删除或复制 16p11.2 基因组区域内 30 个基因的拷贝数变异 (CNV) 会在人类中产生一系列具有高外显率的神经发育表型。尽管识别出了这个小区域，但 16p11.2 CNV 导致疾病的机制尚不清楚。需要相关模型，例如人类皮质类器官（hCO）来了解神经发育疾病的人类特异性机制。我们从 17 名患者和对照中生成了 hCO，通过单细胞 RNA 测序分析对 167,958 个细胞进行了分析，揭示了 16p11.2 区域之外与细胞间粘附、神经元投射生长和神经元特异性相关的基因的差异表达。神经发育障碍。此外，16p11.2 缺失综合征类器官表现出 RBFOX1 的 mRNA 和蛋白质水平降低，RBFOX1 基因还可以含有与神经发育表型相关的 CNV。我们发现先前显示受 RBFOX1 调节的基因在 16p11.2 缺失综合征患者的类器官中也受到干扰，从而确定了与神经元发育和自闭症相关的独立 CNV 之间的新联系。总体而言，这项工作表明信号传导趋同，这表明多种罕见神经元疾病可能存在共同的治疗机制。

Copy number variants (CNVs) that delete or duplicate 30 genes within the 16p11.2 genomic region give rise to a range of neurodevelopmental phenotypes with high penetrance in humans. Despite the identification of this small region, the mechanisms by which 16p11.2 CNVs lead to disease are unclear. Relevant models, such as human cortical organoids (hCOs), are needed to understand the human-specific mechanisms of neurodevelopmental disease. We generated hCOs from 17 patients and controls, profiling 167,958 cells with single-cell RNA-sequencing analysis, which revealed neuronal-specific differential expression of genes outside the 16p11.2 region that are related to cell-cell adhesion, neuronal projection growth, and neurodevelopmental disorders. Furthermore, 16p11.2 deletion syndrome organoids exhibited reduced mRNA and protein levels of RBFOX1, a gene that can also harbor CNVs linked to neurodevelopmental phenotypes. We found that the genes previously shown to be regulated by RBFOX1 are also perturbed in organoids from patients with the 16p11.2 deletion syndrome and thus identified a novel link between independent CNVs associated with neuronal development and autism. Overall, this work suggests convergent signaling, which indicates the possibility of a common therapeutic mechanism across multiple rare neuronal diseases.