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

Why do human females require more autosomal genetic risk to manifest autism compared to males? Why is this also true of other male-biased, childhood-onset conditions with substantial autosomal heritability? Here we propose that the higher female liability threshold for these disorders arises due to gene expression from the human inactive X chromosome (Xi), which buffers the effects of deleterious autosomal variants. In contrast, we posit that gene expression from the Y chromosome is less effective than Xi at mitigating the consequences of such pathogenic autosomal alleles, contributing to the lower liability threshold observed in males. This framework unites epidemiological, genetic, and mechanistic observations across autism. Moreover, via a systematic review of 101 published genetic studies of male-biased conditions, we identify 16 other childhood disorders that empirically demonstrate an FPE – suggesting that Xi’s genetic activity throughout the body enables females to better tolerate autosomal genetic risk for a panoply of pediatric conditions. If correct, this reshapes our understanding of sex differences in disease and highlights the roles of Xi and the Y chromosome in mitigating or enhancing the effects of autosomally mediated liability.