Relationship of 47,XYY Syndrome to ASD: Diffusion MRI Findings

Background: 47,XYY syndrome (XYY) occurs in ~0.1% of population-based males but is reported in 1% of males with autism spectrum disorders (ASD). Approximately 19-36% of males with XYY are reported to satisfy ASD diagnostic criteria. Diffusion tensor MRI (DTI) has implicated widespread differences in white matter (WM) microstructure in ASD versus TD children, with the predominant pattern of compromised WM of the frontal and temporal lobes. We compared these WM patterns of results in boys with XYY versus our previous findings in boys with idiopathic ASD (ASD-I).

Objectives: Using innovative neuroimaging biomarkers derived from DTI, we compared imaging results from boys with XYY with (XYY+ASD) and without ASD (XYY-ASD) versus age-matched typically developing boys (TD).

Methods: We performed ASD, cognitive, social function, and language evaluations and neuroimaging in 12 boys with karyotype-confirmed XYY (mean age 11.5±2.4y), using the Social Communications Questionnaire (SCQ), the Social Responsiveness Scale (SRS), and the Autism Diagnostic Interview-Revised (ADI-R). Verbal abilities were evaluated with the Differential Ability Scales (DAS). DTI results were acquired at Thomas Jefferson University on a Philips 3.0T MRI system and were used in combination with anatomical data to calculate mean diffusivity (MD) and anisotropy along select WM tracts from 12 XYY boys and 12 age-matched TD boys (mean age 11.6±1.8y). The DTIs were post-processed using the DTIstudio software and the tracks of the left arcuate fasciculus (AF) were determined by placing seed and target regions of interest in selected neuroanatomic locations.

Results: Six of the 12 XYY boys (50%) met ASD diagnostic criteria (XYY+ASD), based on thresholds of SCQ, SRS, and ADI-R. Comparison of the XYY+ASD versus XYY-ASD demonstrated that verbal function on the DAS verbal cluster was similar but one-word receptive language (ROWPVT) was relatively impaired in XYY+ASD and their behavioral outcomes on the Child Behavior Scale (CBCL) and SRS were worse. Both XYY groups differed from TD controls on these measures of language and social function, supporting group-wide findings of increased ASD risk in XYY, with differences in aspects of language, behavior, and social function between XYY+ASD and XYY-ASD. The averaged MD in the left AF for each group were: 8.18x10−4mm2/s (XYY+ASD), 7.94 x10−4mm2/s (XYY-ASD), and 7.85 x10−4mm2/s (TD). This 4.2 % increase in XYY+ASD is similar to the previously reported pattern seen in idiopathic ASD relative to TD controls, suggesting the sensitivity of this ASD marker within both the XYY as well as the general ASD-I populations.

Conclusions: These data support the group-wide findings of increased ASD risk in XYY and the overlap in imaging findings in XYY+ASD versus ASD-I. Elevated MD in the left hemisphere AF was observed in boys with XYY+ASD, suggesting a potential marker of ASD in XYY. The strong likelihood that increased Y-chromosome dosage and increased risk of ASD are significantly associated deserves further investigation and may identify a genetic component of the marked male predominance in ASD.