Faulty gene likely to be cause of severe learning difficulties, study finds

A faulty gene is likely to be responsible for many severe learning difficulties, scientists believe after a study they hope will lead to diagnosis tests on the NHS.

On Friday, British experts will apply to have RNU4-2 gene variants added to NHS screening tests, and they have already told several families that their children’s learning difficulties are likely being driven by the mutation.

Severe learning difficulties are intellectual disabilities that occur when the brain does not develop or function properly, leading to below-average intelligence and mental ability and a lack of skills needed for daily living. It often goes hand in hand with conditions such as autism or attention-deficit hyperactivity disorder (ADHD).

But there are no laboratory tests with diagnosis based on an assessment of development, communication, behaviour and social skills.

Scientists now believe that many severe learning difficulties are one disease caused by the malfunctioning gene, and estimate 10,000 and 20,000 cases in Britain could be the result of mutations.

‘Immediate impact’

Dr Andrew Mumford, professor of haematology at Bristol Royal Infirmary, one of the researchers, said: “It’s astounding that we have discovered a genetic illness that is likely to affect that many people.

“This could have an immediate impact. Many families have been on a diagnostic odyssey trying to find an explanation for their child’s condition.

“There is obviously a spectrum where at one end there is a profound intellectual disability, often autism or behavioural problems, with severe motor or sensory disability, while at the other it’s mild.

“This is the real power of genetic testing, to tell families what is going on, to understand the risk to future children, to know what to look out for and to enable families with the same condition to contact each other for mutual support.”

Researchers made the discovery while carrying out genetic analysis using whole-genome sequencing data from 77,539 participants enrolled in the 100,000 Genomes Project, a large UK genetic database created to help researchers identify mutations responsible for diseases with unknown causes.

They discovered that many people with intellectual disabilities had mutations in RNU4-2 – a gene involved in chopping up and connecting sections of the genetic code together to form instructions, a crucial part of cell biology.

The link was validated using three other large databases, and researchers found 73 cases overall suggesting the gene was driving the neurodevelopmental problems.

Although many of the people with the mutation were found to have severe learning problems, sometimes accompanied by seizures or microcephaly (small heads) others had relatively mild symptoms, and were still able to hold down jobs and live independently.

The gene appears to have mutated spontaneously in most cases, with only a handful of instances where it had been inherited.

‘More treatable’

Dr Ernest Turro, associate professor of genetics and genomic sciences, at Icahn School of Medicine at Mount Sinai, New York, said: “It appears to be one of the most common of the neurodevelopmental disorders caused by errors in a single gene.

“We don’t understand precisely why this particular mutation seems to recur over and over again, why it is that DNA replication seems to make this particular error over and over, but that is very striking as well.

“But it also comes with some benefits potentially in the future, because it means that it will be potentially more feasible to develop a therapy that focuses on those effects individuals who have that particular variant so makes it potentially more treatable in the future.”

Not only would a genetic diagnosis help people understand the cause of the disorder, it would also reassure parents that they would not pass on the problem to future children.

The research was published in Nature Medicine.