Sex Chromosome Aneuploidies and the Brain: from Neurodevelopmental Risk to Fundamental Biology

Sex chromosome aneuploidies (SCAs) are collectively common (∼1/400 individuals) conditions that involve loss or gain of one or more X- or Y- chromosomes. A recent surge in SCA research has highlighted their underappreciated penetrance for multiple neuropsychiatric outcomes - motivating this integrative review across the latest epidemiological, behavioral, neuroimaging, and genomic studies. SCAs show a high penetrance-for-prevelance across multiple psychiatric diagnoses, which often exceeds that of better recognized genetic risk factors, and includes substantial symptom burden below diagnostic thresholds. Some clinical outcomes show differential sensitivity to X- vs. Y-chromosome changes. SCAs exert large effects on global brain size, and also reconfigure regional brain anatomy, with strikingly correlated regional effects of X- and Y-chromosome dosage variation. Genomic studies nominate X-Y gametologs as highly dosage sensitive genes that may shape wider SCA effects on autosomal gene expression. These insights advance clinical and mechanistic understanding of SCAs as: impactful genetic disorders in their own right; genetics-first models for broader psychiatry; and, a window onto potential sex chromosome dosage effects in the general population. Major future growth areas in SCA clinical research include: the much-needed founding of new clinical research networks and registries in close partnership with families; studies of early development in prenatally diagnosed children; in vitro cellular models of effects in human neural tissue; and greater translational focus on sources of variability in patient outcomes. The new and emerging work reviewed herein underlines the need for greater recognition and focus on SCAs in psychiatry and related disciplines.