Two papers have highlighted a role for variants in RNU4-2, which encodes the U4 small nuclear RNA, in neurodevelopmental disorders (NDDs). Both papers used data from the Genomics England 100,000 Genomes Project (100KGP), and identified associations between variants in RNU4-2 and NDDs. Chen et al. mapped variants to an 18-bp region in a highly constrained region of RNU4-2, and further analysis suggested that these disrupt 5′ splice site usage. The variants identified by Greene et al. mapped to two regions of RNU4-2 and associated with a novel NDD characterized by hypotonia, intellectual disability, motor delay, short stature and seizures. Their results were replicated in a further three cohorts. Both teams nominate RNU4-2 as the underlying genetic cause of a substantial proportion of NDDs; Chen et al. estimated that collectively, variants in RNU4-2 could explain up to 0.4% of all NDDs, potentially affecting thousands of people. These results showcase the role of the non-coding genome in driving NDDs and the possibility that other such genes might exist. The next step will be to understand how RNU4-2 variants cause NDDs but, for now, these discoveries will come as hopeful news to people with NDDs who remain without a diagnosis, even after genetic testing.

Original references: Nature https://doi.org/10.1038/s41586-024-07773-7 (2024); Nat. Med. https://doi.org/10.1038/s41591-024-03085-5 (2024)

两篇论文强调了RNU4-2 （编码 U4 小核 RNA）变异在神经发育障碍 (NDD) 中的作用。这两篇论文都使用了英国基因组 100,000 基因组计划 (100KGP) 的数据，并确定了RNU4-2变异和 NDD 之间的关联。陈等人。将变体映射到RNU4-2高度受限区域中的 18 bp 区域，进一步分析表明这些变体破坏了 5' 剪接位点的使用。 Greene 等人发现的变体。映射到RNU4-2的两个区域，并与一种以肌张力减退、智力障碍、运动迟缓、身材矮小和癫痫为特征的新型 NDD 相关。他们的结果在另外三个队列中得到了重复。两个团队都提名RNU4-2为大部分 NDD 的根本遗传原因；陈等人。据估计， RNU4-2的变异总共可以解释高达 0.4% 的 NDD，可能影响数千人。这些结果展示了非编码基因组在驱动 NDD 中的作用以及其他此类基因可能存在的可能性。下一步将是了解RNU4-2变异如何导致 NDD，但就目前而言，这些发现对于即使在基因检测后仍未得到诊断的 NDD 患者来说将是一个充满希望的消息。

Original references: Nature https://doi.org/10.1038/s41586-024-07773-7 (2024); Nat. Med. https://doi.org/10.1038/s41591-024-03085-5 (2024)