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Map of disease-causing mutations in neurodevelopmental disorders and cancer revealed

Researchers now understand the functional impact of thousands of genetic changes within the DDX3X gene. This could lead to enhanced diagnosis and treatment of various neurodevelopmental disorders and cancers.

Scientists have created the first extensive map showing how all possible genetic changes can affect health in the gene DDX3X, leading to valuable insights into the underlying mechanisms of neurodevelopmental disorders and cancer.

The new technique outperforms rivals that only rely on AI, revealing the significance of 90 per cent of previously unexplained genetic changes’ impact on health. It promises to speed up diagnosis and bring new avenues for treatment.

Harnessing cutting-edge gene editing technologies, researchers from the Wellcome Sanger Institute and their collaborators at the University of Cambridge focused their attention on the DDX3X gene, to directly assess the impact of over 12,000 genetic changes. A quarter of these alterations were identified as stopping the DDX3X protein from working properly.

The findings, published today (6 December) in Nature Communications, are freely available to doctors so that they can be immediately used to help diagnose patients. This will facilitate diagnosis of DDX3X-related neurodevelopmental disorder and may stimulate the development of new treatments.

The researchers are applying this technique at scale to many other genes relevant for neurodevelopmental disorders and cancer, teaming with scientists around the world to form the Atlas of Variant Effect Alliance1 for future discoveries.

Since 2015, the DDX3X gene has been linked to a specific neurodevelopmental disorder, mainly affecting girls and women. DDX3X-related neurodevelopmental-disorder is typically associated with intellectual disability, developmental delays, and often includes features such as seizures2. Genetic changes in the gene have also been previously linked to certain forms of cancer, but it was unclear whether this caused too much or too little activity of the DDX3X protein.

Diagnosing developmental disorders is highly challenging, especially in young children where symptoms may be still developing. Families often have many medical appointments and undergo many tests before they receive a specific diagnosis. Detecting these early through genetic screening can greatly enhance treatment effectiveness and improve quality of life for individuals affected3 but until now there has been limited understanding of which harmful genetic changes to look out for.

In this new study, the Cambridge-based scientists set out to uncover the impact of all possible genetic changes within the DDX3X gene on protein function and health, including neurodevelopmental disorders and cancer.

Unlike computer-based predictive tools, the team directly tested thousands of these genetic changes by artificially altering the genetic code of human cells grown in a dish, in a process known as ‘saturation genome editing’. To understand the effects of having these genetic alterations, 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 3,432 of the 12,776 different genetic changes prevented the protein from working properly. For most of these genetic changes, doctors previously could not predict whether they affected health. Using the technique, the team were able to discover the significance of up to 93 per cent of genetic changes for which the impact on health was previously unknown. They were able to achieve an accuracy of 99 per cent in pinpointing the DDX3X genetic changes relevant to neurodevelopmental disorders.

The study was able to demonstrate that the genetic changes seen in cancer prevent the DDX3X protein from working properly, an important insight that will facilitate the development of new cancer treatments targeting the gene.

“In the context of genetic conditions, even minor changes in the genetic code can have profound implications for a child’s development. Our approach, which goes beyond computation to assess the effect of mutations, overcomes this diagnostic challenge to reliably distinguish between harmless and harmful rare genetic changes. We hope to apply this technique to other genes, unlocking essential insights hidden within our genetic code.”

Dr Sebastian Gerety, author of the study at the Wellcome Sanger Institute and University of Cambridge

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 David Adams, author of the study and senior group leader at the Wellcome Sanger Institute

“Genetic testing is increasingly integrated into patient care, yet our ability to decode the genetic information has not kept pace, preventing families from receiving the full support they need. These freely available insights will empower doctors to interpret genetic tests and diagnose children earlier, enabling timely intervention and improved quality of life for those affected by DDX3X-linked neurodevelopmental disorders.”

Dr Elizabeth Radford, author of the study at the Wellcome Sanger Institute and Academic Clinical Lecturer in paediatric neurology at the University of Cambridge

Clare Millington, mother of three, discovered that her youngest twins, Pip and Alix, were diagnosed with DDX3X-related disorder at the age of 15 in 2015. Inspired by the need for support, Clare joined fellow parents of children with DDX3X-related disorder in the UK to establish a support group, DDX3X Support UK2, providing a vital resource for patients and families affected by the DDX3X mutations.

“For many of our families it took several years to receive a diagnosis, which caused a lot of uncertainty. We are excited by this study which we hope will speed up the diagnosis of DDX3X-related neurodevelopmental disorder, and stimulate further research to improve the care for people who have this condition.”

Clare Millington mother of two children diagnosed with DDX3X-related disorder

More information

Publication

E.J. Radford et al. (2023) ‘Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation.’ Nature Communications. DOI: 10.1038/s41467-023-43041-4

Footnotes

  1. More information on DDX3X-linked disorders and support groups can be accessed via the DDX3X Foundation: https://ddx3x.org/
  1. In addition to genetic testing, clinical evaluations, medical history, imaging studies, and laboratory tests are often used to guide diagnostic decisions.

Data

These data can be accessed here: https://github.com/HurlesGroupSanger/Saturation_Genome_Editing

Funding

This research was supported by Wellcome and the Medical Research Council. For full funding acknowledgements, please refer to the publication.