Genetic mutation discovered behind brain development and function disorder that affects thousands around the world

A global collaboration of scientists has discovered a gene whose mutations likely cause neurodevelopmental disorders (NDD) in hundreds of thousands of people worldwide.

Neurodevelopmental disorders are defined as a disturbance in the growth and development of both the brain and the central nervous system, or one without the other.

This condition causes severe developmental delay, and many people diagnosed with it are unable to speak, are fed through a tube and have seizures.

This disorder produces distinctive facial features, such as large, arched ears, full cheeks, and a mouth with upturned corners.

The results of the Oxford University-led study, published in the journal Nature, are an exciting first step towards developing future treatments for disorders that have devastating effects on learning, behaviour, speech and movement.

While most neurodevelopmental disorders (NDDs) are thought to be genetic and caused by changes in DNA, about 60% of individuals with these conditions do not yet know the specific DNA change that causes their disorder.

Almost all genes known to be involved in neurodevelopmental disorders make proteins. However, scientists led by the University of Manchester and the University of Oxford have discovered that the gene RNU4-2 instead makes an RNA molecule that plays an important role in how other genes in cells are processed.

The study estimates that these specific changes in the RNU4-2 gene could explain 0.4% of all cases of neurodevelopmental disorder worldwide, potentially affecting hundreds of thousands of families worldwide.

While previous studies have only looked at genes that make proteins, data from the 100,000 Genomes Project, led by Genomics England and NHS England, which the team used, means they can sequence entire genomes allowing them to analyse changes in genes that do not make proteins, such as RNU4-2.

The team, led by Nicola Wiffen, an associate professor at the Big Data Institute and the Centre for Human Genetics at the University of Oxford, found mutations in RNU4-2 in 115 people with neurodevelopmental disorders, many of whom had the same variant that adds a single extra base at a key site in RNA.

“We now have the ability to identify all the variations in people’s DNA that could be causing disease, and can quickly connect families and researchers from all over the world,” said Jamie Ellingford, a researcher at the University of Manchester and principal genomics data scientist at Genomics England. “We hope that the close alliances between computational science, genomics and clinical discovery at the University of Manchester will enable future discoveries like this to help families and other researchers better understand genomic diseases.”

In the future, scientists hope to use AI tools to identify the disorder from facial features alone. If successful, doctors could diagnose patients with the disorder simply by uploading their photos for analysis, since some countries do not have the means to read entire genomes on a large scale.