社交情感和沟通症状是自闭症谱系障碍 (ASD) 的核心，但其严重程度因幼儿而异：一些患有 ASD 的幼儿在很小的时候就表现出不断提高的能力，并发展出良好的社交和语言技能，而其他患有“严重”自闭症的幼儿则一直表现出较低的水平。社交、语言和认知技能，需要终身护理。这些相反的 ASD 社会严重程度亚型和发育轨迹的生物学起源尚不清楚。由于 ASD 涉及早期大脑过度生长和神经元过多，我们测量了 10 名幼儿的 4910 个胚胎期大脑皮质类器官 (BCO) 的大小和生长情况ASD 和 6 个对照（平均测量/受试者 196 个单独的 BCO）。在 2021 年的一批中，我们测量了 10 个 ASD 和 5 个对照组的 BCO。在 2022 年的批次中，我们通过生成和测量来自 6 个 ASD 和 4 个对照受试者的独立批次的 BCO，测试了 BCO 大小和生长效应的可复制性。 BCO 大小是在我们的大型、独一无二的社会症状、社会注意力、社会大脑以及社会和语言心理测量规范数据集（从 N = 266 到 N = 1902 个幼儿）的背景下进行分析的。通过测量类器官发育 1 个月和 2 个月之间的大小变化来检查 BCO 增长率。在细胞水平上检查两个月后的神经发生标记。在分子水平上，我们测量了Ndel1的活性和表达； Ndel1 是细胞周期激活激酶的主要靶标；已知调节细胞周期、增殖、神经发生和生长；在 BCO 水平上，分析显示，2021 年和 2022 年批次的自闭症谱系障碍 (ASD) 中，BCO 大小显着增大了 39% 和 41%。胚胎 BCO 尺寸越大，自闭症谱系障碍 (ASD) 社交症状越严重。 BCO 大小与社会症状之间的相关性在 2021 年批次中为 r = 0.719，在 2022 年重复批次中为 r = 0.873。 ASD BCO 的生长速度比对照快近 3 倍。在细胞水平上，两个最大的 ASD BCO 加速了神经发生。在分子水平上，Ndel1活性与BCO的生长速率和大小高度相关。在自闭症谱系障碍 (ASD) 幼儿中发现了两种 BCO 亚型：一种亚型的 BCO 尺寸非常增大，生长速度和神经发生速度加快；另一种亚型的 BCO 尺寸非常大，生长速度和神经发生速度加快；严重的自闭症临床表型，表现出严重的社会症状、社会注意力减少、认知能力下降、语言和社交智商极低；并显着改变特定皮质社交、语言和感觉区域的生长。第二种亚型的 BCO 增大程度较轻，社交、注意力、认知、语言和皮质差异也较轻。 ASD 幼儿衍生的 BCO 和临床表型的较大样本可能会揭示其他 ASD 胚胎亚型。通过胚胎发生，两种亚型的生物学基础自闭症谱系障碍（ASD）的社交和大脑发育（深度自闭症和轻度自闭症）已经存在并可测量，涉及细胞增殖失调和神经发生和生长加速。自闭症谱系障碍 (ASD) 胚胎 BCO 大小越大，幼儿的社交症状越严重，社交注意力、语言能力和智商下降越严重，社交和语言脑区的生长也越不典型。© 2024。作者）。

Social affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display improving abilities across early ages and develop good social and language skills, while others with "profound" autism have persistently low social, language and cognitive skills and require lifelong care. The biological origins of these opposite ASD social severity subtypes and developmental trajectories are not known.Because ASD involves early brain overgrowth and excess neurons, we measured size and growth in 4910 embryonic-stage brain cortical organoids (BCOs) from a total of 10 toddlers with ASD and 6 controls (averaging 196 individual BCOs measured/subject). In a 2021 batch, we measured BCOs from 10 ASD and 5 controls. In a 2022 batch, we  tested replicability of BCO size and growth effects by generating and measuring an independent batch of BCOs from 6 ASD and 4 control subjects. BCO size was analyzed within the context of our large, one-of-a-kind social symptom, social attention, social brain and social and language psychometric normative datasets ranging from N = 266 to N = 1902 toddlers. BCO growth rates were examined by measuring size changes between 1- and 2-months of organoid development. Neurogenesis markers at 2-months were examined at the cellular level. At the molecular level, we measured activity and expression of Ndel1; Ndel1 is a prime target for cell cycle-activated kinases; known to regulate cell cycle, proliferation, neurogenesis, and growth; and known to be involved in neuropsychiatric conditions.At the BCO level, analyses showed BCO size was significantly enlarged by 39% and 41% in ASD in the 2021 and 2022 batches. The larger the embryonic BCO size, the more severe the ASD social symptoms. Correlations between BCO size and social symptoms were r = 0.719 in the 2021 batch and r = 0. 873 in the replication 2022 batch. ASD BCOs grew at an accelerated rate nearly 3 times faster than controls. At the cell level, the two largest ASD BCOs had accelerated neurogenesis. At the molecular level, Ndel1 activity was highly correlated with the growth rate and size of BCOs. Two BCO subtypes were found in ASD toddlers: Those in one subtype had very enlarged BCO size with accelerated rate of growth and neurogenesis; a profound autism clinical phenotype displaying severe social symptoms, reduced social attention, reduced cognitive, very low language and social IQ; and substantially altered growth in specific cortical social, language and sensory regions. Those in a second subtype had milder BCO enlargement and milder social, attention, cognitive, language and cortical differences.Larger samples of ASD toddler-derived BCO and clinical phenotypes may reveal additional ASD embryonic subtypes.By embryogenesis, the biological bases of two subtypes of ASD social and brain development-profound autism and mild autism-are already present and measurable and involve dysregulated cell proliferation and accelerated neurogenesis and growth. The larger the embryonic BCO size in ASD, the more severe the toddler's social symptoms and the more reduced the social attention, language ability, and IQ, and the more atypical the growth of social and language brain regions.© 2024. The Author(s).