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Developmental biology - Brain Disorders|
Discovery of 'non-gene' neurodevelopment mutations
The study is a positive step towards providing an explanation for children with undiagnosed neurodevelopmental disorders.
Every year in the United Kingdom, thousands of babies are born with errors in their DNA which will dictate they can not develop normally. These genetic changes, or mutations, can lead to conditions such as intellectual disability, epilepsy, autism or heart defects. Due to their rarity, many of these developmental disorders remain undiagnosed.
In 2010 the Deciphering Developmental Disorders (DDD) study was established to use genomics to diagnose children with unknown developmental diseases. So far, around one third of the over 13,000 children in the DDD study have been diagnosed, but two thirds of their families still don't have answers. In this latest study, researchers investigated genetic disorders of the central nervous system, such as developmental brain dysfunction that can lead to impaired learning and language.
They discovered that mutations in regulatory elements, outside of genes, can cause neurodevelopmental disorders. These regulatory elements have been very highly conserved over mammalian evolutionary history, which suggests they play a critical role in early brain development.
"For the first time, we've been able to say how many children with severe neurodevelopmental disorders have damaging genetic changes in parts of the genome called regulatory elements. Of the near 8,000 families we studied, up to 140 children are likely to have these particular mutations that are responsible for their condition. We're getting closer to providing a diagnosis for these families."
To understand the mechanism by which these mutations can cause neurodevelopmental disorders, the mutated regulatory elements must be linked to the genes they target. This can be challenging, as genes and the elements that regulate their expression are often located far apart in the genome.
Dr Matthew Hurles, leader of the DDD Study and lead author from the Wellcome Sanger Institute: "In order to be able to give a genetic diagnosis for these children with neurodevelopmental disorders, we must first associate individual regulatory elements with specific disorders. This will be made possible, in part, by involving larger numbers of families in our studies. Data from the NHS 100,000 Genomes Project, being delivered by Genomics England, could be crucial in providing additional evidence to allow us to define these disorders with sufficient precision to allow diagnoses to be made."
We previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1–3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders. Authors: Patrick J. Short, Jeremy F. McRae, Giuseppe Gallone, Alejandro Sifrim, Hyejung Won, Daniel H. Geschwind, Caroline F. Wright, Helen V. Firth, David R. FitzPatrick, Jeffrey C. Barrett and Matthew E. Hurles.
Funding: This work was supported by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between Wellcome and the UK Department of Health, the Wellcome Sanger Institute (grant WT098051), and the MRC Human Genetics Unit program.
British Society for Genetic Medicine
The British Society for Genetic Medicine (BSGM, http://www.bsgm.org.uk) is an independent umbrella organisation encompassing the Clinical Genetics Society, Association for Clinical Genomic Science, Association of Genetic Nurses and Counsellors and the Foetal and Cancer Genetics Groups, thereby representing the views of approximately 1800 professionals who work as doctors, genetic counsellors, scientists and researchers in supporting families and individuals with genetic or genomic disorders. These professionals work to predict, diagnose, prevent and treat these disorders and have contributed to major research discoveries.
The Wellcome Sanger Institute
The Wellcome Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease. To celebrate its 25th year in 2018, the Institute is sequencing 25 new genomes of species in the UK. Find out more at http://www.sanger.ac.uk or follow @sangerinstitute
Wellcome exists to improve health for everyone by helping great ideas to thrive. We're a global charitable foundation, both politically and financially independent. We support scientists and researchers, take on big problems, fuel imaginations and spark debate. http://www.wellcome.ac.uk
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A research team studied genomes of almost 8,000 children and their parents They focused on genes that control the switching on and off of genes, known as regulatory elements. Image: Public Domain.