Using a similar strategy, Flora Vaccarino, from Yale University, described applying telencephalic organoids to model early developmental trajectories in autism spectrum disorders (ASD). She noted that human-based studies are critical, owing to fundamental differences in cortical development and timing between humans and mice. Concerns with hiPSCs remain, of course, particularly concerning the potential genetic instability of hiPSCs, which show an accumulation of mutations, tracing back in large part to the original fibroblast population: 30% of skin fibroblasts carry one to two large somatic copy number variants (CNVs), and there is wide variability in the frequency of different mosaic mutations among fibroblast cells (15%–0.3%) (Abyzov et al., 2012). Nonetheless, by applying a neuronal differentiation strategy based upon 3D cortical organoids, Vaccarino demonstrated patient-specific molecular and cellular phenotypes in ASD hiPSC-derived neurons. She reported a methodology for generating cortical organoids that are more homogeneous in structure, composed of repeating units of rosettes, and for which RNA sequencing comparison to the BrainSpan dataset revealed closest similarity to early fetal brain tissue. She cautioned that specific transcriptome differences exist between isogenic intact organoids and
