Pathogenic de novo mutations in coding DNA have been implicated in neurodevelopmental disorders such as developmental brain dysfunction, which can lead to impaired learning and language. In fact, according to one estimate, 42% of patients suffering these disorders carry mutations in genes that encode proteins. But it has been unclear how many patients, including patients with undiagnosed developmental disorders, may carry “nongene” mutations. Consequently, scientists based at the Wellcome Sanger Institute decided that they would venture into relatively unfamiliar genomic territory, stretches of DNA that consist of regulatory elements. These nongene regions, the scientists reasoned, might have a role in neurodevelopmental disorders.

The scientists studied the genomes of almost 8000 child and parent trios, focusing on genes that encode proteins as well as noncoding parts of the genome, the regulatory elements that control how genes are switched on and off. These regulatory elements have been very highly conserved over mammalian evolutionary history, suggesting that they have a critical role in early brain development.

The Wellcome Sanger team worked with scientists at the NHS Regional Genetics services to show, for the first time, that mutations outside of genes, in regulatory elements, can cause neurodevelopmental disorders. Detailed findings appeared March 21 in the journal Nature, in an article entitled “De novo Mutations in Regulatory Elements in Neurodevelopmental Disorders.”

“Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders,” the article’s authors wrote. “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.”

According to the Wellcome Sanger Institute, the study is a positive step toward providing an explanation for children with undiagnosed neurodevelopmental disorders, including disorders that manifest as intellectual disability, epilepsy, and autism.

In 2010, the Deciphering Developmental Disorders (DDD) study was established to find diagnoses for children with unknown developmental diseases using genomics. So far, around one third of the over 13,000 children in the DDD study have been diagnosed, but two thirds of the families still don't have answers.

In the latest study, researchers investigated genetic disorders of the central nervous system, such as developmental brain dysfunction that can lead to impaired learning and language.

“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,” said Patrick Short, Ph.D., a Wellcome Sanger Institute scientist and first author of the current study. “Of the near 8000 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.

“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,” added Matthew Hurles, Ph.D., leader of the DDD Study and lead author from the Wellcome Sanger Institute. “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.”

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