – a method that allows scientists to investigate the impact of every possible genetic change within a gene. They did this to test the impact of hundreds of changes across RNU4-2.
The researchers generated and analysed more than 500 distinct genetic changes, including from the NGRL, producing a comprehensive map of how each change affects gene function. Strikingly, their approach could perfectly identify which changes are known to cause ReNU syndrome. They identified other changes that would be predicted to cause the condition, but that haven’t yet been identified in patients. The data enables clinicians to distinguish harmful changes from benign ones with far greater accuracy, providing a powerful new framework for diagnosing people with suspected RNU4-2-related disorders.
Discovery of a new recessive disorder
While analysing the data, the researchers identified a second, unexpected set of changes that significantly impaired gene function but that were not in the part of the gene that is known to be linked to ReNU syndrome.
They demonstrated that these changes cause a distinct neurodevelopmental disorder inherited in a recessive manner — meaning individuals need two changes to be affected by the disorder, often one inherited from each parent.
The companion Nature Genetics study describes the first group of 38 individuals with this newly identified condition, which shares some features with ReNU syndrome — such as severe developmental delay.
Implications for diagnosis and therapy
Together, the two studies provide the most comprehensive understanding to date of how variation in a non-coding gene contributes to human disease.
By defining which genetic changes are harmful and uncovering a previously unrecognised disorder, the work has immediate implications for genetic diagnosis.
“Knowing exactly which DNA changes impair the function of the gene is a critical clinical tool, enabling patients to be quickly and accurately diagnosed,” said Professor Nicola Whiffin.
It also lays the foundation for future therapeutic development. “These studies not only improve our ability to diagnose patients but also reveal entirely new biology that could be useful when designing treatments,” continued Professor Whiffin.
‘An enormous surprise and huge relief’
Oliver Stuart is 15 and was diagnosed with the condition because of the findings. His mother Louise Bamford says that the long-awaited answer has been life-changing: “From a very young age, Oliver showed signs of some kind of intellectual disability and physical disability and we went to a paediatrician who diagnosed him with Global Developmental Delay. We were then put in contact with Genomics England’s 100,000 Genomes Project and have waited years and years for an answer. So to get that phone call last year was an enormous surprise and huge relief.
“We’ve always known that there was something more with Oliver and that it wasn’t just global developmental delay or autism. And now having that answer has opened the door to learning a lot about it. There will now be more information coming through and we can help other families who are yet to be diagnosed. We’ve joined the groups on Facebook already and it’s so nice to be part of something and that we’ve now all got the answers that we’ve been searching for.”
“Rare conditions are incredibly difficult to diagnose, and too many families still wait far too long for answers – around five years on average. Discoveries like this are already helping to end that diagnostic odyssey for some families and will continue to do so for others in the UK and around the world. We are proud of the role that the National Genomic Research Library is playing in that.
“Families who have previously received a ReNU syndrome diagnosis have spoken about how important it’s been in helping them find a community. Sharing experiences and learning from others can sometimes make a real difference in managing their child’s condition, particularly given how recently ReNU was identified.
“It’s encouraging to see genomics continuing to deliver meaningful breakthroughs for patients like Oliver, as it becomes an increasingly important part of healthcare systems worldwide.”
Dr Rich Scott
Chief Executive Officer of Genomics England
Genomics England thanks the patients and participants who consented to donate their data to the NGRL and who made this research and its findings possible.
