Autism is a clinically heterogeneous neurodevelopmental disorder characterized by impaired social interactions, restricted interests, and repetitive behaviors. Despite significant advances in the genetics of autism, understanding how genetic changes perturb brain development and affect clinical symptoms remains elusive. Here, we present a multiplex human pluripotent stem cell (hPSC) platform, in which 30 isogenic disease lines are pooled in a single dish and differentiated into prefrontal cortex (PFC) lineages to efficiently test early-developmental hypotheses of autism. We define subgroups of autism mutations that perturb PFC neurogenesis and are correlated to abnormal WNT/βcatenin responses. Class 1 mutations (8 of 27) inhibit while class 2 mutations (5 of 27) enhance PFC neurogenesis. Remarkably, autism patient data reveal that individuals carrying subclass-specific mutations differ clinically in their corresponding language acquisition profiles. Our study provides a framework to disentangle genetic heterogeneity associated with autism and points toward converging molecular and developmental pathways of diverse autism-associated mutations.

自闭症是一种临床上异类的神经发育障碍，其特征是社交互动受损，兴趣受限和行为重复。尽管自闭症的遗传学取得了重大进展，但了解遗传变化如何扰动大脑发育并影响临床症状仍然难以捉摸。在这里，我们介绍了一个多元化的人类多能干细胞（hPSC）平台，其中将30个同基因疾病谱系合并在一个培养皿中，并分化成前额叶皮层（PFC）谱系，以有效地测试自闭症的早期发育假说。我们定义了干扰PFC神经发生并与异常WNT /βcatenin反应相关的自闭症突变亚组。1类突变（27个中的8个）抑制，而2类突变（27个中的5个）增强PFC神经发生。值得注意的是 自闭症患者数据显示，携带亚类特异性突变的个体临床上在其相应的语言习性方面存在差异。我们的研究提供了一个框架，以解决与自闭症相关的遗传异质性，并指出了各种自闭症相关突变的分子和发育途径的融合。