Thousands of families worldwide now have new hope: researchers at the Icahn School of Medicine at Mount Sinai and collaborators have identified mutations in a small non-coding gene, RNU2-2, as a previously unrecognized cause of neurodevelopmental disorders (NDDs). Published on April 10 in Nature Genetics, this study not only expands our understanding of genetic contributions to NDDs but also offers closure — and a path forward — to families who have long searched for answers.
Neurodevelopmental disorders encompass a range of conditions, such as intellectual disability, autism spectrum disorder, and motor coordination disorders, that originate in early brain development and often persist throughout life. Affected individuals can face challenges in learning, communication, social interaction, and behavior, placing profound emotional and practical burdens on patients and their families.
Researchers from Mount Sinai, the United Kingdom, Belgium, Spain, the Netherlands, and Iceland have found that mutations in a small, non-coding gene called RNU2-2 are responsible for a relatively common NDD. These mutations were previously overlooked because non-coding genes do not produce proteins for cellular use, but recently, are noted to still play essential roles in regulating cell functions.
By analyzing whole-genome sequencing data from 10 of thousands of individuals, including a 50,000-participant dataset contributed by Genomics England, the team detected recurrent spontaneous mutations in RNU2-2 in children presenting with developmental delay and epilepsy. Although RNU2-2 syndrome shares features with the previously described RNU4-2/ReNU syndrome, patients with RNU2-2 mutations tend to have more severe epilepsy and a broader range of developmental challenges.
The authors also found a distinct, age-related mutation in RNU2-2 emerging in otherwise healthy adults, raising the possibility that RNU2-2 dysfunction may contribute to other late-onset conditions.
“This study cements the biological significance of small non-coding genes in NDDs,” says first author Daniel Greene, PhD, Assistant Professor of Genetics and Genomic Sciences at Mount Sinai. Greene and colleagues had only last year described RNU4-2/ReNU syndrome; using their previous findings, they recognized the molecular signature of RNU2-2 mutations in a new cohort.
Senior author Ernest Turro, PhD, Associate Professor of Genetics and Genomic Sciences, estimates that RNU2-2 syndrome may be 20% more common than RNU4-2/ReNU syndrome, which is one of the more frequent genetic NDDs. “There are likely thousands of affected families worldwide,” Turro notes.
“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.”
