Discovery of genes linked to neurodevelopmental disorders offers hope for future treatments

An international collaboration led by scientists at the University of Manchester has discovered a gene with a mutation that could cause neurodevelopmental disorders (NDDs) in hundreds of thousands of people around the world.

According to a study led by Oxford University, Published in Natureis an exciting first step toward developing future treatments for a disorder that has devastating effects on learning, behavior, speech and movement.

Most NDDs are thought to be genetic, caused by changes in DNA, but to date, approximately 60% of people with NDD do not know the specific DNA changes that cause their disorder.

Nearly all of the genes known to be involved in NDDs are responsible for making proteins, but the team found that the RNU4-2 gene produces an RNA molecule that plays an important role in how other genes are processed in the cell.

The study estimates that these specific variations in the RNU4-2 gene could explain 0.4% of NDD cases worldwide, potentially affecting hundreds of thousands of families around the world.

Previous studies had only looked at genes that make proteins, but the 100,000 Genomes Project data used by the team enabled them to sequence the entire genome and analyse changes in genes that don't make proteins, such as RNU4-2.

The study was led by Nicola Wiffin, an associate professor at the Big Data Institute and Centre for Human Genetics at the University of Oxford. The team found mutations in the RNU4-2 gene in 115 people with NDD, many of whom had the exact same mutation that adds an extra base to a critical position in the RNA.

Jamie Ellingford, senior research fellow at the University of Manchester and lead genomic data scientist at Genomics England, said: “This is a really powerful discovery and shows how far we have come as a global scientific and clinical community. It's evidence of how we now have the ability to pinpoint all kinds of differences in people's DNA that may lead to disease, allowing us to rapidly connect families and researchers around the world.”

The discovery builds on research jointly led by the Universities of Manchester and Oxford to understand the impact of DNA differences in parts of the human genome that do not directly code for proteins – previously known as “junk DNA” because its function was unknown.

Ellingford said: Computational Science“We hope that the collaboration between genomics and clinical discovery at the University of Manchester will enable future discoveries that will help families and other researchers gain a better understanding of genomic diseases.”

“When the Undiagnosed Network told us about three years ago that there was nothing else they could do, we had resigned ourselves to the fact that we might never know,” said Nicole Sedour, mother of 10-year-old Mia Joy.

“So you can imagine how shocked we were to hear this news. With the information we received, I have had blood tests done to check my iron levels, a DEXA bone scan next week and a referral to an endocrinologist.

“We are so grateful to the research team who worked tirelessly to find this diagnosis. It's one thing to write a paper and analyze all the data, but it's another to see a family with a precious, unique child live it every day. This is where data meets reality. We call RNU4-2 'Rebirth' because our family is being reborn with this new information and hope for the future.”

Professor Wiffin said: “What's most remarkable about this discovery is how frequently changes in this gene cause NDDs. Most of the protein-coding genes involved in NDDs are several thousand DNA bases long. RNU4-2 is around 50 times smaller, yet changes in this gene cause NDDs almost as frequently as these protein-coding genes. The inclusion of RNU4-2 in standard clinical genetic testing will end the diagnostic journey for thousands of NDD patients around the world and bring much-needed hope to their families.”