The condition is caused by changes in a small noncoding gene called RNU2-2. It is estimated to affect thousands of individuals and accounts for about ten percent of all recessive NDD cases with a known genetic cause.
The work was led by researchers from Icahn School of Medicine at Mount Sinai in New York in collaboration with colleagues from Stanford University and the University of Bristol. Clinical and scientific collaborators from the Netherlands, Belgium, Italy and the UK provided valuable contributions to this research.
The team found that the disorder is caused by a near-complete absence of a molecule called U2-2 RNA, which is produced by the RNU2-2 gene. Children with the condition typically inherit one altered copy of the gene from each parent, although sometimes changes arise spontaneously by genetic mutation. While the parents are unaffected, the combined effect on both copies of the gene in their children leads to disrupted brain development in their child.
Symptoms of this disorder vary widely depending on the child's specific genetic changes. Common features include low muscle tone, developmental delays, and limited speech. Some children have mild learning difficulties or autism traits, while others develop epilepsy, movement disorders, or trouble walking. Brain imaging may appear normal early on but can show changes over time. In the most severe cases, additional challenges may include feeding difficulties or respiratory problems. The wide range of symptoms reflects how the underlying U2-2 RNA deficiency affects each child differently.
"Our discovery gives families something they've often waited years for, a clear molecular explanation for their child's condition," says the study's first author, Daniel Greene, PhD, Assistant Professor of Genetics and Genomic Sciences at the Icahn School of Medicine. "For many families, that clarity can be profoundly meaningful after a long and uncertain diagnostic journey. At the same time, it gives the research community a concrete biological target to guide future therapeutics."
Using whole-genome sequencing data from the UK's National Genomics Research Library, the team examined rare genetic variants in more than 41,000 non-coding genes, genes that produce functional RNA molecules that do not encode proteins. They analysed genetic data from 14,805 individuals with an NDD and 52,861 'controls' without an NDD. Their statistical approach was specifically designed to detect dominant and recessive conditions. RNA sequencing of blood from patients and controls further revealed the immediate biological consequence of the disease-causing variants: the severe reduction of U2-2 RNA.
This discovery builds on two earlier landmark developments from the research group:
- April 2025: They showed that mutations in RNU2-2 cause a related but less common dominant condition, known as dominant ReNU2 syndrome.
- May 2024: The team identified mutations in a related gene, RNU4-2, as the cause of the most prevalent autosomal dominant NDD known to date, now called ReNU syndrome.
The new study expands this story by demonstrating that recessive variants in RNU2-2 cause a distinct and surprisingly prevalent disorder, now referred to as recessive ReNU2 syndrome. Notably, the researchers estimate that this recessive condition may be 60 percent as common as ReNU syndrome, which is unusual. The most prevalent NDDs are dominant rather than recessive.
Andrew Mumford, Emeritus Professor of Genomic Medicine at the University of Bristol says "This research completes a set of three landmark genetic discoveries from our team that have identified faults in two hitherto unsuspected genes as a common cause of what can sometimes be a devastating developmental disorder. This work will rapidly improve genetic diagnosis for families and children and families and lead to significant advancements in clinical care."
The investigators are now enrolling families into the INDEED study at Mount Sinai to help deliver diagnoses and better understand the condition. Future work will focus on deepening the understanding of the biology behind the disorder and identifying paths toward future treatments.
"Our discovery will enable tens of thousands of families affected by this previously hidden genetic condition to receive closure through a genetic diagnosis. Parents will have the opportunity to connect with each other through the recently established ReNU2 Syndrome Foundation. Given the recessive inheritance pattern, diagnoses will provide critical information for family planning," says Dr Ernest Turro, the study's senior author.
"While a specific treatment for recessive ReNU2 syndrome is not yet available, understanding that the disorder stems from a loss of U2-2 RNA points to potential gene replacement strategies in the future," he explains. "We are now enrolling families into the INDEED study to diagnose affected individuals, improve our understanding of the natural course of the condition, develop clinical management guidelines, and uncover precisely how U2-2 RNA loss disrupts neurodevelopment. We hope these steps will lay a strong foundation for future clinical trials."
Paper
'Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder' By D Greene et al. in Nature Genetics.
