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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 these are caused by changes to DNA.
However, until now, around 60 percent of individuals with these conditions do not know the specific DNA change that causes their disorder.
The new findings 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.
The discovery was 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, each individuals’ entire genomes is sequenced. This enables changes in genes that do not make proteins, like RNU4-2, to be analysed as well.
In other words, there are major insights to be found in the 98.5 percent of the genome that does not encode proteins.
The study was led by Nicola Whiffin, Associate Professor at the Big Data Institute and Centre for Human Genetics at the University of Oxford. The team 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 active in the developing brain, and changes in this gene will 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 percent of all NDD cases globally, potentially impacting hundreds of thousands of families across the world.
Commenting on the research, Professor Whiffin says: “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.”
The research appears in the science journal Nature, titled “De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.”