Malwade Susmita, Sellgren Carl M, Vasistha Navneet A, Khodosevich Konstantin
Biotech Research and Innovation Center, Faculty of Health, University of Copenhagen, Copenhagen, Denmark.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Biol Psychiatry Glob Open Sci. 2025 Apr 1;5(4):100495. doi: 10.1016/j.bpsgos.2025.100495. eCollection 2025 Jul.
Multiple copy number variations (CNVs) in the human genome are associated with neurodevelopmental disorders (NDDs). Their markedly larger effect sizes and penetrance than common risk variants make them invaluable for investigating the etiology of NDDs.
We integrated >1 million single-cell transcriptomes from multiple datasets, capturing major brain regions and the entire timeline of human brain development. We performed expression-weighted cell-type enrichment analysis of genes contained in 127 CNVs associated with NDDs to identify human brain cell types, brain regions, and periods of development most susceptible to variations in gene dosage.
We identified 3 groups of CNVs differentially enriched in developing cell types. Two groups of CNVs were preferentially expressed during early fetal brain development. While group A could be defined as developing neuron CNVs, group B was precursor CNVs, which were highly enriched in radial glia. Group A CNVs were associated with synaptic signaling, suggesting that synaptic dysfunction observed in NDDs may originate very early during fetal brain development. Group B CNVs were related to cell cycle and suggest dysfunction in proliferation and differentiation of precursor cells. Postnatally, expression of groups A and B genes was enriched in intratelencephalic neurons that integrate cortical information.
Overall, we showed that although NDDs are only diagnosed during childhood or adolescence, the actual effect of genetic mutations on embryonic progenitor cells or early neurons may be strongest during fetal brain development, which could program the cascade for subsequent developmental changes and, together with further postnatal dysfunction, impair brain function.
人类基因组中的多个拷贝数变异（CNV）与神经发育障碍（NDD）相关。它们的效应大小和外显率比常见风险变异明显更大，这使得它们在研究NDD的病因方面具有极高价值。
我们整合了来自多个数据集的超过100万个单细胞转录组，涵盖了主要脑区和人类大脑发育的整个时间轴。我们对与NDD相关的127个CNV中包含的基因进行了表达加权细胞类型富集分析，以确定最易受基因剂量变异影响的人类脑细胞类型、脑区和发育时期。
我们鉴定出3组在发育中的细胞类型中差异富集的CNV。两组CNV在胎儿早期脑发育期间优先表达。虽然A组可定义为发育中的神经元CNV，但B组是前体CNV，在放射状胶质细胞中高度富集。A组CNV与突触信号传导相关，这表明在NDD中观察到的突触功能障碍可能在胎儿脑发育的早期就已出现。B组CNV与细胞周期相关，提示前体细胞增殖和分化存在功能障碍。出生后，A组和B组基因的表达在整合皮质信息的脑室内神经元中富集。
总体而言，我们表明，尽管NDD仅在儿童期或青少年期被诊断出来，但基因突变对胚胎祖细胞或早期神经元的实际影响在胎儿脑发育期间可能最为强烈，这可能为后续发育变化设定级联反应，并与出生后的进一步功能障碍一起损害脑功能。
