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.
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We thank the families for their participation and patience; the DDD study clinicians, research nurses and clinical scientists in the recruiting centres for their hard work and perseverance on behalf of families; the Exome Aggregation Consortium and Genome Aggregation Database (http://gnomad.broadinstitute.org/) for making their data and code available; S. Gerety, G. Elgar, S. Aerts, and D. Svetlichnyy for discussions; H. Roest Crollius and L. Moyon for help with gene target prediction; J. Mudge and A. Frankish for help in annotating CNEs; and the Sanger HGI and DNA pipelines teams for their support in generating and processing the data. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the UK Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the UK Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee and GEN/284/12, granted by the Republic of Ireland Research Ethics Committee). D.R.F. is funded through an MRC Human Genetics Unit program grant to the University of Edinburgh. D.H.G is funded through 1U01 MH105666 and 1R01 MH110927 (psychENCODE consortium). A.S. is supported by the FWO (Postdoctoral Fellow number 12W7318N).
Extended data figures
This file contains Supplementary Tables 1-3 comprising: (1) Median depth of coverage in 7,930 individuals for each targeted non-coding element and protein-coding exon. It includes chromosome, start, end, and median coverage of each element. (2) Description of the recurrently mutated clusters of conserved non-coding elements. It includes a numerical id for each cluster, the genomic coordinates of the elements in the cluster, number of observed de novo mutations, the genomic coordinates of the observed DNMs, and the p-value of the of observation. (3) All of the individual elements identified as recurrently mutated. It includes the genomic coordinates of the element, annotation as ‘Conserved’ or ‘Enhancer’, the number of observed de novo mutations, the genomic location of the mutations observed, p-value of the of observation, the nearest gene, and any target genes identified by Hi-C in fetal brain.