Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University; Changsha, Hunan 410078, China.
Genetic and Metabolic Central Laboratory, Birth Defects Prevention and Control Institute of Guangxi Zhuang Autonomous Region, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, China.
Sci Adv. 2022 Aug 19;8(33):eabo7112. doi: 10.1126/sciadv.abo7112. Epub 2022 Aug 17.
Stress granules (SGs) are cytoplasmic assemblies in response to a variety of stressors. We report a new neurodevelopmental disorder (NDD) with common features of language problems, intellectual disability, and behavioral issues caused by de novo likely gene-disruptive variants in , which encodes an essential regulator of SG assembly. haploinsufficiency in mouse led to social and cognitive impairments accompanied by disrupted neurogenesis and reduced SG formation during early brain development. On the basis of data from 40,853 individuals with NDDs, we report a nominally significant excess of de novo variants within 29 genes that are not implicated in NDDs, including 3 essential genes (, , and ) in the core SG interaction network. We validated that NDD-related de novo variants in newly implicated and known NDD genes, such as , disrupt the interaction of the core SG network and interfere with SG formation. Together, our findings suggest the common SG pathology in NDDs.
应激颗粒（SGs）是对各种应激源的细胞质组装。我们报告了一种新的神经发育障碍（NDD），其具有语言问题、智力障碍和行为问题的共同特征，这些问题是由编码 SG 组装的必需调节剂的新生可能基因破坏性变异引起的。 在小鼠中杂合不足导致社交和认知障碍，伴有神经发生障碍和早期大脑发育过程中 SG 形成减少。基于 40853 名 NDD 患者的数据，我们报告了在 29 个未涉及 NDD 的基因中，新生变异的数量明显过多，包括核心 SG 相互作用网络中的 3 个必需基因（、和）。我们验证了新涉及的和已知的 NDD 基因（如）中的 NDD 相关新生变异会破坏核心 SG 网络的相互作用并干扰 SG 的形成。总之，我们的研究结果表明 NDD 中存在共同的 SG 病理学。
