Research uncovers link between mutations in RNU4-2 gene and neurodevelopmental disorders

July 26, 2024

Researchers have identified a link between a recurrent mutation in the RNU4-2 gene and neurodevelopmental disorders (NDD), shedding light on a significant cause of rare neurological disease.  

Published in Nature, the study, led by an international team of scientists including Professor Nicola Whiffin from the University of Oxford, estimates that variants in the RNU4-2 gene cause  ~0.4% of all NDD. 

Professor Whiffin said:

We are hearing of patients around the world who are being diagnosed with genetic variants in RNU4-2. There are already hundreds and this will quickly be in the thousands. The impact on families is significant. For many parents, there is relief, that it wasn’t something they did during pregnancy, but instead is a chance occurrence. For some, this knowledge means they can make reproductive decisions, choosing to grow their family. But perhaps the largest impact is being able to connect with other families and build a community. They can support each other, and learn from each other’s experiences, as well as drive forward further research into their condition through advocacy. 

Neurodevelopmental disorders broadly refer to severe conditions that affect brain function and alter neurological development. This impacts individuals' learning, behaviour, speech and cognitive functioning. 

Despite novel approaches to identifying rare developmental disorders, currently ~60% of individuals remain without a diagnosis. Most of the known disease-causing mutations are in the ~1.5% of the human genome which is responsible for encoding proteins. 

While most genes associated with neurodevelopmental disorders are responsible for producing proteins, RNU4-2 is different; it produces an RNA molecule that is crucial for the processing of other genes within cells. 

The RNU4-2 gene is very active during brain development, and changes in this gene impact how cells process other RNA molecules, such as those that encode proteins. When these proteins are produced with abnormal changes, brain development is disrupted. 

Professor Whiffin said:

This discovery opens up many avenues for future research. Firstly, we have so much still to learn about RNU4-2 in terms of exactly which DNA changes cause neurodevelopmental disorders and exactly how they do so. Discovery of the gene that causes disease is also the first step on the road towards developing therapies for the disorder. 

The study describes mutations in the RNU4-2 gene, which is highly expressed in the developing human brain. The researchers analysed 8,841 individuals with undiagnosed NDD and found the variation in 115 individuals with neurodevelopmental delay. 

The discovery was made using data from the 100,000 Genomes Project by Genomics England and NHS England, which sequences individuals' entire genomes, including genes that don't make proteins. 

Professor Whiffin said:

More broadly, this finding will open up research into the role of non-coding genes in rare disease: RNU4-2 is perhaps the most significant finding to date of a gene that doesn’t code for protein in rare disease. 

The team of researchers who contributed to the study included Stephan Sanders, Professor of Paediatric Neurogenetics 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. 

The identification of the RNU4-2 gene mutation as a cause of severe neurodevelopmental disorders represents an important moment in genetic research and offers hope and direction for thousands of affected individuals and their families worldwide.