Summary: Researchers have identified mutations in the noncoding gene RNU2-2 that cause a recently described neurodevelopmental disorder that is often associated with severe epilepsy. The discovery highlights the important role of small noncoding genes in brain development and could affect thousands of families worldwide.
The RNU2-2 gene is linked to RNU4-2 , which has previously been linked to a related condition. This highlights the importance of this class of genes. These findings, made possible by large-scale genomic sequencing, pave the way for better diagnosis, support, and future therapeutic research.
Key data:
- Novel genetic cause: Mutations in the small noncoding gene RNU2-2 are associated with severe neurodevelopmental disorder with epilepsy.
- Spontaneous mutations: These mutations usually occur spontaneously and are not inherited.
- High impact: This disorder can affect thousands of people worldwide and highlights the importance of non-coding genes in brain development.
Source: Mount Sinai Hospital
A groundbreaking study led by researchers at the Icahn School of Medicine at Mount Sinai, working alongside international colleagues in the United Kingdom, Belgium, Spain, the Netherlands, and Iceland, has achieved a significant breakthrough. Their collaborative effort successfully discovered a new genetic cause of neurodevelopmental disorders (NDDs), shedding new light on the origins of these complex conditions.
This crucial finding, resulting from extensive international research, expands the current understanding of the molecular mechanisms underlying NDDs. Identifying the specific genetic cause is a pivotal development that not only deepens scientific knowledge but also opens new avenues for diagnosis, genetic counseling, and the potential development of targeted treatments for affected patients.
This discovery offers both closure and hope for potentially thousands of families around the world who have long been searching for answers.
The study was published on April 10.Online edition of Nature Genetics ,This indicates that mutations in a previously overlooked small noncoding gene, called RNU2-2, are responsible for relatively common NDDs.
Non-coding genes are genes that do not produce proteins but can still play an important role in regulating cellular functions.
Building on last year’s landmark discovery of RNU4-2/ReNU syndrome , the research team has identified a new, related condition caused by mutations in the non-coding gene RNU2-2. While RNU4-2/ReNU syndrome and RNU2-2 syndrome share similarities, patients with RNU2-2 syndrome often experience more severe epilepsy.
RNU2-2 mutations is particularly noteworthy because it highlights the biological importance of a class of small non-coding genes in such disorders.”
These mutations are typically spontaneous new events in the affected individual, meaning they arise randomly rather than being hereditary and passed on from their parents. This signifies that the genetic change originates de novo and is not inherited through the parental germline.
Neurodevelopmental disorders (NDDs) are conditions that affect the development of the brain and nervous system. They include conditions such as intellectual disability, autism spectrum disorder, and motor skills disorders.
These neurodevelopmental disorders (NDDs), which often have a genetic basis, manifest in early childhood and can lead to lifelong learning, behavioral, and communication problems. The current findings describe a newly discovered form of NDD.
“We know from years of experience assisting families and patients with rare genetic disorders that such a diagnosis can be profoundly life-changing,” stated Sarah Wayne, PhD, CEO of Unique. She emphasized that reaching a definitive diagnosis serves as the crucial first step toward unlocking the necessary support and specialized care.
Dr. Wayne, whose organization Unique is dedicated to offering support, information, and a collective voice to individuals impacted by rare chromosome or genetic disorders, underscores the profound significance of this initial finding. For those facing these conditions, the diagnosis is viewed not as an end, but as the beginning of a focused path toward appropriate management and community resources.
Advances in genetic sequencing, including the whole genome sequencing of more than 50,000 individuals by Genomics England, made this development possible. This allowed researchers to identify the cause of the new condition as mutations in the RNU2-2 gene , a gene previously thought to be inactive.
The authors also discovered a distinct mutation in RNU2-2 that often arises with age in unaffected individuals, which could have implications for age-related diseases.
The prevalence of RNU2-2 disorder is about 20 percent higher than that of RNU4-2/ReNU syndrome , which is one of the most common monogenetic neurodevelopmental disorders. This means that the number of affected families worldwide must be in the thousands,” said the study’s lead author, Ernest Toro, PhD, an associate professor of genetics and an associate professor of medicine at Mount Sinai.
“Genetic diagnosis allows families to connect with others in similar situations, share valuable experiences, and better understand how to cope with the disease. This discovery also opens the door to future research to investigate the molecular mechanisms underlying this condition,” said Dr. Toro.
About This Genetics and Neurodevelopment Research News
Author: Karin Eskenazi
Source: Mount Sinai Hospital
Contact: Karin Eskenazi – Mount Sinai Hospital
Image: The image is credited to StackZone Neuro
Original Research: Open access.
“Mutations in the snRNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy” by Daniel Greene et al. Nature Genetics
Abstract
Mutations in the snRNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy.
The spliceosome complex consists of five small nuclear RNAs (snRNAs): U1, U2, U4, U5 and U6, each encoded by multiple genes. We recently demonstrated that mutations in RNU4-2 , the gene encoding the U4-2 snRNA, cause one of the most common monogenic neurodevelopmental disorders.
We report the identification of recurrent germline mutations in the gene RNU2-2 (previously known as the pseudogene RNU2-2P), a 191 base pair sequence that codes for the U2-2 snRNA. These specific mutations are responsible for the associated genetic defect. Researchers identified recurrent de novo single nucleotide mutations occurring at positions 4 and 35 of the RNU2-2 gene, a finding that was replicated in 16 additional cases, bringing the total number of confirmed cases to 25.
The condition resulting from these genetic changes is known as RNU2-2 syndrome. The disorder is clinically characterized by a range of neurological and developmental features, including intellectual disability, autism-like behavior, microcephaly (small head size), hypotonia (low muscle tone), epilepsy, and hyperventilation.
A consistently presented and defining feature across all documented cases is a phenotype of severe and complex seizures. Furthermore, the prevalence of RNU2-2 syndrome is estimated to be significantly lower than that of a related condition, RNU4-2 syndrome, at approximately 20% of the frequency.
We observed that canonical U2-2 and U2-1 were expressed similarly in blood. Although mutant U2-2 was expressed in patient blood samples, we found no evidence of abnormal splicing.
Our findings confirm the role of key spliceosomal snRNAs in the etiology of neurodevelopmental disorders.
