Exploration of non-coding genes leads to identification of neurodevelopmental disorder

An international team of researchers has identified a previously unknown recessive neurodevelopmental disorder (NDD) that appears to be the most prevalent of all recessive NDDs discovered to date.

Daniel Greene and colleagues say the newly identified NDD results from the nearly total absence of a molecule called U2-2 RNA, which is produced by a non-coding gene called RNU2-2. (Non-coding genes are genes that do not code for proteins but play critical roles in regulating gene expression.) Children with two copies of the mutated gene exhibit symptoms including low muscle tone, developmental delays, and limited speech, and some have autistic traits, epilepsy, learning disabilities, and/ or movement disorders. The condition may also lead to feeding or respiratory problems.

The researchers identified the mutation using gene-sequencing data from the United Kingdom’s National Genomics Research Library to search for rare genetic variants in more than 41,000 non-coding genes, analyzing data from 14,805 individuals with NDDs and 52,861 controls. Subsequently, they analyzed blood samples from patients in order to determine the consequences of the mutation.

The researchers say the condition, called recessive ReNU2 syndrome, may account for around 10% of all recessive NDD cases with a known genetic cause. Previously, members of the team reported that several mutations in RNU2-2 or a related gene, RNU4-2, can cause dominant NDDs (conditions that occur if only one parent carries the mutation, or if a gene spontaneously mutates). They found that symptoms are much more variable in those with the recessive form than in those with the dominant forms.

Greene comments, “Our discovery gives families something they’ve often waited years for—a clear molecular explanation for their child’s condition. 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.”

Senior study author Ernest Turro adds, “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.”

Cornelius Gross, head of the European Molecular Biology Laboratory, who did not participate in the study, comments, “It can be considered a breakthrough because of the surprisingly high abundance of these variants—more than three times higher than the next recessive mutation causing severe neurodevelopmental disorders. This finding makes it of general medical relevance because it shows that non-coding genes are hot spots for disease and deserve greater attention in our search for the genetic basis for disease.”

Citations

“Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder,” Daniel Greene, Rodrigo Mendez, Jon Lees, Mafalda Barbosa, Alessandro Bruselles, Luigi Chiriatti, Federico Ferraro, Cecilia Mancini, Rachel Schot, Frank Sleutels, Enrico Bertini, Devon E. Bonner, Arjan Bouman, Alice S. Brooks, Thomas A. Cassini, Kimberly M. Ezell, Natalia Gomez-Ospina, Tjitske Kleefstra, Michael O’Donoghue, Lynette Rives, Vandana Shashi, Rebecca C. Spillmann, Mohamed Wafik, Undiagnosed Diseases Network, Kathleen Freson, Tahsin Stefan Barakat, Marco Tartaglia, Jonathan A. Bernstein, Andrew D. Mumford, Matthew T. Wheeler, and Ernest Turro, Nature Genetics, March 30, 2026 (free online). Address: Ernest Turro, [email protected].

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“Newly discovered recessive neurodevelopmental disorder may be most prevalent ever,” news release, Mount Sinai Hospital, March 30, 2026.

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“Scientists discover the most prevalent recessive neurodevelopmental disorder to date,” Bioengineer.org, March 30, 2026.

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“Expert reaction to identification of most common recessive neurodevelopmental disorder,” Science Media Centre, March 30, 2026.