Researchers identify genetic cause of intellectual disability that affects tens of thousands

This discovery will improve clinical diagnostic services for patients with neurodevelopmental disorders.

Through rigorous genetic analysis, the researchers were able to RNU4-2 Intellectual disability causes a range of developmental symptoms that have not previously been linked to a clear genetic disorder. Non-coding genes are parts of DNA that do not produce proteins. Using whole-genome sequence data from the UK National Genomic Research Library, the researchers compared the burden of rare genetic variants in 41,132 non-coding genes between 5,529 unrelated cases with intellectual disability and 46,401 unrelated controls.

“This discovery is significant as it represents one of the most common single-gene genetic causes of this disease, second only to Rett syndrome among patients sequenced by the UK Genomic Medicine Service. Notably, these mutations are typically spontaneous and not inherited, providing important insight into the nature of the disease.”

“We conducted a large-scale genetic association study to identify rare variants in non-coding genes that may be causative of neurodevelopmental disorders,” said lead study author Daniel Green, PhD, assistant professor of Genetics and Genomics Sciences at Icahn Mount Sinai and visiting scholar at the University of Cambridge. “Today, it is extremely rare to find a single gene that has a causative genetic variant in tens of thousands of patients with a rare disease. Our discovery has eluded researchers for years due to a variety of sequencing and analytical challenges.”

More than 99 percent of genes with mutations that cause neurodevelopmental disorders code for proteins. Researchers have hypothesized that non-coding genes, which do not produce proteins, may also harbor mutations that lead to intellectual disability. Neurodevelopmental disorders often manifest before elementary school entry and involve developmental disorders that affect personal, social, academic, or occupational functioning. Intellectual disability specifically includes significant limitations in intellectual functioning (e.g., learning, reasoning, problem solving) and adaptive behaviors (e.g., social and practical skills).

“The genetic change we found affects a very short gene, just 141 units long, but this gene plays a critical role in a fundamental cellular biological function called gene splicing that is present in all animals, plants and fungi,” said study lead author Ernest Turo, PhD, associate professor of genetics and genomic sciences at Icahn Mount Sinai and visiting scholar at the University of Cambridge. “Most people with neurodevelopmental disorders do not receive a molecular diagnosis after genetic testing. Thanks to this study, tens of thousands of families will be able to receive a molecular diagnosis for affected family members, putting an end to many diagnostic journeys.”

Next, the researchers plan to ly investigate the molecular mechanisms underlying this syndrome. This deeper understanding aims to provide biological insights that may lead to targeted interventions in the future.

“What surprised me was that such a common cause of neurodevelopmental disorders has been overlooked in the field because we've focused on coding genes,” says Heather Mefford, MD, PhD, of the Center for Pediatric Neurological Disorders Research at St. Jude Children's Research Hospital, who was not involved in the study. “The discovery of mutations in noncoding genes in this study, specifically RNU4-2, highlights an important cause that has been overlooked and emphasizes the need to look beyond coding regions, which may uncover many other genetic causes and open up new diagnostic possibilities and research opportunities.”

The title of this paper is “Mutations in the U4 snRNA Gene.” RNU4-2 It causes one of the most common monogenic neurodevelopmental disorders.”

The remaining authors of the paper are Chantal Thys (KU Leuven, Belgium), Ian R. Berry, MD (University of Bristol, UK), Joanna Jarvis, MD (Birmingham Women's Hospital, UK), Els Ortibus, MD, PhD (KU Leuven, Belgium), Andrew D. Mumford, MD (University of Bristol, UK), and Kathleen Freson, PhD (KU Leuven, Belgium).

This research was supported in part by NIH grants R01HL161365 and R03HD111492.