Intellectual disability (ID) is a condition characterized by cognitive impairment and difficulties in adaptive functioning. In our research, we identified two de novo mutations (c.955C>T and c.732C>A) at the KDM2A locus in individuals with varying degrees of ID. In addition, by using the Gene4Denovo database, we discovered five additional cases of de novo mutations in KDM2A. The mutations we identified significantly decreased the expression of the KDM2A protein. To investigate the role of KDM2A in neural development, we used both 2D neural stem cell models and 3D cerebral organoids. Our findings demonstrated that the reduced expression of KDM2A impairs the proliferation of neural progenitor cells (NPCs), increases apoptosis, induces premature neuronal differentiation, and affects synapse maturation. Through ChIP-Seq analysis, we found that KDM2A exhibited binding to the transcription start site regions of genes involved in neurogenesis. In addition, the knockdown of KDM2A hindered H3K36me2 binding to the downstream regulatory elements of genes. By integrating ChIP-Seq and RNA-Seq data, we made a significant discovery of the core genes' remarkable enrichment in the MAPK signaling pathway. Importantly, this enrichment was specifically linked to the p38 MAPK pathway. Furthermore, disease enrichment analysis linked the differentially-expressed genes identified from RNA-Seq of NPCs and cerebral organoids to neurodevelopmental disorders such as ID, autism spectrum disorder, and schizophrenia. Overall, our findings suggest that KDM2A plays a crucial role in regulating the H3K36me2 modification of downstream genes, thereby modulating the MAPK signaling pathway and potentially impacting early brain development.

智力障碍（ID）是一种以认知障碍和适应功能困难为特征的疾病。在我们的研究中，我们在不同程度 ID 的个体中发现了KDM2A基因座的两个从头突变（c.955C>T 和 c.732C>A） 。此外，通过使用Gene4Denovo数据库，我们发现了另外5例KDM2A从头突变的病例。我们发现的突变显着降低了 KDM2A 蛋白的表达。为了研究KDM2A在神经发育中的作用，我们使用了 2D 神经干细胞模型和 3D 大脑类器官。我们的研究结果表明， KDM2A表达减少会损害神经祖细胞 (NPC) 的增殖，增加细胞凋亡，诱导神经元过早分化，并影响突触成熟。通过 ChIP-Seq 分析，我们发现 KDM2A 表现出与神经发生相关基因的转录起始位点区域的结合。此外，KDM2A的敲低阻碍了 H3K36me2 与基因下游调控元件的结合。通过整合 ChIP-Seq 和 RNA-Seq 数据，我们发现核心基因在 MAPK 信号通路中显着富集。重要的是，这种富集与 p38 MAPK 通路特异性相关。此外，疾病富集分析将鼻咽癌和脑类器官的 RNA-Seq 鉴定出的差异表达基因与神经发育障碍（如智力障碍、自闭症谱系障碍和精神分裂症）联系起来。总的来说，我们的研究结果表明KDM2A在调节下游基因的 H3K36me2 修饰中发挥着至关重要的作用，从而调节 MAPK 信号通路并可能影响早期大脑发育。