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eNeuro. 2018 Nov 29;5(5). pii: ENEURO.0265-18.2018. doi: 10.1523/ENEURO.0265-18.2018. eCollection 2018 Sep-Oct.

Carriage of Supernumerary Sex Chromosomes Decreases the Volume and Alters the Shape of Limbic Structures.

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Developmental Neurogenomics Unit, Human Genetics Branch, National Institute of Mental Health, Bethesda, Maryland 20892.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5T 1R8, Canada.
Neurosciences and Mental Health, the Hospital for Sick Children, Toronto, Ontario M5T 3H7, Canada.
Cerebral Imaging Centre, Douglas Mental Health University Institute, McGill University, Montreal, Quebec H3A OG4, Canada.
Department of Psychiatry, McGill University, Montreal, Quebec H3A OG4, Canada.


Sex chromosome aneuploidy (SCA) increases risk for several psychiatric disorders associated with the limbic system, including mood and autism spectrum disorders. Thus, SCA offers a genetics-first model for understanding the biological basis of psychopathology. Additionally, the sex-biased prevalence of many psychiatric disorders could potentially reflect sex chromosome dosage effects on brain development. To clarify how limbic anatomy varies across sex and sex chromosome complement, we characterized amygdala and hippocampus structure in a uniquely large sample of patients carrying supernumerary sex chromosomes (n = 132) and typically developing controls (n = 166). After adjustment for sex-differences in brain size, karyotypically normal males (XY) and females (XX) did not differ in volume or shape of either structure. In contrast, all SCAs were associated with lowered amygdala volume relative to gonadally-matched controls. This effect was robust to three different methods for total brain volume adjustment, including an allometric analysis that derived normative scaling rules for these structures in a separate, typically developing population (n = 79). Hippocampal volume was insensitive to SCA after adjustment for total brain volume. However, surface-based analysis revealed that SCA, regardless of specific karyotype, was consistently associated with a spatially specific pattern of shape change in both amygdala and hippocampus. In particular, SCA was accompanied by contraction around the basomedial nucleus of the amygdala and an area crossing the hippocampal tail. These results demonstrate the power of SCA as a model to understand how copy number variation can precipitate changes in brain systems relevant to psychiatric disease.



CNV; amygdala; hippocampus; sex chromosome aneuploidy

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