大脑皮层神经发生的变化与神经发育异常障碍包括自闭症谱系障碍 (ASDs) 有关。除了ASD风险基因外，遗传背景对于皮层神经发生的贡献仍未得到充分研究。我们使用等位基因诱导多能干细胞（iPSC）-衍生的神经前体细胞（NPC）和皮层器官模型，在本研究中报告称，在ASD遗传背景的依赖性下，发现了在一个患有宏颅畸形的ASD个体中发现的PTEN c.403A>C (p.Ile135Leu) 杂合变异体对皮层神经发生进行了失调。在关于神经发生、神经发展和突触信号传递的基因的批量和单细胞水平的转录组分析表明，PTEN c.403A>C 变异和ASD遗传背景影响了这些基因。我们还发现，这个PTEN p.Ile135Leu变异导致了NPC亚型以及深层神经元和上层神经元的过多产生，而这种现象只在ASD遗传背景中出现，而不是在对照的遗传背景中出现。这些发现提供了实验证据，表明PTEN p.Ile135Leu变异和ASD遗传背景都与伴有宏颅畸形的ASD的细胞特征相关。版权所有©2023年美国人类遗传学会。由Elsevier Inc.出版。保留所有权利。

Alterations in cortical neurogenesis are implicated in neurodevelopmental disorders including autism spectrum disorders (ASDs). The contribution of genetic backgrounds, in addition to ASD risk genes, on cortical neurogenesis remains understudied. Here, using isogenic induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) and cortical organoid models, we report that a heterozygous PTEN c.403A>C (p.Ile135Leu) variant found in an ASD-affected individual with macrocephaly dysregulates cortical neurogenesis in an ASD-genetic-background-dependent fashion. Transcriptome analysis at both bulk and single-cell level revealed that the PTEN c.403A>C variant and ASD genetic background affected genes involved in neurogenesis, neural development, and synapse signaling. We also found that this PTEN p.Ile135Leu variant led to overproduction of NPC subtypes as well as neuronal subtypes including both deep and upper layer neurons in its ASD background, but not when introduced into a control genetic background. These findings provide experimental evidence that both the PTEN p.Ile135Leu variant and ASD genetic background contribute to cellular features consistent with ASD associated with macrocephaly.Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.