Influence of the X-chromosome on neuroanatomy: evidence from Turner and Klinefelter syndromes

Abstract

Studies of sex effects on neurodevelopment have traditionally focused on animal models investigating hormonal influences on brain anatomy. However, more recent evidence suggests that sex chromosomes may also have direct upstream effects that act independently of hormones. Sex chromosome aneuploidies provide ideal models to examine this framework in humans, including Turner syndrome (TS), where females are missing one X-chromosome (45X), and Klinefelter syndrome (KS), where males have an additional X-chromosome (47XXY). As these disorders essentially represent copy number variants of the sex chromosomes, investigation of brain structure across these disorders allows us to determine whether sex chromosome gene dosage effects exist. We used voxel-based morphometry to investigate this hypothesis in a large sample of children in early puberty, to compare regional gray matter volumes among individuals with one (45X), two (typically developing 46XX females and 46XY males), and three (47XXY) sex chromosomes. Between-group contrasts of TS and KS groups relative to respective sex-matched controls demonstrated highly convergent patterns of volumetric differences with the presence of an additional sex chromosome being associated with relatively decreased parieto-occipital gray matter volume and relatively increased temporo-insular gray matter volumes. Furthermore, z-score map comparisons between TS and KS cohorts also suggested that this effect occurs in a linear dose-dependent fashion. We infer that sex chromosome gene expression directly influences brain structure in children during early stages of puberty, extending our understanding of genotype-phenotype mechanisms underlying sex differences in the brain.

Keywords: Klinefelter syndrome; Turner syndrome; neuroimaging; sex chromosome.

Figure 1.

Between-group comparisons for TS and KS cohorts relative to respective sex-matched controls, demonstrating GMV differences associated with X-chromosome complement. a, GMV differences between TS and TD females: blue, TS females > TD females; yellow, TD females > TS females. b, GMV differences between KS and TD males: blue, KS males > TD males; yellow, TD males > KS males. c, Conjunction analyses demonstrating intersection between contrasts illustrated in a and b: blue, overlap between TS > TD females and TD males > KS males contrasts; yellow, overlap in clusters between TD females > TS and KS males > TD males contrasts. For all analyses, clusters are considered significant at p < 0.05 FWE, voxel-height p < 0.001, and include TGMV, age, and FSIQ as covariates.

Figure 2.

T test comparison between TS and KS groups using z-score maps relative to respective sex-matched controls. Increased GMV noted for the TS group in frontotemporal regions (blue, TS females > KS males) and for the KS group in parietal regions (yellow, KS males > TS females). Clusters are considered significant at p < 0.05 FWE, voxel-height p < 0.001. Covariates include total GMV, age, and FSIQ.