Neurodevelopmental disorders have a strong genetic component, but despite widespread efforts, the specific genetic factors underlying these disorders remain undefined for a large proportion of affected individuals. Given the accessibility of exome sequencing, this problem has thus far been addressed from a protein-centric standpoint; however, protein-coding regions only make up ∼1% to 2% of the human genome. With the advent of whole genome sequencing we are in the midst of a paradigm shift as it is now possible to interrogate the entire sequence of the human genome (coding and noncoding) to fill in the missing heritability of complex disorders. These new technologies bring new challenges, as the number of noncoding variants identified per individual can be overwhelming, making it prudent to focus on noncoding regions of known function, for which the effects of variation can be predicted and directly tested to assess pathogenicity. The 3'UTRome is a region of the noncoding genome that perfectly fulfills these criteria and is of high interest when searching for pathogenic variation related to complex neurodevelopmental disorders. Herein, we review the regulatory roles of the 3'UTRome as binding sites for microRNAs or RNA binding proteins, or during alternative polyadenylation. We detail existing evidence that these regions contribute to neurodevelopmental disorders and outline strategies for identification and validation of novel putatively pathogenic variation in these regions. This evidence suggests that studying the 3'UTRome will lead to the identification of new risk factors, new candidate disease genes, and a better understanding of the molecular mechanisms contributing to neurodevelopmental disorders.

中文翻译：

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了解神经发育障碍：3'UTRome 调节变异的前景

神经发育障碍具有很强的遗传成分，但尽管做出了广泛的努力，但对于大部分受影响的个体而言，这些障碍背后的特定遗传因素仍未确定。鉴于外显子组测序的可及性，这个问题迄今已从以蛋白质为中心的角度得到解决。然而，蛋白质编码区仅占人类基因组的 1% 到 2%。随着全基因组测序的出现，我们正处于范式转变之中，因为现在可以询问人类基因组的整个序列（编码和非编码）以填补复杂疾病缺失的遗传性。这些新技术带来了新的挑战，因为每个人识别出的非编码变体的数量可能是巨大的，因此谨慎地关注具有已知功能的非编码区域，可以预测变异的影响并直接测试以评估致病性。3'UTRome 是非编码基因组的一个区域，它完全符合这些标准，并且在寻找与复杂神经发育障碍相关的致病变异时具有很高的兴趣。在此，我们回顾了 3'UTRome 作为 microRNA 或 RNA 结合蛋白的结合位点，或在替代聚腺苷酸化过程中的调节作用。我们详细说明了这些区域导致神经发育障碍的现有证据，并概述了识别和验证这些区域中新的假定致病变异的策略。这一证据表明，研究 3'UTRome 将导致识别新的风险因素、新的候选疾病基因、