UNDERSTANDING SEX DIFFERENCES IN AUTISM SPECTRUM DISORDER

Abstract

Autism spectrum disorder (ASD) is diagnosed more frequently in boys than in girls, at ratios of approximately 3-4:1. There is increasing appreciation that behavioral features, genetic risk factors, developmental paths, and treatment response differ across sexes, and girls with ASD remain an understudied group. Clare Harrop, PhD, examined sex-specific performance in visual attention. Christine Nordahl, PhD, employed fMRI to evaluate sex differences in amygdala structure and function. Dorothy Grice, MD, carried out deep phenotyping of DDX3X syndrome, a major cause of ASD in girls. Donna Werling, PhD, analyzed RNA-sequence data from prenatal and postnatal human prefrontal cortex in males and females. Dr. Harrop showed that visual interactive paradigms produced the largest differences in total attention between the ASD and typically developing (TD) groups; attention was greater when the sex of the subjects and gender of the objects were congruent. Dr. Nordahl demonstrated that global patterns of amygdala functional connectivity show robust sex differences in TD participants, but differences were attenuated in children with ASD; amygdala volume was positively correlated with internalizing behaviors in girls with ASD, but not in boys. Dr. Grice showed that 80% of individuals with DDX3X syndrome met the criteria for intellectual disability, 60% for ASD, and 53% for ADHD. Dr. Werling demonstrated that ASD risk genes were more likely to show female-skewed expression; however, the magnitude of the shifts was minimal. Male-biased expression was enriched for ASD-upregulated immune function–associated genes and for markers of endothelial cells and microglia. Studies of visual attention support the importance of reevaluating prior studies conducted with majority-male samples to consider biological sex and gender. Sex-specific patterns of amygdala development in ASD suggest differing etiologies and may be predictive of differential outcomes and treatment approaches. DDX3X syndrome provides an opportunity to examine genetic pathways to ASD and related phenotypes in girls. Transcriptome analyses indicate that sex effects act downstream from ASD risk genes via interacting pathways. Studies that delineate sex differences in ASD provide deeper understanding of risk pathways and trajectories and opportunities for more specific interventions. The discussants are Meng-Chuan Lai, MD, PhD, and Allison Jack, PhD, who will contextualize the talks to the larger field.