KMT2C Knockdown impairs neuronal differentiation in human induced pluripotent stem cell-derived neural stem cells

KMT2C mutations are strongly associated with autism spectrum disorder (ASD). Whereas multiplexed CRISPR screens show complete KMT2C knockout impairs neuronal differentiation, mixed-genotype pools cannot exclude non-autonomous paracrine effects. Furthermore, the functional effect of partial loss of function remains unclear. Here, we targeted KMT2C via shRNA knockdown in single-genotype cultures of human induced pluripotent stem cell-derived neural stem cells. Reduced KMT2C expression decreased the neuronal markers MAP2, HuC/D, and DCX. Our results demonstrate that partial, strictly cell-autonomous KMT2C insufficiency impairs neuronal stem cell differentiation into neurons, modeling the haploinsufficiency observed in patients to reveal a neurodevelopmental pathogenesis for ASD.