Transcriptomic changes in Tatton-Brown-Rahman Syndrome models of neuronal development

Human pluripotent stem cell (hPSC) models of Tatton-Brown-Rahman Syndrome (TBRS) were generated (R882H and P904L) and compared to isogenically paired controls (C-WT and WT, respectively). These models were used to specify cells as MGE-like ventral telencephalic neuronal progenitors (V-NPCs) and subsequently differentiate these into cortical GABAergic-like interneurons (V-INs) or to specify cells as dorsally patterned neuronal progenitors modelling the cortical ventricular zone (D-NPCs) and to subsequently differentiate these cells into cortical glutamatergic-like pyramidal neurons (D-INs). Finally, cells were directly reprogrammed from hPSCs to glutamatergic-like pyramidal neurons (iGluts) through overexpression of Neurogenin2. Overall design: For each cell type and cell line, 3-4 biological replicates were generated from independent differentiations of hPSCs and used to compare differences between each TBRS model and the paired isogenic control (R882H vs C-WT and P904L vs WT).