Map published of gene mutations that cause neurodevelopmental disorders

A map showing how all possible genetic changes in a specific gene can affect health is the first of its kind, British scientists say.

The new map, unveiled yesterday, reveals the significance of 90% of previously unexplained genetic changes’ impact on health in a gene linked to neurodevelopmental disorders, according to its developers.

Researchers at the Wellcome Sanger Institute say the mapping of the gene DDX3X could lead to valuable insights into the underlying mechanisms of neurodevelopmental disorders and cancer and speed up diagnosis and bring new avenues for treatment.

The research team, with colleagues at the University of Cambridge, examined the DDX3X gene, to directly assess the impact of more than 12,000 genetic changes. A quarter of these alterations were identified as stopping the DDX3X protein from working properly.

The open-source findings are published in Nature Communications.

The DDX3X gene has been linked to a specific neurodevelopmental disorder, mainly affecting girls and women, and is typically associated with intellectual disability, developmental delays and seizures.

Genetic changes in the gene have also been linked to some cancers, but it was unclear if this caused too much or too little activity of the DDX3X protein.

In this study, the researchers looked at the impact of all possible genetic changes within the DDX3X gene on protein function and health, including neurodevelopmental disorders and cancer.

They tested thousands of these genetic changes by undertaking saturation genome editing and to understand the effects, they compared the experimental data with health data from the UK Biobank cohort, and from databases of genetic changes seen in people with neurodevelopmental disorders and cancer.

They identified that out of the 12,776 genetic changes, 3,432 prevented the protein from working properly. For most of these genetic changes, doctors had been unable to predict if they affected health.

Using the saturation genome editing the technique, the team found the significance of up to 93% genetic changes for which the impact on health was previously unknown. They also achieved 99% accuracy in pinpointing the DDX3X genetic changes relevant to neurodevelopmental disorders.

This study also found the genetic changes seen in cancer prevent the DDX3X protein from working properly. This finding could help with the development of new cancer treatments targeting the gene.

Study author Dr Sebastian Gerety, of the Wellcome Sanger Institute and University of Cambridge, said: “We currently can read the letters in the genetic code – A, C, T and G – but often do not understand what they mean. Even apparently minor changes can profoundly impact a child’s development in genetic conditions.

“Our approach, which goes beyond computation to assess the effect of mutations, enables us to reliably differentiate between harmless and harmful rare genetic changes.”

Study author Dr David Adams, senior group leader at the Wellcome Sanger Institute, added: “DDX3X is altered in a range of cancers and in particular in childhood brain cancers. Understanding exactly which mutations are disease-causing facilitates diagnosis and can help ensure patients get the most suitable treatment for their disease.”

Dr Elizabeth Radford, author of the study at the Wellcome Sanger Institute and academic clinical lecturer in paediatric neurology at the University of Cambridge, said the team’s freely available insights will enable doctors to interpret genetic tests and diagnose children earlier.

E.J. Radford et al. Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation. Nature Communications 6 December 2023


, , ,

Leave a Reply

Your email address will not be published. Required fields are marked *



Monthly Posts

Our Clients

Practice Index