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Subset of Neurodevelopmental Disorder Cases Linked to Regulatory Element Mutations

NEW YORK (GenomeWeb) – De novo mutations in some fetal brain-expressed regulatory elements contribute to a small significant subset of undiagnosed neurodevelopmental disorder cases, new research suggests.

As they reported online today in Nature, researchers from the UK and the US used targeted sequencing to assess sequences for suspected regulatory elements in more than 7,900 individuals with severe, undiagnosed developmental disorders, who were recruited (along with their parents) for a Deciphering Developmental Disorders (DDD) study.

Based on de novo mutation patterns across 4.2 megabases of sequence per participant — spanning thousands of highly conserved non-coding elements, enhancer verified through prior studies, or suspected heart enhancers — the team identified an over-representation in such mutations in the set of regulatory elements that was highly conserved over evolutionary time and active during fetal brain development.

"Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements in this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders," senior author Matthew Hurles, a group leader in the genetics of developmental disorders at the Wellcome Trust Sanger Institute, and his colleagues wrote.

Past estimates have suggested that pathogenic de novo mutations in protein-coding sequences are likely a factor in more than 40 percent of severe developmental disorder cases, he and his co-authors noted. But while non-coding variants have been implicated in several other conditions, their role in genetically heterogeneous neurodevelopmental conditions "has not been firmly established."

To explore non-coding contributions to developmental conditions, the researchers performed targeted sequencing on samples from 7,930 individuals with severe, undiagnosed developmental disorders, focusing on 4.2 megabases of sequence, more than 4,300 non-coding elements that are highly conserved over evolutionary time, almost 600 more enhancers that were previously validated in the lab, and more than 1,200 putative heart enhancer sequences. They also considered more than 6 megabases of intronic elements.

For its subsequent analyses, the team took into account non-coding allele frequency shifts related to selection and came up with a catalogue of predicted non-coding element activity across dozens of tissue types, based on documented DNase I hypersensitivity profiles.

The researchers uncovered suspicious protein-coding de novo mutations or inherited developmental disease risk variants in almost 1,700 of the neurodevelopmental cases. Across the cases lacking obvious protein-coding contributors, their analyses led to thousands of fetal brain-expressed conserved non-coding elements where de novo mutations were over-represented in neurodevelopment disorder-affected individuals.

"The excess of [de novo mutations] observed in fetal brain-active [conserved non-coding enhancers] is concentrated exclusively within the 79 percent of exome-negative probands with neurodevelopmental phenotypes," the authors wrote, "with no significant enrichment observed in those without neurodevelopmental phenotypes."

Just a fraction of a percent of de novo mutations in these conserved, brain-active elements seem to prompt neurodevelopmental conditions in a dominant manner, the researchers reported. But in undiagnosed neurodevelopmental disorder cases without explanatory changes in protein-coding sequences, they put the odds of a pathogenic de novo mutation in the conserved elements from the fetal brain at anywhere from about 1 percent to 3 percent.

"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," Hurles said in a statement. "This will be made possible, in part, by involving larger numbers of families in our studies."