Recessive gene variant causes neurodevelopmental disorder

A newly described neurodevelopmental disorder has been linked to changes in a small noncoding gene.

Research groups from the Icahn School of Medicine in New York and the University of Manchester have independently identified a previously unknown neurodevelopmental disorder caused by variants in a noncoding gene called RNU2-2. Both groups show that the disorder is recessive: children with the condition inherit one mutated copy of the RNU2-2 gene from each parent, who are typically unsymptomatic. This helps to explain why the disorder has remained undetected until now.

'Our discovery gives families something they've often waited years for – a clear molecular explanation for their child's condition,' Dr Daniel Greene, first author and assistant professor of genetics and genomic sciences at the Icahn School of Medicine said. 'For many families, that clarity can be profoundly meaningful after a long and uncertain diagnostic journey.'

This discovery builds on earlier work from both groups, which highlighted the importance of RNU noncoding genes in brain development and function. Previous studies showed that mutations in RNU2-2 and a related gene, RNU4-2, can cause dominant neurodevelopmental disorders. This prompted further investigation into these noncoding genes, which were previously dismissed as 'junk' DNA because they do not encode proteins. Instead, they provide the genetic blueprints for RNA molecules important for accurate protein production.

The Icahn School of Medicine group, publishing their findings in Nature Genetics, and the University of Manchester group, also sharing their results in Nature Genetics, used whole-genome sequencing data from the 100,000 Genome Project by Genomics England. Both groups identified recessive RNU2-2 syndrome caused by a wide range of RNU2-2 variants. These genetic changes lead to a near-loss of the U2-2 RNA molecule, encoded by the RNU2-2 gene. The findings were confirmed in selected patients using a blood test.

More than 80 children have now been diagnosed, but researchers estimate that around one in 40,000 people may be living with recessive RNU2-2 syndrome, while approximately one in 100 people could be carriers. Symptoms vary but typically include drug-resistant seizures and severe developmental delays, often presenting within the first year of life.

'Research into the RNU2-2 gene is an important and promising step in helping us better understand what's driving these conditions. It is still early days but progress like this brings hope for improved support and future treatments,' said Tom Shillito, health improvement and research manager at Epilepsy Action.

Researchers hope that this major development will guide the future development of gene-based treatments for recessive RNU2-2 syndrome.

A study published in Nature Genetics independently identified a distinct recessive neurodevelopmental disorder caused by variants in RNU4-2, which appears to be much less common than recessive RNU2-2 syndrome. Complementary functional work published in Nature using saturation genome editing further demonstrated that different classes of RNU4-2 variants can give rise to both dominant and recessive disorders.

Together, these findings highlight the importance of noncoding genes in human disease and their growing relevance in genetic research.