Fig. 1: Cell-type-specific dysregulation of synapse and neurodevelopmental pathways in FCDII.

a, Study workflow. SnRNA-seq was employed to identify transcriptional changes related to epilepsy in FCDII tissues. Genotyping on mutation sites was used to compare Mut. nuclei, which carried the somatic mutation, and Ref. nuclei, where only the reference allele was detected. Integration with spatial resolution linked transcriptional changes to cellular morphology and spatial disorganization. b, Patient cohort overview: ten patients with FCDII (pt1–10) and mTOR pathway mutations in MTOR, DEPDC5 (mTOR repressor) and RHEB (mTOR activator). Dysplastic areas in pt1, -4 and -9 extended to an entire hemisphere, with pt4 and -9 diagnosed with hemimegalencephaly. N/A, not available (no somatic hit identified). c, Left, UMAP of integrated patients and controls, snRNA-seq data with cell-type annotations from a previous study²² (Methods). Dashed lines outline cluster densities. Right, cell-type proportions across controls and patients with focal or hemispherical dysplasia. d, UMAP visualization showing overlapping cell types between control and patient nuclei, with a subset of GluNs enriched in pt8 and pt9. e, Cell-type-specific differential gene expression analysis between focal FCDII and controls. Left, number of DEGs per cell type (significant genes expressed in at least 25% of cells with absolute log₂(FC) > 0.4). Middle, specific and shared DEGs across cell types; examples of DEGs specific to one cell type are indicated. Right, proportion of DEGs specific to one or more cell types. f, Top significant GOs and genes downregulated in FCDII GluNs. CC, corticocortical projection neurons; L, layer.