Sex chromosomes and the brain: a study of neuroanatomy in XYY syndrome

Abstract

AIM To assess global and regional brain matter variations associated with XYY syndrome by comparison with Klinefelter syndrome and typical development. METHOD We used two conceptually distinct voxel-based magnetic resonance imaging methods to examine brain structure in young males with XYY syndrome: (1) volumetric comparison to assess global grey and white matter volumes and (2) support vector machine-based multivariate pattern classification analysis to assess regional neuroanatomy. We assessed verbal, non-verbal, and spatial abilities with the Differential Ability Scales (DAS), and we measured autism diagnostic criteria in eight males with XYY syndrome using the Social Responsiveness Scale and the Autism Diagnostic Interview-Revised (ADI-R). RESULTS A comparison of 36 typically developing males (mean age 11y, SD 1y 9mo), 31 males with Klinefelter syndrome (mean age 9y 8mo, SD 1y 8mo), and eight males with XYY syndrome (mean age 11y 6mo, SD 1y 11mo) showed that total white and grey matter volumes were significantly, or nearly significantly, higher in males with XYY syndrome than in males belonging to the other two groups (grey matter: XYY males vs typically developing males, p<0.006; XYY vs males with Klinefelter syndrome, p<0.001; white matter: XYY males vs typically developing males, p=0.061; XYY males vs males with Klinefelter syndrome, p=0.004). Voxel-based multivariate pattern classification analysis indicates that, after controlling for global volumes, regional brain variations in XYY syndrome are more like those found in Klinefelter syndrome than those occurring in typical development. Further, visualization of classification parameters suggests that insular and frontotemporal grey matter and white matter, including known language areas, are reduced in males with XYY syndrome, similar to what is seen in Klinefelter syndrome. In males with XYY syndrome, DAS verbal and non-verbal scores were significantly lower than in typically developing participants (both p<0.001). DAS scores were not significantly different between XYY and Klinefelter syndrome groups. In five of eight males with XYY syndrome, the Social Responsiveness Scale score exceeded the cut-off for a likely diagnosis of autism spectrum disorder (ASD). In three of eight males with XYY syndrome, the ADI-R score met the cut-off for ASD diagnosis; in another two, ADI-R scores within the social and communication domains met the cut-off values for a diagnosis of ASD. INTERPRETATION The results suggest that genetic variations associated with XYY syndrome result in increased brain matter volumes, a finding putatively related to the increased frequency of ASDs in individuals with this condition. In addition, frontotemporal grey and white matter reductions in XYY syndrome provide a likely neuroanatomical correlate for observed language impairments.

Brain morphology in children with 47,XYY syndrome: a voxel‐ and surface‐based morphometric study

“…Here, both VBM and SBM techniques were used on a homogenous cohort of boys with 47,XYY, revealing regional differences that might have been missed using manual tracing approaches. However, our observations of increased total GM and WM are in agreement with previous work using a subset of the present sample (Bryant et al ), and agree with observations of enlarged head circumference in individuals with 47,XYY (Geerts et al ; Nicolson et al ). Interestingly, increased brain volume is one of the few consistent findings in ASD neuroimaging research (Courchesne et al ; Freitag et al ; Redcay & Courchesne ), and enlarged head circumference has been linked with delayed speech acquisition and higher ADI‐R score in the ASD population (Lainhart et al ).…”

“…While the neurocognitive and behavioral phenotype associated with XYY syndrome is increasingly documented, only two studies have used imaging modalities to investigate the impact of a supernumerary Y‐chromosome on neuroanatomy. While the first study conducted by Warwick et al () did not reveal significant differences compared to control adult males, a more recent study reported increased total gray matter (GMV) and white matter volumes (WMV) in 47,XYY (Bryant et al ). In the second study, multivoxel pattern analysis was used to establish that brain morphology of boys with 47,XYY was more similar to boys with Klinefelter syndrome (XXY) than to male controls (XY).…”

An Allometric Analysis of Sex and Sex Chromosome Dosage Effects on Subcortical Anatomy in Humans

“…Moreover: (1) studies in transgenic mice have established the presence of gonad-independent SCD effects on both cortical and subcortical anatomy (Corre et al, 2014;Raznahan et al, 2014), and (2) neuroimaging studies in human sex-chromosome aneuploidy (SCA) have established that changes in X-and Y-chromosome count can modify the anatomy of cortical regions with known subcortical projections (Bryant et al, 2011(Bryant et al, , 2012Hong et al, 2014;Raznahan et al, 2016). To date however, it is not known whether and how SCD influences subcortical morphology in humans.…”

47,XYY Syndrome: Clinical Phenotype and Timing of Ascertainment

“…Both the increased HC and the increased risk for seizure activity may be related to increased cerebral grey matter and white matter described in XYY. 42 Increased grey matter may be the result of reduced synaptic pruning, leading to altered synaptic function and perhaps increased seizure risk.…”