Hemispheric Module-Specific Influence of the X Chromosome on White Matter Connectivity: Evidence from Girls with Turner Syndrome

Abstract

Turner syndrome (TS) is caused by the congenital absence of all or part of one of the X chromosomes in females, offering a valuable human "knockout model" to study the functioning patterns of the X chromosome in the human brain. Little is known about whether and how the loss of the X chromosome influences the brain structural wiring patterns in human. We acquired a multimodal MRI dataset and cognitive assessments from 22 girls with TS and 21 age-matched control girls to address these questions. Hemispheric white matter (WM) networks and modules were derived using refined diffusion MRI tractography. Statistical comparisons revealed a reduced topological efficiency of both hemispheric networks and bilateral parietal modules in TS girls. Specifically, the efficiency of right parietal module significantly mediated the effect of the X chromosome on working memory performance, indicating that X chromosome loss impairs working memory performance by disrupting this module. Additionally, TS girls showed structural and functional connectivity decoupling across specific within- and between-modular connections, predominantly in the right hemisphere. These findings provide novel insights into the functional pathways in the brain that are regulated by the X chromosome and highlight a module-specific genetic contribution to WM connectivity in the human brain.

Keywords: Turner syndrome; functional connectivity; module; structural connectivity; the X chromosome.