Advances in genome editing and induced pluripotent stem cell-derived organoids has made it possible for researchers to recapitulate patient mutations and dissect complex neurodevelopmental disorders, such as autism spectrum disorder (ASD), in vitro. In this issue, Rana Fetit and colleagues model 16p11.2 microdeletions, one of the most common genetic linkages to ASD, in ventral telencephalic organoids. They find that the deletion organoids are not consistently different in size compared with control, but they do show a greater variation in growth rate. They observe larger and more abundant neural rosettes in the 16p11.2 deletion organoids but detect no difference in progenitor proliferation. The authors discover that the cell cycle is longer in the mutant organoids, primarily due to a prolonged G1 phase. The increase in G1 phase is associated with increased expression of TUJI and GAD67, markers of interneuron differentiation, suggesting that neurogenic cell divisions are beginning earlier in the 16p11.2 deletion organoids. Together, these data show that 16p11.2 microdeletions lead to increase variability in neurodevelopment and support a link between premature differentiation into interneurons and ASD.
