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 neurodevelopmental disorders (NDDs). 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.
Rare Diseases BioResource
The NIHR BioResource has a longstanding interest in the genomics of rare diseases and collaboration with other institutions to bring together patients with rare diseases via our Rare Disease BioResource to power discoveries like this one. This new study follows on from the Turro et al 2020 publication on the utility of whole genome sequencing in a healthcare setting by using the initial data generated from our new RNA phenotyping dataset to add insights into non-coding genes causing developmental disorders.
Head of Sample Management at the BioResource, Dr Kathy Stirrups, who is one of several authors from the BioResource on the paper, explains:
"This study is the first publication deriving from this new rare disease omics dataset that will be completing patient recruitment later this year.
"Then the resulting Whole Genome Sequencing (WGS), RNA sequencing and proteomics data will become more widely available for further discoveries across a wide range of rare diseases and hopefully end the diagnostic odyssey for some of the patients that have generously joined the study."
What are neurodevelopmental disorders (NDDs)?
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, behaviour, and communication. The current findings involve a newly discovered form of NDD.
The study's first author, Daniel Greene, PhD, Assistant Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai says:
"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.
"While this diagnosis does not immediately lead to a cure, it provides closure for families and, importantly, creates new opportunities for understanding the disease."
Sarah Wynn, PhD, Chief Executive Officer of Unique - an organisation that provides support, information, and a voice for all those affected by rare chromosome or gene disorders - says:
"New gene variant discoveries such as those in RNU2-2 are exciting scientific developments.
"Even more vitally importantly, they provide much-needed answers for patients and families, who have often been searching for the reason for their child’s symptoms and features for a long time.
"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.
"Crucially, families are also able to connect with others who have received the same diagnosis."
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.
Senior study author Ernest Turro, PhD, Associate Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, says:
"We estimate the prevalence of RNU2-2 disorder to be approximately 20 percent that of RNU4-2 / ReNU syndrome, which means there are thousands of affected families worldwide.
"Our discovery will allow families affected by this comparatively common form of NDD to receive the definitive molecular diagnosis they have long been searching for.
"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."
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].
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