In this study, we generated cerebral organoids using iPSCs derived from two XLID patients with loss-of-function mutations of CUL4B. By comparing to their isogenic controls, we demonstrate that CUL4B deficiency results in premature cell cycle exit and precocious neuronal differentiation of neural progenitor cells (NPCs), unbalanced production of deep-layer and upper-layer neurons, increased synapse formation and neuronal hyperexcitability in cerebral organoids. Here, CUL4B is linked to cask-related x-linked intellectual disability.