Sex differences in autism spectrum disorder: behavioral and sensory phenotypes in humans and mouse models

Sex differences in autism spectrum disorder (ASD) are increasingly recognized, not only in symptom presentation but also in underlying neurobiology and response to environmental factors. However, current diagnostic practices and animal models are male-centric, overlooking female-specific phenotypes and mechanisms. We conducted a multimodal, cross-species study to assess sex-dependent ASD phenotypes. In high-functioning adults with ASD and typically developing (TD) controls, we evaluated self-reported autistic traits, self-reported sensory sensitivity, and clinician-observed behaviors using standardized tools: Autism-Spectrum Quotient, Adolescent/Adult Sensory Profile, and Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). In parallel, we assessed behavioral phenotypes in a paternal 15q11-q13 duplication mouse model (15q dup/+) using open-field, light-dark transition, and augmented reality-based behavioral assays. Among humans, individuals with ASD showed greater self-reported sensory sensitivity and autistic traits than TD individuals. Within the ASD group, female participants reported greater self-reported sensory sensitivity and exhibited lower clinician-rated impairments (ADOS-2) than male participants, despite comparable self-reported autistic traits. No sex differences were found among TD individuals. In contrast, female 15q dup/+ mice exhibited heightened light-related sensory reactivity and reduced exploratory behavior under bright light. These findings suggest that sex differences in light-related sensory reactivity may be more readily detected through behavioral measures in animal models. Our findings underscore the importance of considering sex as a biological and behavioral variable in ASD research. Cross-species, phenotype-oriented approaches that integrate human and animal data may uncover subtle phenotypic variations and enhance sex-informed diagnostics and interventions.