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Nature. 2018 Mar 29;555(7698):611-616. doi: 10.1038/nature25983. Epub 2018 Mar 21.

De novo mutations in regulatory elements in neurodevelopmental disorders.

Author information

1
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
2
Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
3
Center for Autism Research and Treatment, Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
4
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
5
Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Level 4, Royal Devon & Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK.
6
East Anglian Medical Genetics Service, Box 134, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
7
MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.

Abstract

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.

PMID:
29562236
PMCID:
PMC5912909
DOI:
10.1038/nature25983
[Indexed for MEDLINE]
Free PMC Article

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