原发性孤独症谱系障碍（ASD）是高度异质性的，对于受影响个体中的共同生物学过程如何导致症状仍不清楚。在这里，我们使用大脑皮层器官和单细胞转录组学，模拟了13个家庭中患有原发性孤独症谱系障碍的男孩与未受影响的父亲之间前脑发育的改变。转录组变化表明，巨脑和正常头围的患者中的ASD发病机制涉及到背侧皮质板的兴奋性神经元和来自疑似前板的早期生成神经元等其他谱系之间平衡的相反破坏。这种不平衡源于在早期皮质发育过程中驱动细胞命运的转录因子的差异表达。尽管我们没有在患者中发现解释观察到的转录组变化的基因组变异，但已报告的罕见变异影响的ASD风险基因与转录组中被改变的转录本之间存在显著重叠，表明罕见ASD形式和原发性孤独症谱系障碍中发育转录组之间存在一定程度的基因汇聚。© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Idiopathic autism spectrum disorder (ASD) is highly heterogeneous, and it remains unclear how convergent biological processes in affected individuals may give rise to symptoms. Here, using cortical organoids and single-cell transcriptomics, we modeled alterations in the forebrain development between boys with idiopathic ASD and their unaffected fathers in 13 families. Transcriptomic changes suggest that ASD pathogenesis in macrocephalic and normocephalic probands involves an opposite disruption of the balance between excitatory neurons of the dorsal cortical plate and other lineages such as early-generated neurons from the putative preplate. The imbalance stemmed from divergent expression of transcription factors driving cell fate during early cortical development. While we did not find genomic variants in probands that explained the observed transcriptomic alterations, a significant overlap between altered transcripts and reported ASD risk genes affected by rare variants suggests a degree of gene convergence between rare forms of ASD and the developmental transcriptome in idiopathic ASD.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.