Landmark study identifies new genetic cause of neurodevelopmental disorders, bringing long-awaited answers to families

New York, NY [April 10, 2025]—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,” says the study's first author, Daniel Greene, PhD, Assistant Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai. “These mutations tend to occur spontaneously, rather than being inherited from an affected person’s parents.”

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.”

For the full list of authors, as well as details on funding and competing interests, please refer to the Nature Genetics paper: [DOI: 10.1038/s41588-025-02159-5].

About the Icahn School of Medicine at Mount Sinai 

The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the eight- member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City’s large and diverse patient population.  

The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master’s degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,600 clinical residents and fellows training throughout the Health System. Its Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 500 postdoctoral research fellows. 

Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges.  More than 4,500 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.

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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Beth Israel; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.