X chromosome contribution to the female protective effect in autism and neurodevelopmental disorders

Determine whether and quantify how much the female protective effect observed in autism spectrum disorder and other neurodevelopmental disorders is attributable to genetic and dosage-related factors on the X chromosome.

Background

Risk gene discovery on the X chromosome is complicated by male hemizygosity, reduced genetic diversity relative to autosomes, and mosaic X-chromosome inactivation (XCI) in females, with 15-30% of genes escaping XCI and exhibiting atypical expression. These features make dosage sensitivity and constraint metrics difficult to interpret and contribute to sex-specific variability.

In psychiatric genetics, the female protective effect—where affected females carry higher mutational burdens than males—adds an additional layer of complexity. The extent to which this protective effect is driven by X-linked mechanisms remains unresolved, motivating experiments and analyses (e.g., isogenic iPSC models) that can isolate X-linked dosage and expression effects despite challenges such as XCI erosion.

References

Within the field of psychiatric genetics, this complexity is even further compounded by the female protective effect in autism and other neurodevelopmental disorders, where affected females carry greater mutational burdens than males 51,52, although it is not known if or how much of it is due to chromosome X.

— Advancing Risk Gene Discovery Across the Allele Frequency Spectrum  (2511.04637 - Caballero et al., 6 Nov 2025) in Section 1.2, Risk discovery on the X chromosome faces numerous challenges