Sex chromosome dosage effects on human brain structure and function: a systematic review of neuroimaging findings in sex chromosome aneuploidies

Sex chromosomal aneuploidies (SCAs) are a group of genetic disorders characterized by an abnormal number of X or Y chromosomes compared to the typical karyotype of 46,XX in females and 46,XY in males. In the last three decades, there has been an increased interest in the neurobiological effects in SCAs, including effects on brain structure and function. The current work aimed to provide a comprehensive overview of results of neuroimaging studies in SCAs to summarize sex chromosome dosage effects on human brain structure and function. We included 48 studies, and results revealed a complex pattern of widespread structural and functional brain changes associated with alterations in sex chromosome dosage compared to the typical karyotype of 46,XX in females and 46,XY in males. Both convergent and divergent effects of X and Y chromosome dosage on brain structure and function were identified, with varying impacts depending on developmental stage, mosaicism, and genomic imprinting. These findings not only shed light on brain alterations observed in individuals with SCAs across the lifespan but also provide insights into the role of sex chromosomes in shaping normative sex differences in the brain.