Researchers at the Icahn School of Medicine at Mount Sinai and other institutions have discovered a neurodevelopmental disorder which is caused by mutations in a single gene and impacts tens of thousands of individuals across the globe. This breakthrough will lead to better clinical diagnostic services for patients with neurodevelopmental disorders. The research was published in the May 31 online issue of Nature Medicine and was carried out in collaboration with colleagues at the University of Bristol.The findings will enhance clinical diagnostic services for patients with neurodevelopmental disorders. By conducting thorough genetic analysis, the team identified that mutations in the non-coding gene RNU4-2 lead to a range of developmental symptoms not previously associated with a specific genetic disorder. Non-coding genes are segments of DNA that do not generate proteins. The researchers utilized whole-genome sequencing data from the United Kingdom’s National Genomic Research Library.The study aimed to compare the prevalence of rare genetic variants in 41,132 non-coding genes between 5,529 individuals with intellectual disability and 46,401 individuals without the condition. This discovery is important because it is one of the most common genetic causes of such disorders, second only to Rett syndrome among patients analyzed by the UK’s Genomic Medicine Service. It is noteworthy that these mutations are usually spontaneous and not inherited, which provides valuable insights into the nature of the condition. The researchers conducted a comprehensive genetic association analysis to identify rare variants in non-coding genes that could be associated with intellectual disability.The study’s lead author, Daniel Greene, PhD, Assistant Professor of Genetics and Genomics Sciences at Icahn Mount Sinai and a Visitor at the University of Cambridge, commented, “The discovery of a single gene responsible for thousands of patients with a rare disease is incredibly rare. Our findings were elusive to researchers for years due to sequencing and analytical challenges.” Greene added that “More than 99 percent of genes known to cause neurodevelopmental disorders encode proteins, but the researchers hypothesized that non-coding genes may also play a role.”ich” mutations that do not produce proteins may contribute to intellectual disability. Neurodevelopmental disorders, which typically manifest in early childhood, cause deficiencies in personal, social, academic, or occupational abilities. Intellectual disability encompasses substantial limitations in intellectual functioning (such as learning and problem-solving) and adaptive behavior (such as social and practical skills).
“We discovered genetic alterations in a very small 141-unit gene that is essential for gene splicing, a fundamental cellular function.”Found in all animals, plants, and fungi,” stated Ernest Turro, PhD, Senior Study Author and Associate Professor of Genetics and Genomic Sciences at Icahn Mount Sinai and a Visitor at the University of Cambridge. He added, “Most individuals with a neurodevelopmental disorder do not receive a molecular diagnosis after genetic testing. Thanks to this study, numerous families will now have the opportunity to receive a molecular diagnosis for their affected family members, finally ending many diagnostic journeys.”
In the future, the researchers aim to investigate the molecular mechanisms behind this syndrome through experiments. This deeper understanding is intended to enhance our knowledge of the condition.provide valuable insights into the biological processes that may eventually lead to targeted treatments,” explained Heather Mefford, MD, PhD, from the Center for Pediatric Neurological Disease Research at St. Jude Children’s Research Hospital. Mefford, who was not part of the study, emphasized the significance of the discovery of mutations in non-coding genes such as RNU4-2, which has been overlooked in the field. This finding underscores the importance of expanding the focus beyond coding genes and exploring non-coding regions for potential breakthroughs in understanding and treating neurodevelopmental disorders.
The article discusses the discovery of new genetic causes that could lead to new ways of diagnosing and researching medical conditions. The paper, titled “Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders,” was authored by Chantal Thys (KU Leuven, Belgium); Ian R. Berry, MD (University of Bristol, UK); Joanna Jarvis, MD (Birmingham Womens’ Hospital, UK); Els Ortibus, MD, PhD (KU Leuven, Belgium); Andrew D. Mumford, MD (University of Bristol, UK); and Kathleen Freson, PhD (KU Leuven, Belgium). The research received support from NIH awards R01HL161365 and R03HD11149.2.Â
