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Scientists from the Wellcome Sanger Institute and the University of Cambridge have developed the first extensive map of the DDX3X gene that shows the impacts to the health of any genetic changes in that gene. The team of researchers directly assessed the impact of more than 12,000 genetic changes in the gene finding that roughly a quarter of the alterations prevented the DDX3X protein from working properly and had implications in the development of diseases including neurodevelopmental disorders and cancer.

The study was published in Nature Communications. The researchers have made the data freely available and can be used immediately by clinicians to facilitate the diagnosis of DDX3X-related neurodevelopmental disorder and may pave the way for the creating new treatments targeting the gene and protein.

“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,” said study author Elizabeth Radford, PhD, of the Wellcome Sanger Institute and an academic clinical lecturer in pediatric neurology at the University of Cambridge. “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.”

Diagnosing developmental disorders is typically difficult, especially in very young children whose symptoms are still emerging. The map of the gene should help give people with developmental disorders linked to the gene get an earlier diagnosis and help avoid the so-called “diagnostic odyssey” many patients experience where it can often take years to root out the cause of disease. Early detection can significantly improve the effectiveness of treatments and improve patients’ quality of life.

The new map was developed by a gene editing technique known as “saturation genome editing.” Using this method, the Sanger and Cambridge team were able to direct test thousands of genetic changes by artificially altering the genetic code of human cells grown in the lab. The investigators then compared the genetic changes in DDX3X with health data housed in the UK Biobank cohort and from other databases containing the genetic information of people with neurodevelopmental disorders.

Of the 12,776 genetic changes created in the gene, the investigators identified 3,432 alterations that prevented the DDX3X protein from functioning as it should. The majority of these genetic changes—93%—were previously unknown as having any effect on health. The researchers noted they achieved an accuracy of 99% in pinpointing the DDX3X genetic changes relevant to neurodevelopmental disorders.

The researchers noted they are now applying the saturation genome editing technique at scale to a range of other genes that have been implicated in neurodevelopment disorders and cancer in previous research and are teaming with other researchers around the world to create the Atlas of Variant Effect Alliance to aggregate future discoveries and data.

“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,” noted co-author Sebastian Gerety, PhD, of the Sanger and the University of Cambridge. “As part of the Atlas of Variant Effects Alliance, we will continue to uncover essential insights hidden within our genetic code.”

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