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Researchers at the Icahn School of Medicine at Mount Sinai, alongside international collaborators, have identified a neurodevelopmental disorder caused by mutations in a single non-coding gene. The discovery, published in the May 31 issue of Nature Medicine, sheds light on a condition affecting tens of thousands of people worldwide and promises to enhance clinical diagnostic services for patients with neurodevelopmental disorders.
The team, which included scientists from the University of Bristol, KU Leuven, and the NIHR BioResource at the University of Cambridge, conducted a rigorous genetic analysis revealing that mutations in a small non-coding gene, RNU4-2, lead to developmental symptoms previously not attributed to a distinct genetic disorder. Non-coding genes, which do not produce proteins, have often been overlooked in genetic studies. This research utilized whole-genome sequencing data from the UK’s National Genomic Research Library, comparing rare genetic variants in 41,132 non-coding genes between 5,529 individuals with intellectual disability and 46,401 controls.
“This discovery is exceptionally unusual and significant, as it ranks second only to Rett syndrome among single-gene causes of neurodevelopmental disorders,” said Dr. Daniel Greene, the study’s first author and Assistant Professor of Genetics and Genomic Sciences at Icahn Mount Sinai. “Our findings highlight the importance of considering non-coding genes in genetic analyses.”
Neurodevelopmental disorders, often manifesting before grade school, impact personal, social, academic, or occupational functioning. Intellectual disability specifically involves significant limitations in intellectual and adaptive functioning. More than 99 percent of genes linked to such disorders encode proteins, but the researchers hypothesized that non-coding genes could also harbor impactful mutations.
“The genetic changes we found affect a very short gene, only 141 units long, but this gene plays a crucial role in gene splicing, a basic biological function present in all animals, plants, and fungi,” explained Dr. Ernest Turro, the study’s senior author. “Most people with a neurodevelopmental disorder do not receive a molecular diagnosis following genetic testing. Thanks to this study, tens of thousands of families will now be able to obtain a molecular diagnosis for their affected family members.”
Heather Mefford, MD, PhD, of the Center for Pediatric Neurological Disease Research at St. Jude Children’s Research Hospital, who was not involved with the research, noted the significance of the findings. “This study’s discovery of mutations in non-coding genes, especially RNU4-2, highlights a significant and previously overlooked cause. It underscores the need to look beyond coding regions, which could reveal many other genetic causes, opening new diagnostic possibilities and research opportunities.”
The researchers plan to explore the molecular mechanisms underlying this syndrome to gain deeper biological insights that could lead to targeted interventions.
The paper, titled “Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders,” includes contributions from Chantal Thys, Ian R. Berry, MD, Joanna Jarvis, MD, Els Ortibus, MD, PhD, Andrew D. Mumford, MD, and Kathleen Freson, PhD. The work was supported by NIH awards R01HL161365 and R03HD111492.
