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.

中文翻译：

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神经发育障碍中调节元件的从头突变

我们之前估计，42% 的严重发育障碍患者在编码序列中携带致病性从头突变。从头突变在影响与发育障碍相关基因或其他基因的调节元件中的作用基本上尚未探索。我们在近 8,000 名发育障碍患者中发现了三类推定的调节元件的从头突变。在这里，我们表明高度进化保守的胎儿大脑活性元素的从头突变在神经发育障碍中显着且特别丰富。我们确定了反复突变元素的显着双重富集。我们估计，在全基因组范围内，1-3% 的没有诊断编码变异的患者在胎儿脑活性调节元件中携带致病性从头突变，并且在高度保守的胎儿脑活性元件内所有可能的突变中只有 0.15% 会导致具有主导机制的神经发育障碍。我们的研究结果代表了对调控元件中从头突变对这种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确定遗传疾病调控原因的重要性。