与自闭症谱系障碍 (ASD) 相关的罕见遗传变异患者中，参与突触功能的基因更为丰富。皮质神经发生失调被认为是自闭症谱系障碍病理生理学中的一种趋同机制，但“突触”自闭症谱系障碍风险基因如何促成这些在突触发生之前出现的表型仍不清楚。在这里，我们发现突触 Ras GTP 酶激活 (RASGAP) 蛋白 1（SYNGAP1，ASD 顶级风险基因）在人放射状胶质细胞 (hRGC) 的顶端域内表达。在 SYNGAP1 单倍体不足的人类皮质类器官模型中，我们发现细胞骨架动力学失调，损害 hRGC 的支架和分裂平面，导致层压破坏和皮质投射神经元加速成熟。此外，我们还证实了 Syngap1 单倍体不足的小鼠模型中祖细胞与神经元的比例不平衡。因此，SYNGAP1 相关的大脑疾病可能是通过非突触机制引起的，这凸显了研究与不同人类细胞类型和发育阶段的神经发育障碍 (NDD) 相关的基因的必要性。© 2023。作者，获得独家许可施普林格自然美国公司

Genes involved in synaptic function are enriched among those with autism spectrum disorder (ASD)-associated rare genetic variants. Dysregulated cortical neurogenesis has been implicated as a convergent mechanism in ASD pathophysiology, yet it remains unknown how 'synaptic' ASD risk genes contribute to these phenotypes, which arise before synaptogenesis. Here, we show that the synaptic Ras GTPase-activating (RASGAP) protein 1 (SYNGAP1, a top ASD risk gene) is expressed within the apical domain of human radial glia cells (hRGCs). In a human cortical organoid model of SYNGAP1 haploinsufficiency, we find dysregulated cytoskeletal dynamics that impair the scaffolding and division plane of hRGCs, resulting in disrupted lamination and accelerated maturation of cortical projection neurons. Additionally, we confirmed an imbalance in the ratio of progenitors to neurons in a mouse model of Syngap1 haploinsufficiency. Thus, SYNGAP1-related brain disorders may arise through non-synaptic mechanisms, highlighting the need to study genes associated with neurodevelopmental disorders (NDDs) in diverse human cell types and developmental stages.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.