Genetic Sequencing Leads to Major Discovery in Neurodevelopmental Disorders

A seminal study from researchers at the Icahn School of Medicine at Mount Sinai and their collaborators in the United Kingdom, Belgium, Spain, the Netherlands, and Iceland has uncovered a new genetic cause of neurodevelopmental disorders (NDDs). The discovery offers both closure and hope to potentially thousands of families worldwide who have long been searching for answers.

The study, published in the April 10 online issue of Nature Genetics [DOI: 10.1038/s41588-025-02159-5], reveals that mutations in a small, previously overlooked non-coding gene called RNU2-2 are responsible for relatively common NDD. Non-coding genes are genes that don't produce proteins but may still play critical roles in regulating cell functions.

Building on their landmark discovery of RNU4-2 / ReNU syndrome last year, the research team has identified the new, related disorder caused by mutations in the non-coding gene RNU2-2. RNU4-2 / ReNU syndrome and RNU2-2 syndromes share similarities, but patients with RNU2-2 syndrome tend to be more severely affected by epilepsy.

Our identification of RNU2-2 mutations as a cause of NDDs is particularly notable because it cements the biological significance of a class of small non-coding genes in NDDs. These mutations tend to occur spontaneously, rather than being inherited from an affected person's parents."

Daniel Greene, PhD, study's first author, Assistant Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai

NDDs are disorders that affect the development of the brain and nervous system. They include conditions such as intellectual disability, autism spectrum disorder, and motor disorders. These NDDs, which often have a genetic basis, manifest in early childhood and can lead to lifelong challenges in learning, behavior, and communication. The current findings involve a newly discovered form of NDD.

"We know from years of experience supporting patients and families with rare genetic conditions how receiving a diagnosis like this can be life-changing and the first step on the journey to putting in place the right support and care," says Sarah Wynn, PhD, Chief Executive Officer of Unique, an organization that provides support, information, and a voice for all those affected by rare chromosome or gene disorders.

Advances in genetic sequencing, including whole-genome sequencing of more than 50,000 individuals by Genomics England, made the development possible. This enabled the researchers to identify the cause of the novel disorder as mutations in RNU2-2, a gene once thought to be inactive. The authors also identified a separate mutation in RNU2-2 that tends to arise in unaffected individuals as they age, which may have implications for age-related conditions.

"We estimate that the prevalence of RNU2-2 disorder is approximately 20 percent that of RNU4-2 / ReNU syndrome, one of the most common monogenic types of NDD. This means there must be thousands of affected families worldwide," says senior study author Ernest Turro, PhD, Associate Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai.

"With a genetic diagnosis in hand, families can connect with others in similar situations, share valuable experiences, and gain a better understanding of how to manage the condition. This discovery also makes possible further research to explore the molecular mechanisms underlying the disorder," says Dr. Turro.

The paper is titled "Mutations in the snRNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy."