Significance: Despite clear differences in female and male immunity that may contribute to variations in response to infections and predisposition to cancer and autoimmunity, the exact mechanisms that drive this stark contrast remain insufficiently characterized. Neutrophils play essential roles in homeostasis and disease, but little is known about how sex differences modulate their phenotype and function. Using transcriptomic and functional approaches, we report that healthy young adult females have an activated/mature neutrophil profile characterized by enhanced type I IFN pathway activity, enhanced proinflammatory responses, and distinct bioenergetics. We further show that these differences are cell specific and likely driven by sex hormones. Modulation of these pathways in neutrophils may provide more individualized, sex-specific therapeutic options in a variety of disease states.

Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80–90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.