New genetic cause of intellectual disability potentially uncovered in 'junk DNA'

Medical illustration of a single strand of messenger RNA in pink. The molecule is slightly twisted and extends across the width of the image. The background is blurred but is a mixture of blue, pink, purple and green colors.
Mutations in a gene that codes for part of a molecular complex in cells could explain some cases of intellectual disability. (Image credit: KATERYNA KON/SCIENCE PHOTO LIBRARY via Getty Images)

Scientists have uncovered a rare genetic cause of intellectual disability in a historically overlooked part of the human genome: so-called junk DNA. 

This knowledge could someday help to diagnose some patients with these disorders, the researchers say. 

An intellectual disability is a neurodevelopmental disorder that appears during childhood and is characterized by intellectual difficulties that impact people's learning, practical skills and ability to live independently. Such conditions affect approximately 6.5 million Americans

Factors such as complications during birth can trigger intellectual disabilities. However, in most cases, the disorders have an underlying genetic cause. So far, around 1,500 genes have been linked with various intellectual disabilities — but clinicians are still not always able to identify the specific cause of every patient's condition. 

Related: Rates of autism diagnosis in children are at an all time high, CDC report suggests

One possible explanation for this gap in knowledge is that previous approaches for reading DNA have only focused on a tiny portion of it. Specifically, they've looked at the roughly 2% of the genome that codes for proteins, known as coding DNA. About 98% of the genome contains DNA that doesn't code for proteins. This DNA was once considered "junk DNA," but scientists are now discovering that it actually performs critical biological functions.

In a new study, published Friday (May 31) in the journal Nature Medicine, scientists used whole-genome sequencing technology to identify a rare genetic mutation within non-coding DNA that seems to contribute to intellectual disability. 

The team compared the whole genomes of nearly 5,530 people who have a diagnosed intellectual disability to those of about 46,400 people without the conditions. These data were gathered from the U.K.-based 100,000 Genomes Project

The researchers discovered that 47 of the people with intellectual disabilities — about 0.85% — carried mutations in a gene called RNU4-2. They then validated this finding in three additional large, independent genetic databases, bringing the total number of cases to 73. 

RNU4-2 doesn't code for proteins but rather for an RNA molecule, a cousin of DNA; RNA's code can either be translated into proteins or stand on its own as a functional molecule. The RNA made by RNU4-2 makes up part of a molecular complex called the spliceosome. The spliceosome helps to refine RNA molecules after their codes are copied down from DNA by "splicing" out certain snippets of the code.

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Close-up image of a scientists' hand as they pipette liquid into a test tube. They are wearing blue lab gloves and a white lab coat. The background is blurred but other lab equipment can be seen

The authors of the new study believe the findings could result in more patients with intellectual disability being accurately diagnosed. (Image credit: Luis Alvarez via Getty Images)

To further determine the prevalence of this new disorder, the team then launched a separate analysis where they looked at the genomes of another 5,000 people in the U.K. who'd been diagnosed with "neurodevelopmental abnormality." This is a term that refers to any deviation from "normal" in the neurodevelopment of a child. 

The team's analysis revealed that, out of those 5,000 people, 21 carried mutations in RNU4-2. That made the mutations the second most common type seen in the overall group, following mutations on the X chromosome known to cause a disorder called Rett syndrome. If changes in RNU4-2 can be confirmed as a cause of intellectual disability, this finding hints that the mutations may contribute significantly to a variety of conditions. 

The new study joins a second that also linked RNU4-2 to intellectual disabilities. The research has opened up "an exciting new avenue in ID [intellectual disability] research," Catherine Abbott, a professor of molecular genetics at the University of Edinburgh in the U.K. who was not involved in either study, told Live Science in an email.

"These findings reinforce the idea that ID can often result from mutations that have a cumulative downstream effect on the expression of hundreds of other genes," Abbott said. RNA molecules that don't make proteins often help control the activity of genes, turning them on or off. The findings also stress the importance of sequencing the whole genome rather than just coding DNA, she said.

The scientists behind the new study say the findings could be used to diagnose certain types of intellectual disability. 

The team now plans to investigate the precise mechanism by which RNU4-2 causes intellectual disabilities — for now, they've only uncovered a strong correlation. 

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Emily Cooke
Staff Writer

Emily is a health news writer based in London, United Kingdom. She holds a bachelor's degree in biology from Durham University and a master's degree in clinical and therapeutic neuroscience from Oxford University. She has worked in science communication, medical writing and as a local news reporter while undertaking journalism training. In 2018, she was named one of MHP Communications' 30 journalists to watch under 30. (