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New Genetic Cause Of Intellectual Disability Potentially Uncovered In 'junk DNA'

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.

Related: 'Look at all this we don't understand': Study unravels whole new layer of Alzheimer's disease

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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'It's So Traumatic' Says Geordie Shore Star Aaron Chalmers' Ex Talia As She Reveals Ill Son 'didn't Eat For 16 Days'

GEORDIE Shore star Aaron Chalmer's ex Talia has revealed that their son "hasn't eaten for 16 days" after catching a deadly infection.

Oakley, who was born with the rare genetic disorder Apert Syndrome, was rushed to surgery to drain the serious infection from his head.

Aaron Chalmer's ex Talia said the ordeal has been 'traumatic'Credit: instagram

Talia shared an update on her son Oakley's healthCredit: Instagram/talia.Oatway

Last week, the young tot woke from his coma and started breathing on his own for the first time in days.

Mum-of-three Talia has now revealed that her son is in critical care and is awaiting results on whether he'll have to undergo another operation.

Talia shared an emotional video on her Instagram from hospital.

The doting mum told fans: "I've had the team round, basically they have clamped Oakley's lumber drain that's draining fluid from his head out of his lumber.

Mutations In A Non-coding Gene Associated With Intellectual Disability

Enlarge / The spliceosome is a large complex of proteins and RNAs. NCBI reader comments 28

Almost 1,500 genes have been implicated in intellectual disabilities; yet for most people with such disabilities, genetic causes remain unknown. Perhaps this is in part because geneticists have been focusing on the wrong stretches of DNA when they go searching. To rectify this, Ernest Turro—a biostatistician who focuses on genetics, genomics, and molecular diagnostics—used whole genome sequencing data from the 100,000 Genomes Project to search for areas associated with intellectual disabilities.

His lab found a genetic association that is the most common one yet to be associated with neurodevelopmental abnormality. And the gene they identified doesn't even make a protein.

Trouble with the spliceosome

Most genes include instructions for how to make proteins. That's true. And yet human genes are not arranged linearly—or rather, they are arranged linearly, but not contiguously. A gene containing the instructions for which amino acids to string together to make a particular protein—hemoglobin, insulin, serotonin, albumin, estrogen, whatever protein you like—is modular. It contains part of the amino acid sequence, then it has a chunk of DNA that is largely irrelevant to that sequence, then a bit more of the protein's sequence, then another chunk of random DNA, back and forth until the end of the protein. It's as if each of these prose paragraphs were separated by a string of unrelated letters (but not a meaningful paragraph from a different article).

In order to read this piece through coherently, you'd have to take out the letters interspersed between its paragraphs. And that's exactly what happens with genes. In order to read the gene through coherently, the cell has machinery that splices out the intervening sequences and links up the protein-making instructions into a continuous whole. (This doesn't happen in the DNA itself; it happens to an RNA copy of the gene.) The cell's machinery is obviously called the spliceosome.

There are about a hundred proteins that comprise the spliceosome. But the gene just found to be so strongly associated with neurodevelopmental disorders doesn't encode any of them. Rather, it encodes one of five RNA molecules that are also part of the spliceosome complex and interact with the RNAs that are being spliced. Mutations in this gene were found to be associated with a syndrome with symptoms that include intellectual disability, seizures, short stature, neurodevelopmental delay, drooling, motor delay, hypotonia (low muscle tone), and microcephaly (having a small head).

Supporting data

The researchers buttressed their finding by examining three other databases; in all of them, they found more people with the syndrome who had mutations in this same gene. The mutations occur in a remarkably conserved region of the genome, suggesting that it is very important. Most of the mutations were new in the affected people—i.E. Not inherited from their parents—but there was one case of one particular mutation in the gene that was inherited. Based on this, the researchers concluded that this particular variant may cause a less severe disorder than the other mutations.

Many studies that look for genes associated with diseases have focused on searching catalogs of protein coding genes. These results suggest that we could have been missing important mutations because of this focus.

Nature Medicine, 2024. DOI: 10.1038/s41591-024-03085-5

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