De novo mutations in regulatory elements cause neurodevelopmental disorders
Patrick J. Short,
Jeremy F McRae,
Daniel H. Geschwind,
Caroline F. Wright,
Helen V. Firth,
David R. FitzPatrick,
Jeffrey C Barrett,
Matthew E Hurles,
on behalf of the DDD study
Posted 13 Mar 2017
bioRxiv DOI: 10.1101/112896 (published DOI: 10.1038/nature25983)
Posted 13 Mar 2017
De novo mutations in hundreds of different genes collectively cause 25-42% of severe developmental disorders (DD). The cause in the remaining cases is largely unknown. The role of de novo mutations in regulatory elements affecting known DD-associated genes or other genes is essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 DD patients. Here we show that de novo mutations in highly conserved fetal-brain active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant two-fold enrichment of recurrently mutated elements. We estimate that, genome-wide, de novo mutations in fetal-brain active elements are likely to be causal for 1-3% of patients without a diagnostic coding variant and that only a small fraction (<2%) of de novo mutations in these elements are pathogenic. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasise the importance of combining functional and evolutionary evidence to delineate regulatory causes of genetic disorders.
- Downloaded 2,051 times
- Download rankings, all-time:
- Site-wide: 3,222 out of 83,521
- In genetics: 256 out of 4,398
- Year to date:
- Site-wide: 79,003 out of 83,521
- Since beginning of last month:
- Site-wide: 68,056 out of 83,521
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!