Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
Nature. 2018 Mar 29;555(7698):611-616. doi: 10.1038/nature25983. Epub 2018 Mar 21.
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.
我们之前估计，42%的患有严重发育障碍的患者携带编码序列中的致病变异体新突变。调节元件中的新突变对与发育障碍相关的基因或其他基因的影响，基本上尚未被探索。我们在近 8000 名患有发育障碍的患者中鉴定了三类假定的调节元件中的新突变。在这里，我们表明，在高度进化保守的胎儿脑活性元件中的新突变在神经发育障碍中显著且特异性富集。我们发现经常发生突变的元件显著富集了两倍。我们估计，在全基因组范围内，没有诊断性编码变异的患者中有 1-3%携带胎儿脑活性调节元件中的致病性新突变，而在高度保守的胎儿脑活性元件内所有可能突变中，仅有 0.15%导致具有显性机制的神经发育障碍。我们的研究结果代表了调节元件中新突变对这组遗传异质性疾病的贡献的可靠估计，并强调了结合功能和进化证据来识别遗传疾病的调节原因的重要性。
