A newly identified recessive neurodevelopmental disorder (NDD) linked to variants in the RNU2-2 gene may be among the most common genetic causes of intellectual disability and epilepsy, new research showed.

The findings suggest that the condition, described as recessive ReNU2 syndrome, could account for up to 10% of all recessive NDD cases with a known genetic cause.

One of the most surprising findings in the study was the apparent frequency of RNU2-2-related disease. Among families with a genetic diagnosis of recessive NDDs, this condition may represent a significant proportion of cases, which researchers said makes it one of the most prevalent monogenic recessive causes identified to date.

“Our discovery gives families something they’ve often waited years for — a clear molecular explanation for their child’s condition,” lead investigator Daniel Greene, PhD, assistant professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai, New York City, said in a news release.

“At the same time, it gives the research community a concrete biological target to guide future therapeutics,” he added.

The study was published online in Nature Genetics.

A Growing Body of Work

RNU2-2 encodes a small nuclear RNA that is part of the U2 spliceosomal complex, a key component in RNA splicing. Disruption of this process is increasingly recognized as a contributor to NDD.

The current findings are based on a series of studies by Greene and colleagues, who in 2024 first identified mutations in another gene involved in RNA splicing, RNU4-2. Researchers found that the mutations caused a previously unidentified NDD, which the team named ReNU syndrome. The condition is estimated to affect tens of thousands of children around the world.

Patients with the disorder usually present with global developmental delay, intellectual disability, and speech impairment, often accompanied by early-onset seizures.

Additional features can include low muscle tone, movement disorders, and behavioral characteristics such as autism. In more severe cases, patients may experience feeding difficulties, respiratory issues, and progressive neurologic impairment.

Phenotypic severity varies, ranging from severe epileptic encephalopathy to milder neurodevelopmental impairment. Neuroimaging may appear normal in early life but can reveal structural changes over time in more severe cases.

The team’s initial finding was followed a year later with the discovery that mutations in the RNU2-2 gene lead to a related condition, which the team named dominant ReNU2 syndrome.

Now, the team has extended this work with the identification of recessive ReNU2 syndrome, which typically results when a child receives one gene variant from each parent. The combination of both copies of the gene leads to disrupted brain development.

For this effort, researchers analyzed whole-genome sequencing (WGS) data from the 100,000 Genomes Project within the Genomics England Research Environment. The analysis included 78,051 individuals, including 6762 with unsolved NDDs and 71,289 who did not have an NDDs. 

The study was specifically designed to identify recessive inheritance patterns, which are often missed by standard diagnostic testing. To assess the functional impact of the variants, the investigators performed RNA sequencing of blood samples from affected individuals and control individuals.

The analysis showed a marked reduction in U2-2 RNA levels among individuals carrying pathogenic variants, supporting a loss-of-function disease mechanism.

Recessive vs Dominant

The recessive RNU2-2 disorder described in the new study is mechanistically different from the team’s 2025 reports on dominant RNU2-2-related conditions.

In recessive cases, individuals typically show a near-complete loss of U2-2 expression, whereas in dominant forms, expression is relatively intact despite the presence of disease. The underlying biology remains poorly understood, investigator Ernest Turro, PhD, associate professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai, told Medscape Medical News.

The inability of related RNAs to compensate for U2-2 loss may explain why complete loss of its function leads to disease, whereas less severe disruptions can result in different clinical presentations, he added.

RNU2-2-related disease can occur in both dominant and recessive forms, but the current study specifically identified and characterized the recessive form, which researchers found may be more prevalent than previously thought.

“This high prevalence is particularly intriguing because the most common monogenic neurodevelopment disorders tend to be dominant rather than recessive,” Turro said.

There is no treatment for recessive ReNU2 syndrome, but researchers say this new finding offers a potential target for gene replacement therapy in the future.

Genetic Counseling and Diagnosis

The identification of a recessive inheritance pattern also has important implications for genetic counseling.

“Due to the recessive nature of this condition, there is a risk of recurrence if both parents are carriers of pathogenic variants,” Turro said. “It may be appropriate to inform prospective parents of such risks.”

He also noted that carrier status may be detectable through expression studies, even in individuals without a known affected child. Many affected individuals may go undiagnosed because RNU2-2 is not included on standard exome sequencing panels, unless clinicians pursue more comprehensive testing strategies.

The gene may have been overlooked because of its earlier classification as a pseudogene, delaying clinical and functional investigation. “That designation changed last year when we described a dominant form of RNU2-2 related NDD,” Turro said.

Turro outlined several practical approaches for laboratories and clinicians, such as the use of WGS to ensure coverage of noncoding regions like RNU2-2. In some cases, targeted sequencing approaches may also be considered, particularly when WES fails to confirm a diagnosis.

With the increasing availability of WGS, clinicians should consider earlier use of genome-wide approaches in patients with unexplained NDDs, especially when epilepsy or developmental delay is present, Turro said.

Exploring the ‘Dark Genome’

Two separate but related studies published in the same issue of Nature Genetics offer even more details on these NDDs.

In one, researchers systematically analyzed small nuclear RNA genes and confirmed that both dominant and recessive RNU2-2 variants are linked to NDDs with frequent epilepsy. This reinforces the gene’s role in developmental and epileptic encephalopathy across independent cohorts, researchers said.

Another study published in the same issue replicated and expanded these findings in a large cohort, identifying additional individuals with pathogenic RNU2-2 variants who share the same neurodevelopmental and epileptic phenotype. The study demonstrated that these rare variants are more common in affected individuals than in control individuals.

“These studies present strong evidence that variants in RNU2-2 gene can cause neurodevelopmental disorders autosomal dominantly and, even more frequently, recessively,” Núria Setó-Salvia, PhD, senior postdoctoral researcher, Reta Lila Weston Institute and Queen Square Brain Bank for Neurological Disorders, University College London, London, England, said in a statement from the UK nonprofit Science Media Centre (SMC).

The new research highlights the growing recognition that noncoding regions of the genome affect neurologic disease, noted Cornelius Gross, PhD, head of the European Molecular Biology Laboratory, Rome, Italy.

“This study is a significant advance in understanding neurodevelopment disorders because it identifies a set of surprisingly common recessive disease mutations in the dark genome — the 98% of our genome that is noncoding,” Gross said in the SMC statement.

“Tracking down such mutations has been much harder than finding disease mutations in coding genes and the study is an example of how improved sequencing methods and annotations have opened a door on new disease genes.”

As genomic technologies continue to evolve, Turro said he expects additional noncoding variants to emerge as clinically relevant contributors to NDDs, particularly in patients who remain undiagnosed after standard testing.

Disclosure information for study authors is available in the original study publication. Setó-Salvia declared having no conflicts of interest. Disclosure information for Gross was unavailable.