This proposal addresses two topics of great importance to the autism spectrum disorder (ASD) community: mechanisms of variable clinical expression of ASD and mechanisms underlying conditions co-occurring with ASD, including seizures, attention, and anxiety disorders. Autism is common in the United States, affecting 1 in 66 children (it is four times more common in males). It is also highly variable with regard to its causes, associated symptoms, and outcomes. A known genetic risk factor for ASD is found in the male sex chromosome disorder, 47,XYY syndrome (XYY), in which affected males have two instead of one Y chromosome. XYY occurs in one out of a thousand males but has been reported in up to 1 in 100 males with ASD. Approximately one-third of males with XYY satisfy diagnostic criteria for ASD (XYY+ASD), yet the association between XYY and ASD is understudied.
This proposed project will highlight XYY, a compelling model for ASD in males, and will provide unique insight into the effects of the extra Y chromosome on male brain development and behavior. XYY accounts for a relatively small subset of the total ASD population; however, ASD-related behavioral and neuroimaging measures are similar in both the narrower XYY+ASD and the broader general ASD groups. This overlap between XYY and ASD suggests the powerful effects of increased Y chromosome gene dosage on brain development. Understanding the relationships among genes, brain, and behavior in ASD has been made difficult by the high variability in genetic causes of autism and in features of autism. This problem can be improved by determining the clinical features and brain imaging measurements for a genetically defined ASD subgroup such as XYY, as has already been demonstrated with fragile X syndrome.
In this 2-year study, we will recruit three age-matched groups of 6- to 16-year-old boys: 20 with XYY and ASD (XYY+ASD), 20 with idiopathic autism (ASD-I), and 20 typically developing controls. We will compare the behavioral and brain imaging findings in the three groups of boys. Our goals are to examine the behavioral and brain imaging markers of ASD and specifically to compare the variance (variability across people) of these measurements in XYY+ASD with those in ASD-I. Having established the level at which boys with XYY+ASD have more uniform imaging findings, the mechanism underlying these measures will be examined via analysis of key brain neurotransmitters using MRI (magnetic resonance imaging) to study brain chemistry. Finally, the associations between these brain measures and the clinical/behavioral features will be identified, including conditions co-occurring with ASD (seizures, attention, and anxiety disorders). The proposed multidisciplinary (expertise in ASD, genetic disorders, and neuroimaging) study of boys with XYY, where affected individuals have a well-defined genetic background (two copies of Y chromosome genes), provides an exciting and rare opportunity for examining the critical contributions of genetic and behavioral factors to their ASD features. Combining the behavioral analysis and sophisticated brain imaging approaches in this study is not only innovative, but is also critical for understanding how ASD develops in this genetically defined model of autism. Results from this study will also add important clinical information to guide clinicians, genetic counselors, psychologists, and educators and will lead to improved diagnostic information and earlier diagnosis and interventions in boys with XYY. Better understanding of the brain mechanisms in boys with XYY and ASD will enlighten our understanding of the broader autism spectrum and will act as a roadmap to basic neuroscientists and the medical community researching the underlying biophysical causes of autism. This innovative research will result in new bidirectional insights ("bench to bedside") into brain development and behavior that will advance our understanding of ASD-associated brain biological mechanisms, relevant biomarkers (useful for diagnosis, as well as guiding therapies), other symptoms such as seizures and anxiety, and new treatments.