Researchers led by a team at the Icahn School of Medicine at Mount Sinai have identified and described a previously unknown neurodevelopmental disorder (NDD) that appears to be the most common neurodevelopmental disorder ever discovered. The condition, caused by a mutation in a small gene called RNU2-2it is estimated to affect thousands of people in the United States and accounts for about 10% of all cases of NDD that are caused by a known gene. The team discovered that the problem is caused by the absence of a small nuclear RNA (snRNA) called U2-2 RNA, which is produced by RNU2-2 hereditary.
Children with this condition usually inherit one mutated copy of the gene from each parent, although sometimes the mutations occur spontaneously through genetic mutations. Although the parents are not affected, the combined effect on both copies of the gene in their children leads to stunted brain development in their child.
The symptoms of this disease vary greatly depending on the specific genetic changes of the child. Common features include low muscle tone, delayed growth, and limited speech. Some children have mild learning difficulties or autism spectrum disorders, while others have epilepsy, movement disorders, or difficulty walking. Brain reactions may seem normal but can show changes over time. In more severe cases, additional problems may include feeding problems or breathing problems. Many different symptoms show how basic RNA deficiency affects each child differently.
The findings provide long-awaited answers for many families and may inform future drug development. Daniel Greene, PhD, assistant professor of genetics and genomic sciences at the Icahn School of Medicine, says: “Our findings give families something they’ve been waiting for for years—a clear molecular explanation for their child’s condition. “For many families, that clarity can have deep meaning after a long and uncertain journey of diagnosis. At the same time, it provides the research community with a solid biological target to guide future treatments.”
The study was conducted in collaboration with US colleagues in the Undiagnosed Diseases Network led by colleagues at Stanford University, as well as international colleagues in the United Kingdom, the Netherlands, Belgium and Italy. Greene is the first author, and Ernest Turro, PhD, assistant professor of genetics and genomic sciences at the Icahn School of Medicine, is the senior and corresponding author of the group’s published paper. Nature Geneticsentitled “Biallelic variants in RNU2-2 causing the most common known recessive neurodevelopmental disorder.”
The new discovery builds on two earlier developments from the research team led by Turro. In April 2025, the group indicated that changes are in place RNU2-2 cause a related but rare rare condition, known as dominant ReNU2 syndrome. In May 2024, the team identified mutations in a related gene, RNU4-2as the cause of the most common autosomal recessive NDD known to date, now called ReNU syndrome.
In their new records Nature Genetics In the paper, the researchers went on to explain, “We recently reported that there are different types of paralogs RNU4-2 and RNU2-2 causes two very common neurodevelopmental disorders (NDDs). These findings have been confirmed in separate reports by other groups, two of which have identified a third less common NDD caused by different species. RNU5B-1.”
For the study, using genome sequence data from the United Kingdom’s National Genomics Research Library, Turro, Greene and colleagues analyzed genetic variants in more than 41,000 non-coding genes. “We selected a recessive version of the RNU2-2 Syndrome through a joint analysis of the statistics of the 100,000 Genomes Project (100KGP) and the Genomic Medicine Service (GMS) data at the National Genomic Research Library (NGRL) from UK descendants with rare disorders, “they explained. to detect the main and extreme levels of the blood sequence from the patients and the systems also revealed the immediate effects of the pathogens that cause the disease: a strong decrease in U2-2 RNA.
“Having identified statistical relationships between prominent NDDs and variables in RNU4-2 and RNU2-2now we have shown a statistical relationship with the third weak NDD caused by different types in RNU2-2,” the authors said in their paper.
The findings extend those of previous reported studies, by showing that there are different types RNU2-2 cause a rare and incredibly common disease, now called recessive ReNU2 syndrome. In fact, researchers estimate that this extreme condition may be 60% as common as ReNU disease, which is unusual, since the most common NDDs control rather than decrease. In their report the authors went on to note, “Combining across monoallelic and biallelic cases in 100KGP, the number of cases RNU2-2 the disease—which has recently been called ReNU2 syndrome because of its familial basis—accounts for 79 percent of the population with ReNU syndrome.”
Turro added, “Our discovery will enable tens of thousands of families affected by this previously hidden gene to find closure through genetic testing. Parents will have the opportunity to contact the newly established ReNU2 Syndrome Foundation.”
Researchers are currently enrolling families in the INDEED study in Mount Sinai to help provide assessments and better understand the situation. Future work will focus on deepening the understanding of the biology behind the disease and identifying pathways to future treatments. “Although a specific treatment for ReNU2 syndrome has not yet been found, understanding that the disease is caused by the loss of U2-2 RNA points to possible methods of genetic modification in the future,” Turro continued. “We are currently enrolling families in the INDEED study to evaluate affected individuals, to improve our understanding of the natural course of this condition, to develop guidelines for the management of medications, and to reveal precisely how the loss of U2-2 RNA disrupts the development of the heart.
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