The inactive X chromosome as a female protector in autism and beyond

Female individuals require greater autosomal genetic risk than male individuals to manifest autism, yet the biological basis of this 'female protective effect' (FPE) remains unknown. Based on insights into the human sex chromosomes, we propose that the FPE arises from higher expression of a subset of X-linked genes in females due to transcription from both the active (Xa) and inactive (Xi) X chromosomes. These higher expression levels enable females to buffer mutations in autosomal genes and in pathways regulated by Xi-expressed genes. This framework unifies epidemiological, genetic and mechanistic observations across autism and other male-biased congenital and developmental disorders, suggesting that the combined activity of Xa and Xi allows females to better tolerate autosomal genetic risk across many pediatric conditions. If correct, this reshapes our understanding of sex differences in human disease and positions Xi as a genetic suppressor of autosomal mutations in autism and beyond.