Nonsyndromic craniosynostosis (nsCS), characterized by premature cranial suture fusion, is considered a primary skull disorder in which impact on neurodevelopment, if present, results from the mechanical hindrance of brain growth. Despite surgical repair of the cranial defect, neurocognitive deficits persist in nearly half of affected children. Therefore, the authors performed a functional genomics analysis of nsCS to determine when, where, and in what cell types nsCS-associated genes converge during development.

The authors integrated whole-exome sequencing data from 291 nsCS proband-parent trios with 29,803 single-cell transcriptomes of the prenatal and postnatal neurocranial complex to inform when, where, and in what cell types nsCS-mutated genes might exert their pathophysiological effects.

The authors found that nsCS-mutated genes converged in cranial osteoprogenitors and pial fibroblasts and their transcriptional networks that regulate both skull ossification and cerebral neurogenesis. Nonsyndromic CS–mutated genes also converged in inhibitory neurons and gene coexpression modules that overlapped with autism and other developmental disorders. Ligand-receptor cell-cell communication analysis uncovered crosstalk between suture osteoblasts and neurons via the nsCS-associated BMP, FGF, and noncanonical WNT signaling pathways.

These data implicate a concurrent impact of nsCS-associated de novo mutations on cranial morphogenesis and cortical development via cell- and non–cell-autonomous mechanisms in a developmental nexus of fetal osteoblasts, pial fibroblasts, and neurons. These results suggest that neurodevelopmental outcomes in nsCS patients may be driven more by mutational status than surgical technique.

非综合征性颅缝早闭 (nsCS) 的特征是颅缝过早融合，被认为是一种原发性颅骨疾病，其中对神经发育的影响（如果存在）是由大脑生长的机械障碍造成的。尽管对颅骨缺损进行了手术修复，但近一半受影响的儿童仍然存在神经认知缺陷。因此，作者对 nsCS 进行了功能基因组学分析，以确定 nsCS 相关基因在发育过程中何时、何地以及在何种细胞类型中聚合。

作者将 291 个 nsCS 先证者父母三人组的全外显子组测序数据与产前和产后神经颅复合体的 29,803 个单细胞转录组整合起来，以了解 nsCS 突变基因何时、何地以及在哪些细胞类型中可能发挥其病理生理学作用。

作者发现 nsCS 突变基因聚集在颅骨骨祖细胞和软脑膜成纤维细胞及其调节颅骨骨化和脑神经发生的转录网络中。非综合征性 CS 突变基因也聚集在与自闭症和其他发育障碍重叠的抑制性神经元和基因共表达模块中。配体-受体细胞-细胞通讯分析揭示了缝合线成骨细胞和神经元之间通过 nsCS 相关的 BMP、FGF 和非典型 WNT 信号通路进行的串扰。

这些数据表明，nsCS 相关的从头突变通过胎儿成骨细胞、软脑膜成纤维细胞和神经元发育关系中的细胞和非细胞自主机制对颅骨形态发生和皮质发育产生同时影响。这些结果表明，nsCS 患者的神经发育结果可能更多地由突变状态而非手术技术驱动。