New York, NY, March 30, 2026 (GLOBE NEWSWIRE) — Researchers at the Icahn School of Medicine at Mount Sinai in New York have identified and described a previously unknown recessive neurodevelopmental disorder (NDD) that appears to be the most prevalent ever discovered. The condition is caused by changes in a small noncoding gene called RNU2-2. It is estimated to affect thousands of individuals in the United States and account for about 10 percent of all recessive NDD cases with a known genetic cause.
The work was done in collaboration with U.S. collaborators in the Undiagnosed Diseases Network led by colleagues at Stanford University and international collaborators in the United Kingdom, the Netherlands, Belgium, and Italy. The findings, published in the March 30 issue of Nature Genetics [https://doi.org/10.1038/s41588-026-02539-5], provide long-awaited answers for many families and may inform future drug development.
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 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 United Kingdom’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 analyzed 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 led by Ernest Turro, PhD, Associate Professor of Genetics and Genomic Sciences at the Icahn School of Medicine.
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.
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. Turro, the senior study 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.”
The paper is titled “Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder.”
The study’s authors, as listed in the journal, are 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, Kathleen Freson, Tahsin Stefan Barakat, Marco Tartaglia, Jonathan A. Bernstein, Andrew D. Mumford, Matthew T. Wheeler, and Ernest Turro.
For details on funding, please refer to the Nature Genetics paper: [https://doi.org/10.1038/s41588-026-02539-5].
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- Histogram of log-scale U2-2 RNA levels in unaffected individuals