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A global collaboration led by scientists at the University of Oxford has discovered that genetic variants in a specific gene cause a rare neurodevelopmental disorder (NDD). NDD is a collective term for severe impairments in how the brain functions that impact learning, behaviour, speech, and movement. Most NDDs are thought to be genetic and caused by changes to DNA, however, to date, around 60% of individuals with these conditions do not know the specific DNA change that causes their disorder.

Mia Joy Cedor with her mother Nicole

These findings, published in Nature, give answers to many families, and offer the first step in longed-for hope for the development of a treatment in the future. The specific gene is called RNU4-2. While nearly all genes known to be involved in NDD are responsible for making proteins, RNU4-2 is not; instead, it makes an RNA molecule that plays an important role in how other genes are processed in cells.

This discovery was initially made using data from the 100,000 Genomes Project, a pioneering study led by Genomics England and NHS England. While previous studies have only looked at genes that make proteins, in the 100,000 Genomes Project, individuals’ entire genomes are sequenced, enabling changes in genes that don’t make proteins, like RNU4-2, to be analysed too. The study was an international collaboration, spanning the US, Australia, and Europe, that was led by Nicola Whiffin, Associate Professor at the Big Data Institute and Centre for Human Genetics at the University of Oxford. The team found mutations in RNU4-2 in 115 people with NDDs, many of whom had the exact same variant which adds a single extra base at an important position in the RNA.

RNU4-2 is very active in the developing brain, and changes in this gene affect how the cell processes other RNA molecules, including those that go on to make proteins. It is the changes to these other proteins that disrupt brain development. The study estimates that these specific changes in the RNU4-2 gene can explain 0.4% of all NDD cases globally, potentially impacting hundreds of thousands of families across the world.

Jessica, the mother who created the Facebook group connecting RNU4-2 families worldwide, said “After a lonely 13-year diagnostic odyssey searching for the cause of my son’s medical challenges, learning about this discovery has been life-changing! One parent beautifully described this diagnosis as the light that has illuminated our journeys and that’s exactly how I feel. This has opened the door for treatments to be developed and provides new hope. We can finally build a united community, raise awareness and help advance research toward a brighter future for our children.”

Nicole Cedor, mother to 10-year-old Mia Joy, said: “When Undiagnosed Network told us about three years ago that there was nothing else they could do, we resigned ourselves to the fact that we may never find out.  So, you can imagine our shock to get this news. With the information we have gained, we are getting blood work to check iron levels, getting a DEXA bone scan next week, and we have a referral in for endocrinology.”

“We are so grateful to each person on the research teams that worked tirelessly to find this diagnosis.  It is one thing to write papers and crunch all that data, then another to see a family with a precious unique child who is living it day by day.  This where the data meets real life. We like to refer to RNU4-2 as "renew", as our family is being renewed by this new information and hope for the future.”

Professor Whiffin said: “What is most remarkable about this discovery is how often changes in this gene result in NDD. Most protein-coding genes involved in NDD are thousands of DNA bases long. RNU4-2 is around 50 times smaller but changes in this gene are almost as frequent a cause of NDD as these protein-coding genes. Including RNU4-2 in standard clinical genetic testing will end diagnostic odysseys for thousands of NDD patients worldwide and provide long-awaited hope to families.”

Yuyang Chen, PhD student at the Big Data Institute who led the analysis for the project, said “We were looking at variants in genes that make RNA molecules and this gene really stood out. It was really exciting when we realised that RNU4-2 is critical for processing other RNA and protein molecules, as it meant we could work out why these variants lead to NDD.” The research by authors Yuyang Chen, Ruebena Dawes and Hyung Chul Kim is fully funded by Novo Nordisk Research Centre Oxford ltd and Novo Nordisk A/S and they are co-supervised by Novo Nordisk Research Centre Ltd.

The collaborative team included Stephan Sanders, Professor of Paediatric Neurogenetics at the Institute of Developmental & Regenerative Medicine and Department of Paediatrics at the University of Oxford, Anne O’Donnell-Luria, co-director of the Center for Mendelian Genomics at the Broad Institute of MIT and Harvard, and Dr Joanna Howson, Vice President Human Genetics CoE at Novo Nordisk, as well as teams from the Australian Centre for Population Genomics, Genomics England, the National Human Genomics Research Institute’s GREGoR Consortium, and the Undiagnosed Diseases Network.

Professor Sanders said: “This is a critical finding. From a research perspective, it shows there are major insights to be found in the 98.5% of the genome that does not encode proteins. Clinically, finding this relationship to NDD is the vital first step in seeking therapeutic approaches that can improve the lives of the individuals and families affected.”

Dr Sarah Wynn, CEO of the charity Unique which connects families with rare conditions, said: “At Unique we are always delighted to hear about new gene discoveries and this ground-breaking research identifying RNU4-2 as the underlying reason for so many undiagnosed children’s developmental delay is truly astounding. Many families have waited a long time before receiving a diagnosis and tell us that it can bring a wave of relief at finally having a reason. Receiving a diagnosis is absolutely vital for accessing support and information and connecting with others with the same condition to share experiences and feel less alone.”

Dr Susan Walker, Head of Translational Genomics at Genomics England and study co-author said: “It’s very unusual to find a single gene in which deleterious variants – or variants that impact the gene’s function - account for such a large number of diagnoses for patients with rare conditions. This discovery has enabled hundreds of patients in the UK and internationally to receive new information about their health questions. This discovery would not have been possible without the participants in the 100,000 Genomes Project and NHS Genomic Medicine Service agreeing to share their data to support genomic research. It’s exciting to think about the potential for more discoveries like this emerging in the future.”

Professor Dame Sue Hill, Chief Scientific Officer and senior responsible officer for Genomics, NHS England, said: “This is an exciting development for people with neurodevelopmental disorders where often no genetic cause can be found. This study showed the importance of looking for changes in non-coding genes - parts of our DNA that do not lead to protein production - and made possible through analysing the whole genome sequences of a large groups of individuals with this condition. This will bring a diagnosis to some individuals and will help inform the development of effective treatment leading to more personalised care for these patients in the future.

“This is another example of how data from the 100,000 Genomes Project which was conducted in partnership with the NHS, helped make this discovery possible and is an example of the power of genomics in healthcare.”