Autism spectrum disorder (ASD) is heterogeneous at every level, from behavior to molecular pathways, limiting the value of subgrouping schemes built on surface phenotypes alone. We synthesize evidence that biologically anchored subtypes, defined by convergent genetics, developmental timing, and brain-body crosstalk, offer a tractable path to precision medicine. Leveraging advances in large-scale genomic resources and computational analytics, we propose a multi-axis framework: (i) genetic architecture spanning rare variants and polygenic load, (ii) developmental windows from mid-gestation to infancy divergence and regression, and (iii) brain-body interactions shaping plasticity and symptom expression. This framework enables mechanism-guided therapeutic strategies through biomarker-stratified enrollment, target-engagement readouts, and circuit-anchored outcomes. Preclinical platforms, genetically engineered mice and patient-derived induced pluripotent stem cells (iPSCs), demonstrate convergence onto limited synaptic and connectivity "neurotypes," enabling causal links from gene to circuit to behavior and proof-of-concept rescue. We close with priorities: standardized multi-platform characterization, decision tools linking subtype labels to interventions, and stratified trials that co-report clinical and biological endpoints, with ethical guardrails to ensure early stratification expands opportunity while advancing individualized care.
Choi et al. (2025) studied this question.