A global collaboration led by scientists at the University of Oxford has discovered that genetic variants in a specific gene cause a rare neurodevelopmental disorder (NDD).

NDD is a collective term for severe impairments in how the brain functions that impact learning, behaviour, speech, and movement.

Most NDDs are thought to be genetic and caused by changes to DNA, however, to date, around 60% of individuals with these conditions do not know the specific DNA change that causes their disorder.

The findings, published in Nature, offer the first step in longed-for hope for the development of a treatment in the future.

The specific gene is called RNU4-2. While nearly all genes known to be involved in NDD are responsible for making proteins, RNU4-2 is not; instead, it makes an RNA molecule that plays an important role in how other genes are processed in cells.

This discovery was initially made using data from the 100,000 Genomes Project, a study led by Genomics England and NHS England.

While previous studies have only looked at genes that make proteins, in the 100,000 Genomes Project, individuals’ entire genomes are sequenced, enabling changes in genes that don’t make proteins, like RNU4-2, to be analysed too.

The study was an international collaboration, spanning the US, Australia, and Europe, that was led by Nicola Whiffin, Associate Professor at the Big Data Institute and Centre for Human Genetics at the University of Oxford.

Long-awaited hope for families

The team, funded by Novo Nordisk, found mutations in RNU4-2 in 115 people with NDDs, many of whom had the exact same variant which adds a single extra base at an important position in the RNA.

RNU4-2 is very active in the developing brain, and changes in this gene affect how the cell processes other RNA molecules, including those that go on to make proteins. It is the changes to these other proteins that disrupt brain development.

The study estimates that these specific changes in the RNU4-2 gene can explain 0.4% of all NDD cases globally, potentially impacting hundreds of thousands of families across the world.

Professor Whiffin said: “What is most remarkable about this discovery is how often changes in this gene result in NDD. Most protein-coding genes involved in NDD are thousands of DNA bases long. RNU4-2 is around 50 times smaller but changes in this gene are almost as frequent a cause of NDD as these protein-coding genes. Including RNU4-2 in standard clinical genetic testing will end diagnostic odysseys for thousands of NDD patients worldwide and provide long-awaited hope to families.”

Diana Spencer, Senior Digital Content Editor, DDW