Relationship between X chromosome mosaicism, neuroanatomy and cognitive performance in females

Females have two X chromosomes, one of which is inactivated early in development with specific regions and genes ‘escaping’ inactivation. Thus, X chromosome loss putatively results in decreased ‘dosage’ of X chromosome escapee and pseudoautosomal genes, impacting downstream pathways. Evidence from Turner syndrome (TS) indicates that X chromosome monosomy results in consistent neuroanatomical and cognitive phenotypes. However, it remains unclear whether mosaic karyotypes, with mixed proportions of 45X and 46XX cells, attenuate these phenotypes. Using support vector regression, we examined whether X chromosome mosaicism is predicted by features derived from structural brain MRI and neurocognitive assessments of 48 pre- and early pubertal girls with monosomic TS, with mosaic TS, and without TS. Higher proportion of 46XX cells was significantly predicted by structural properties in somatosensory, motor, visual, and language brain areas, and by performance in visuospatial, fine-motor, and language tasks. Thus, mosaicism partially ‘rescues’ phenotypes linked to full 45X monosomy and may explain the role of the X chromosome not only across heterogeneous phenotypic expression in females, but also in sex differences observed in neuropsychiatric conditions. X chromosome mosaicism in Turner syndrome partly mitigates the brain and cognitive effects of X monosomy. Higher proportions of 46XX cells predict more typical brain structure and better visuospatial, motor, language, and cognitive performance.