16p11.2 deletion is one of the most influential copy number variations (CNVs) associated with autism spectrum disorder (ASD). Previous studies have investigated the pathophysiology of 16p11.2 deletion both in vitro and in vivo, and have identified features such as NMDAR dysfunction, excitation-inhibition imbalance, transcriptional dysregulation, and impaired cortical development. However, little is known about the transcriptional profiles of human neural cells. Here, we constructed an isogenic human embryonic stem (hES) cell model with 16p11.2 deletion using a CRISPR/Cas9 system and performed transcriptome analyses of hES-derived 2-dimensional neural cells. We identified several characteristics which may correlate with the neuropathology of 16p11.2 deletion: predisposition to differentiate into neural lineages, enhanced neurogenesis, and dysregulation of G protein-coupled receptor signaling and RAF/MAPK pathway. We also found upregulation of fragile X mental retardation protein (FMRP) target genes including GRM5, which is implicated as a common trait between 16p11.2 deletion and fragile X syndrome. Extending our knowledge into other ASD models would help us to understand the molecular pathology of this disorder.

16p11.2 缺失是与自闭症谱系障碍 (ASD) 相关的最具影响力的拷贝数变异 (CNV) 之一。以前的研究已经在体外和体内研究了 16p11.2 缺失的病理生理学，并确定了 NMDAR 功能障碍、兴奋抑制失衡、转录失调和皮质发育受损等特征。然而，人们对人类神经细胞的转录谱知之甚少。在这里，我们使用 CRISPR/Cas9 系统构建了一个具有 16p11.2 缺失的同基因人类胚胎干 (hES) 细胞模型，并对 hES 衍生的二维神经细胞进行了转录组分析。我们确定了可能与 16p11.2 缺失的神经病理学相关的几个特征：分化为神经谱系的倾向、神经发生增强以及 G 蛋白偶联受体信号传导和 RAF/MAPK 通路的失调。我们还发现脆性 X 智力低下蛋白 (FMRP) 靶基因的上调，包括 GRM5，这被认为是 16p11.5 之间的共同特征。2 缺失和脆性 X 综合征。将我们的知识扩展到其他 ASD 模型将帮助我们了解这种疾病的分子病理学。