The findings are reported today in two companion papers published in Nature and Nature Genetics.
The studies, led by scientists including Professor Nicola Whiffin (Department of Paediatrics, Centre for Human Genetics), Dr. Gregory Findlay (Francis Crick Institute) and Professor Cas Simons (Centre for Population Genomics, Australia), focus on RNU4-2, a non-coding gene that produces a small RNA molecule essential for RNA splicing — a fundamental cellular process required to correctly process genetic information.
A non-coding gene with a major impact on disease
Unlike most genes implicated in human disease, RNU4-2 does not encode a protein. Instead, it produces an RNA component of the ‘spliceosome’, the molecular machinery that edits RNA before it is translated into proteins.
Previous work led by Professor Whiffin in 2024, using data in Genomics England’s National Genomic Research Library, identified that specific mutations in RNU4-2 cause ReNU syndrome, a neurodevelopmental disorder. Around 20 mutations in a small critical region of the gene are now known to cause this condition.
The discovery was striking: these mutations 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 was the first time a non-coding gene was found with such a significant role in any rare disorder. To top it all, the RNU4-2 gene is tiny: at only 145 DNA bases long it is 100-times smaller than most known disease causing genes.
Systematically testing every possible mutation
In the new Nature study, the team sought to understand why only certain mutations cause ReNU syndrome, despite many more occurring naturally in the population.
To address this, they applied Saturation Genome Editing (SGE) — a method pioneered by Dr Gregory Findlay — to test the functional impact of hundreds of mutations across the entire gene. In a major technical advance, first author Dr Joachim De Jonghe (Francis Crick Institute) successfully adapted this approach to RNU4-2, making it the first non-coding gene ever studied using SGE.
The researchers generated and analysed more than 500 distinct genetic variants, producing a comprehensive map of how each mutation affects gene function. Strikingly, their approach could perfectly identify which mutations are known to cause ReNU syndrome, with the amount of functional disruption matching the severity of disease observed in patients. They also identified other mutations that would be predicted to cause ReNU syndrome, but that haven’t yet been identified in patients. The data enable clinicians to distinguish harmful mutations from benign ones with far greater accuracy, providing a powerful new framework for diagnosing individuals with suspected RNU4-2-related disorders.
Discovery of a new recessive disorder
While analysing the data, the researchers identified a second, unexpected set of mutations that significantly impaired gene function but that were not in the same region of the gene that is known to be linked to ReNU syndrome.
Through collaboration with international clinical teams, they demonstrated that these mutations cause a distinct neurodevelopmental disorder inherited in a recessive manner — meaning individuals need two mutations to be affected by the disorder, often inheriting one from each parent.
“This work shows the power of systematically testing every possible mutation in a gene. Applying these approaches to other non-coding regions of the genome could uncover many more hidden causes of human disease.” Said Dr Gregory Findlay.
The companion Nature Genetics study, a collaboration led by Professor Whiffin and Professor Cas Simons and coordinated by Dr Rocio Rius (Centre for Population Genomics) and Dr Alexander Blakes (University of Manchester), describes the first cohort of 38 individuals with this newly identified condition.
They found that although patients with the recessive disorder share some features with ReNU syndrome — such as severe developmental delay — the new disorder has some important differences:
- Patients often have distinctive changes on brain MRI, including characteristic white matter abnormalities
- Molecular analyses indicate a different disease mechanism, likely involving reduced levels of RNU4-2 RNA rather than the splicing disruption seen in ReNU syndrome
These findings establish that mutations in different regions of the same tiny RNA gene can lead to two mechanistically distinct diseases.
"Many families spend years searching for a reason behind their child's condition. Each new gene discovery has the potential to end that search, providing the answers that families and their clinicians need." Said Dr Cas Simons.
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 mutations 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. “For example, in individuals with the recessive condition, we see a reduction in the amount of the RNU4-2 RNA. This helps us to determine safe amounts by which we can reduce RNU4-2 levels in therapies currently in development for ReNU syndrome.”
Dr. Abhijit Dixit, Consultant Clinical Geneticist at Nottingham University Hospitals NHS Trust, was able to diagnose the condition in one of his patients as a result of these findings. “For nine years we have not been able to give Oliver and his parents a diagnosis for his condition but this research partnership has changed that.”
“I got a message from Dr. Blakes to ask me if there was anything unusual about the MRI scan in one of my patients who had been recruited to the 100,000 genomes project about nine years earlier. I have a specific interest in MRI and had noticed the fluid-filled spaces around the ventricles in the brain that appear like a bunch of grapes and are very distinct. You don’t see this in any other type of disorder.”
“Even if it doesn’t change the treatment or the problem, giving the family an answer to ‘why’ changes their world. It is mostly because there are unacknowledged worries about what they may have done as parents; they latch onto some small element and carry a burden of guilt that their actions may have caused this condition. With a diagnosis, we can see that burden visibly lift. They have an answer to the why, and this is the evidence to absolve them.”
Oliver Stuart is 15 and has the condition. His mother Louise Bamford says that 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 (GDD). 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 phonecall 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 development or autism. And now having that answer has opened the doors 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 is so nice to be part of something and that we’ve now all got the answers that we’ve been searching for, for a long time.”
Oliver, who enjoys football and supports Nottingham Forest, has suffered from epileptic seizures since he was 13 and struggles with speech and making himself understood. “Speech has always been a big issue.” Louise explains. “He’s had speech therapy since he was about two years old but the epilepsy has caused it to regress so he seems to have gone backwards a little bit. It is difficult for an outsider to understand him and this has caused him to struggle with relationships and how to deal with them. His school are helping him learn how to process things though, and particularly how to process his emotions, especially through puberty and the changes in his own body”.
This research was made possible using data from Genomics England’s 100,000 Genomes Project conducted in partnership with the NHS, and is an example of the power of genomics in healthcare.
Dr Rich Scott, Chief Executive Officer of Genomics England, said: “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.”