RT Journal Article SR Electronic T1 De novo mutations in regulatory elements cause neurodevelopmental disorders JF bioRxiv FD Cold Spring Harbor Laboratory SP 112896 DO 10.1101/112896 A1 Patrick J. Short A1 Jeremy F. McRae A1 Giuseppe Gallone A1 Alejandro Sifrim A1 Hyejung Won A1 Daniel H. Geschwind A1 Caroline F. Wright A1 Helen V. Firth A1 David R. FitzPatrick A1 Jeffrey C. Barrett A1 Matthew E. Hurles A1 on behalf of the DDD study YR 2017 UL http://biorxiv.org/content/early/2017/03/13/112896.abstract AB 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 (<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.