Transcriptome-based classification in mice with ASD-risk mutations.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a strong genetic component. Large-scale human genetic studies have identified >1200 ASD-risk genes. We report a sex-balanced atlas of 1008 prefrontal RNA sequencing (RNA-seq) profiles from 17 mouse lines carrying ASD-risk mutations. Our analysis identified two opposing transcriptomic states. The two groups differed in sex bias, regional specificity, developmental stability, cell type remodeling, and responses to fluoxetine and lithium. Single-nucleus RNA-seq revealed broader cell type remodeling in group 1 than in group 2, and cell type-specific modules showed reciprocal associations that mirrored bulk transcriptomic signatures. The framework classifies independent mouse lines and identifies subgroups with conserved synaptic directionality, supporting molecular stratification.