title: 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.
authors.affiliation: Center for Interdisciplinary Brain Sciences Research, Stanford, California 94305, Department of Psychiatry, University of California, San Francisco, California 94143, Department of Bioengineering, Stanford University, Stanford, California 94305, Division of Pediatric Endocrinology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and Department of Psychiatry and Behavioral Sciences and Department of Radiology, Stanford University, Stanford, California 94305.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Fumiko
authors.initials: F
authors.lastname: Hoeft
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Marzelli
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Lepage
authors.forename: David
authors.initials: D
authors.lastname: Roeltgen
authors.forename: Judith
authors.initials: J
authors.lastname: Ross
authors.forename: Allan L
authors.initials: AL
authors.lastname: Reiss
mesh_terms: D001921:Brain / Q000033:anatomy & histology / Q000473:pathology*; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D007361:Intelligence Tests; D007713:Klinefelter Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000523:psychology; D008297:Male; D014424:Turner Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000523:psychology
keywords: Klinefelter syndrome; Turner syndrome; neuroimaging; sex chromosome