TAIPEI, TAIWAN, Jun 30, 2024- In a significant medical breakthrough, researchers from the Icahn School of Medicine at Mount Sinai, in collaboration with the University of Bristol, KU Leuven, and the NIHR BioResource, have identified a new neurodevelopmental disorder caused by mutations in a noncoding gene. This disorder impacts tens of thousands of people worldwide and sheds light on a previously unrecognized genetic cause of intellectual disability (ID).
Intellectual disability involves significant limitations in a person's intellectual functioning and adaptive behaviors. These limitations can affect learning, reasoning, problem-solving, and social and practical skills, often becoming apparent in early childhood.
Noncoding genes, unlike most genes, do not produce proteins. Despite this, they play crucial roles in various biological processes. Over 99% of the genes known to cause neurodevelopmental disorders are protein-coding. However, many cases of intellectual disability remain unexplained even after genetic testing. This led researchers to investigate whether noncoding genes might also be responsible for these conditions.
The researchers utilized whole-genome sequencing data from the U.K.’s National Genomic Research Library. They compared rare genetic variants in 41,132 noncoding genes between 5,529 individuals with ID and 46,401 individuals without ID. Their analysis revealed that RNU4-2 gene, which encodes U4 small nuclear Ribo-Nucleic Acid (U4 snRNA), known to be involved in intron splicing regulation, is strongly associated with intellectual disability.
The study identified de novo (spontaneous) mutations in RNU4-2 in 47 individuals with a syndrome characterized by:
Intellectual disability
Small head size (microcephaly)
Short stature
Low muscle tone (hypotonia)
Seizures
Delayed motor development
The findings were confirmed in additional cohorts, bringing the total number of affected individuals to 73. Notably, 19 of these cases involved new mutations that were not inherited from parents, providing crucial insights into the nature of the disorder. This makes the RNU4-2 gene one of the most common single-gene causes of such disorders, second only to Rett syndrome in the U.K.'s Genomic Medicine Service.
The discovery of RNU4-2’s role in intellectual disability is particularly significant because it highlights the importance of noncoding genes, which have often been overlooked in genetic studies. This finding could revolutionize the diagnosis and understanding of neurodevelopmental disorders, offering new hope for affected families. The researchers plan to delve deeper into the molecular mechanisms behind this syndrome. A better understanding could lead to targeted treatments in the future.
This groundbreaking research marks a pivotal moment in the field of genetics. By continuing to explore the molecular mechanisms of RNU4-2, scientists hope to develop targeted treatments that could significantly improve the quality of life for individuals affected by this disorder. Families affected by intellectual disabilities now have new hope for a diagnosis and potential future therapies.
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