Autism-Risk Mutations Form Two Opposing Transcriptomic Clusters in Mouse Prefrontal Cortex

The team generated and compared more than 1,000 prefrontal cortex transcriptomes across mutations affecting synaptic, transcriptional, and signaling genes. Single-nucleus profiling of roughly one million nuclei confirmed the two-group distinction extended across multiple cell types. Sex and developmental stage modulated assignment in seven lines, while the pattern weakened markedly in the hippocampus, indicating context dependence rather than fixed gene categories.

This framework reframes autism genetic heterogeneity as convergence onto limited molecular states rather than uniform pathology. Differential responses to fluoxetine and lithium between groups suggest the clusters may predict drug sensitivity, yet the study remains observational and limited to early postnatal windows in rodents. No human data or clinical endpoints were assessed.

Future work must test whether analogous subgroups exist in human postmortem tissue or induced pluripotent stem cell models and whether they correlate with behavioral trajectories or treatment outcomes in prospective cohorts. Without such validation, therapeutic stratification remains speculative.