TY - JOUR T1 - <em>De novo</em> mutations in regulatory elements cause neurodevelopmental disorders JF - bioRxiv DO - 10.1101/112896 SP - 112896 AU - Patrick J. Short AU - Jeremy F. McRae AU - Giuseppe Gallone AU - Alejandro Sifrim AU - Hyejung Won AU - Daniel H. Geschwind AU - Caroline F. Wright AU - Helen V. Firth AU - David R. FitzPatrick AU - Jeffrey C. Barrett AU - Matthew E. Hurles AU - on behalf of the DDD study Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/03/13/112896.abstract N2 - Summary 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 fetaLbrain active elements are likely to be causal for 1-3% of patients without a diagnostic coding variant and that only a small fraction (&lt;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. ER -