Research uncovers previously unknown recessive condition 

Researchers have discovered how genetic mutations can cause neuro-developmental disorders, including a previously unknown recessive condition. 

Scientists at the University of Oxford and the Francis Crick Institute, in collaboration with international partners, have made advances in understanding how mutations in a single non-coding gene contribute to neurodevelopmental disorders. 

The research, published in Nature and Nature Genetics, centres on RNU4-2, the non-coding gene that produces a small RNA molecule essential for RNA splicing — a fundamental cellular process required to correctly process genetic information. 

Genetic mutations in the RNU4-2 gene are estimated to account for approximately 100,000 cases of neurodevelopmental disorders globally. This includes ReNU syndrome, a spliceosomal disorder identified as one of the most prevalent known neurodevelopmental disorders. 

“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, who co-led the research. 

 “These studies not only improve our ability to diagnose patients but also reveal entirely new biology that could be useful when designing treatments. 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.” 

Innovative approach could ‘uncover hidden causes of human disease’ 

In the study, scientists applied Saturation Genome Editing (SGE), a method pioneered by Dr Gregory Findlay, to test the functional impact of hundreds of mutations across the entire RNU4-2 gene.  

Dr Joachim De Jonghe (Francis Crick Institute) successfully adapted the SGE 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. Their approach could identify which mutations are known to cause ReNU syndrome, with the amount of functional disruption matching the severity of disease observed in patients.  

Through collaboration with international clinical teams, researchers 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,” Findlay said.  

“Applying these approaches to other non-coding regions of the genome could uncover many more hidden causes of human disease.”  

Mutations in same RNA gene can cause different diseases

While analysing the data, 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. 

In the parallel study published in Nature Genetics, researchers characterised 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. This includes distinctive changes on brain MRI and different disease mechanism, likely involving reduced levels of RNU4-2 RNA rather than the splicing disruption seen in ReNU syndrome. 

These findings suggest mutations in different regions of the same tiny RNA gene can lead to two mechanistically distinct diseases. 

The research could allow clinicians to diagnose genetic conditions and lay future foundations for therapeutic development. 

“Rare conditions are incredibly difficult to diagnose, and too many families still wait far too long for answers – around five years on average,” said Dr Rich Scott, Chief Executive Officer of Genomics England. 

“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.” 

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