New Genetic Syndrome Linked to Seizures and Developmental Delay Emerges

Scientists have discovered that mutations in a small gene called RNU2-2, previously thought to have no function, can cause a rare neurological disorder. Children with this mutation have intellectual disability, autism, epilepsy, and other serious symptoms. This discovery shows that even very small genes that are not involved in protein production can play a crucial role in brain development.

More than 4,000 genes have been identified as the cause of rare diseases. Most of these genes are involved in protein production, but only 69 of them are “non-coding” genes, meaning they do not directly produce proteins.

Even so, some of these non-coding genes have essential functions in the body. Three of them (RNU4ATAC, RNU12, and RNU4-2) produce small pieces of RNA called snRNAs, which participate in an important process called “splicing.” This process works like an edit in the RNA that prepares the genetic instructions before they are turned into proteins.

Some mutations in these genes can cause serious diseases. For example, mutations in the RNU4ATAC gene can cause rare conditions that affect growth and development, such as primordial dwarfism, Roifman syndrome, and Lowry-Wood syndrome.

Mutations in the RNU12 gene are linked to problems such as motor incoordination (ataxia) and a syndrome called CDAGS. These diseases are inherited as autosomal recessive genes, meaning that a person must inherit two defective copies of the gene (one from each parent) to develop the condition.

The RNU4ATAC and RNU12 genes are part of a group that edits less than 1% of the body’s RNA, using a special type of “cellular machinery” called the minor spliceosome. The majority of RNA (more than 99%) is edited by another, larger set, the major spliceosome.

One of these major components, called U4-2, also has its own gene (RNU4-2). Recently, mutations in the RNU4-2 gene were found to cause one of the most common neurodevelopmental disorders caused by a single gene. This was confirmed by two different research groups.

The major spliceosome requires five types of snRNAs: U1, U2, U4, U5, and U6. Each of these has multiple genes that produce them. In this new study, the researchers found that mutations in another gene, RNU2-2 (previously considered a pseudogene, or “inactive” gene), also cause a brain-related developmental disorder. This gene produces a version of the U2 snRNA, called U2-2.

Specific mutations in a single “letter” of DNA were found in nine people, and this finding was confirmed in 16 more, totaling 25 cases. This indicates that the condition associated with RNU2-2 is less common than that of RNU4-2, but still relevant, about 20% of the frequency of that other syndrome.

Children affected by this new syndrome usually have intellectual disability, autism-like behavior, a smaller than normal head (microcephaly), weak muscles (hypotonia), epilepsy and respiratory problems such as hyperventilation. All have had severe and complex epileptic seizures.

Clinical photographs of individuals with G1, G4, S3, R1, and I1-6 syndromes. The individuals in these cases have common features: long palpebral fissures with slight eversion of the lateral lower eyelids, long eyelashes, a broad nasal root, large, low-set ears, a wide mouth, and widely spaced teeth. The approximate ages of the individuals when the photographs were taken are shown. Photographs of individual M2, who has Radium-Tartaglia syndrome in addition to RNU2-2 syndrome. The researchers involved obtained specific consent from the families to publish these clinical photographs. m, months; yr, years.

Even if the mutated RNU2-2 gene was active in the blood of the patients, the scientists found no evidence that it was directly disrupting the splicing process. However, the simple fact that it is linked to such a clear syndrome shows that it plays an important role in the functioning of the developing brain.

This discovery reinforces the idea that even these small RNAs, which often go unnoticed, may be fundamental to neurological health.

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Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy

Greene, D., De Wispelaere, K., Lees, J. et al. 

Nat Genet (2025). 

https://doi.org/10.1038/s41588-025-02159-5

Abstract:

The major spliceosome includes five small nuclear RNA (snRNAs), U1, U2, U4, U5 and U6, each of which is encoded by multiple genes. We recently showed that mutations in RNU4-2, the gene that encodes the U4-2 snRNA, cause one of the most prevalent monogenic neurodevelopmental disorders. Here, we report that recurrent germline mutations in RNU2-2 (previously known as pseudogene RNU2-2P), a 191-bp gene that encodes the U2-2 snRNA, are responsible for a related disorder. By genetic association, we identified recurrent de novo single-nucleotide mutations at nucleotide positions 4 and 35 of RNU2-2 in nine cases. We replicated this finding in 16 additional cases, bringing the total to 25. We estimate that RNU2-2 syndrome has a prevalence of ~20% that of RNU4-2 syndrome. The disorder is characterized by intellectual disability, autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype. We found that U2-2 and canonical U2-1 were similarly expressed in blood. Despite mutant U2-2 being expressed in patient blood samples, we found no evidence of missplicing. Our findings cement the role of major spliceosomal snRNAs in the etiologies of neurodevelopmental disorders.