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.