Differential functional neural circuitry behind autism subtypes with marked imbalance between social-communicative and restricted repetitive behavior symptom domains

Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and is underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here we developed a phenotypic stratification model that makes highly accurate (96-98%) out-of-sample SC=RRB, SC>RRB, and RRB>SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n=509), we find replicable somatomotor-perisylvian hypoconnectivity in the SC>RRB subtype versus a typically-developing (TD) comparison group. In contrast, replicable motor-anterior salience hyperconnectivity is apparent in the SC=RRB subtype versus TD. Autism-associated genes affecting astrocytes, excitatory, and inhibitory neurons are highly expressed specifically within SC>RRB hypoconnected networks, but not SC=RRB hyperconnected networks. SC-RRB balance subtypes may indicate different paths individuals take from genome, neural circuitry, to the clinical phenotype.