A common recessive NDD caused by RNU2-2 mutations disrupts brain development and opens paths for diagnosis and therapy.
Scientists at the Icahn School of Medicine at Mount Sinai in New York have identified a newly recognized recessive neurodevelopmental disorder (NDD) that may be the most common of its kind discovered so far. The condition is linked to mutations in a small noncoding gene called RNU2-2. Researchers estimate it affects thousands of people in the United States and may account for about 10 percent of all recessive NDD cases with a known genetic cause.
The research involved collaboration with teams in the Undiagnosed Diseases Network, led by Stanford University, as well as partners in the United Kingdom, the Netherlands, Belgium, and Italy. The results were published in Nature Genetics and offer long-awaited answers for many families while pointing toward possible future treatments.
Investigators determined that the disorder results from a near-total loss of U2-2 RNA, a molecule produced by the RNU2-2 gene. Affected children usually inherit one altered copy of the gene from each parent, though some mutations arise spontaneously. Parents typically show no symptoms, but having two altered copies disrupts brain development in their children.
Genetic Cause and Symptom Spectrum
Symptoms vary widely depending on the specific genetic changes. Common signs include low muscle tone, developmental delays, and limited speech. Some children experience mild learning challenges or autism-related traits, while others develop epilepsy, movement disorders, or difficulty walking.
Brain scans may appear normal early in life, but can show changes later. In more severe cases, children may also face feeding difficulties or breathing problems. This broad range of outcomes reflects how differently the loss of U2-2 RNA can affect each individual.
“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.”
Large-Scale Genomic Analysis and RNA Findings
To uncover the cause, researchers analyzed whole-genome sequencing data from the United Kingdom’s National Genomics Research Library. They examined rare variants across more than 41,000 noncoding genes, which produce functional RNA rather than proteins, using data from 14,805 people with an NDD and 52,861 controls without the condition.
Their analytical approach was designed to detect both dominant and recessive disorders. Follow-up RNA sequencing of blood samples from patients and controls showed a clear biological effect, a major reduction in U2-2 RNA linked to the disease-causing variants.
This work builds on earlier findings from the same research group led by Ernest Turro, PhD, Associate Professor of Genetics and Genomic Sciences at Mount Sinai.
- In April 2025, they reported that mutations in RNU2-2 can also cause a related but less common dominant condition called dominant ReNU2 syndrome.
- In May 2024, they identified mutations in a related gene, RNU4-2, as the cause of the most common autosomal dominant NDD, now known as ReNU syndrome.
Recessive ReNU2 Syndrome Prevalence and Ongoing INDEED Study
The latest findings show that recessive variants in RNU2-2 lead to a separate and unexpectedly common condition, now called recessive ReNU2 syndrome. Researchers estimate it may be about 60 percent as common as ReNU syndrome, which is notable because most widespread neurodevelopmental disorders are dominant rather than recessive.
Scientists are currently enrolling families in the INDEED study at Mount Sinai to improve diagnosis and better understand how the condition develops. Future research aims to clarify the underlying biology and identify possible treatment strategies.
Future Research, Diagnosis, and Treatment Directions
“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.”
Reference: “Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder” by 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, 30 March 2026, Nature Genetics.
DOI: 10.1038/s41588-026-02539-5
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