Structural and Functional Characteristics of XYY - Relationship to ASD

Background:

47,XYY syndrome (XYY) is a male sex chromosome disorder (two instead of one Y chromosome) associated with significantly increased risk (ranging from 19-50% in pre- and post-natally diagnosed cohorts) of autism spectrum disorder (ASD) diagnosis. While XYY occurs in ~0.1% of males in the general population it is reported in approximately 1% of males with ASD. This increased level of risk coupled with the 4:1 male preponderance in idiopathic ASD (ASD-I) and the recent interest in Y chromosome genes (i.e. NLGN4Y) makes XYY a potentially compelling genetic model of ASD.

Objectives: The focus of this study is to investigate, and potentially disambiguate, the effects of genotype (XYY vs. XY) and clinical phenotype (ASD vs. non-ASD) on neuroimaging measures of structure and function. ASD related neuroimaging measures were contrasted between four groups of boys (6-17 years old), ASD-I, typically developing (TD) and XYY boys meeting (XYY+ASD) and not meeting (XYY-ASD) diagnostic criteria for ASD.

Methods: Neuroimaging data was acquired from 10 XYY+ASD boys (12.8±4.1 years), 7 XYY-ASD (12.4±3.9 years), 16 TD (11.0±3.1 years) and 19 ASD-I (10.2±1.4 years) boys. The neuroimaging protocol consisted of a 3T structural MRI (1mm isotropic resolution), diffusion MRI (b1000s/mm² DTI) and whole cortex magnetoencephalography (MEG) recordings acquired during a passive auditory paradigm (500Hz sinusoidal tones). Statistical methods included an age-covaried 4x1 ANOVA to investigate Group differences and 2x2 age-covaried LMMs to investigate main effects of XYY and/or ASD status. Hemisphere was considered as an additional factor in omnibus LMMs; subsequently hemispheres were interrogated separately.

Results: There were no significant differences between groups, nor main effects of XYY or ASD status on structural MRI measures such as total grey matter volume. Fractional anisotropy values, derived from the white matter of Heschl’s gyrus (as a surrogate for the thalamocortical auditory radiations) showed a strong tendency towards left hemisphere-only reduction of FA as a main effect of XYY status (XYY: FA=0.30+/-0.02; XY: FA=0.35+/-0.01, p=0.08). Commensurately, in the left hemisphere only, evoked responses from auditory cortex showed significantly delayed M100 latency values as a main effect of XYY status (XYY: M100=162+/-8ms; XY: M100=128+/-5ms, p<0.01). Effect of genotype (XYY status) dominated effects of clinical diagnosis (ASD status), but there was a tendency towards an additive interaction (M100 latency was most prolonged in the XYY+ASD group, although the interaction did not reach significance).

Conclusions: The XYY genotype appears to be associated with atypical maturation of auditory pathway white matter, with consequent significant delays in auditory cortex evoked responses. While these phenomena have previously been associated with idiopathic ASD cohorts, our observations implicates genotype as the dominant basis for these structural and functional sequelae.