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. We would like to thank all the participants and families who participated in the research. We would like to thank Dr.

Jennifer Phillips and the students of the Stanford Neurodevelopmental Assessment Practicum Program for their support in neuropsychological assessment administration and scoring, and Sharon Bade Shrestha who assisted with data acquisition. This work was funded by the NIH (K23MH097120 to D.S.H., R21MH099630 and R01HD049653 to A.L.R.), the Sharon Levine Foundation, and the Niggeman Family Foundation. D.S.H. and I.K. also received funding from the Stanford Maternal Child Health Research Institute in support of this work.

Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, Stanford, USA Iliana I. Karipidis, Megan Klabunde, Tracy Jordan, Lindsay C. Hong Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich, University of Zurich, Zurich, Switzerland Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland Institute of Psychiatry, Psychology and Neuroscience at Kings College London, London, UK Department of Psychology, Arizona State University, Tempe, USA M.K. is an advisor for the JABBS Foundation for Women and Girls.

H.H. has financial interest in Walnot, Inc. D.S.H. has served on the advisory board of Little Otter Health, Inc. All other authors declare no competing interest.