Mutations in ASH1L cause a neurodevelopmental disorder with sex differences in epilepsy and autism

To understand brain phenotypes associated with ASH1L, we used a mouse model, performing analysis in different genetic backgrounds: C57BL/6 and CD-1. We found that in both lines, ASH1L mutations result in seizures. Mice from both lines have microcephaly, and also less complex dendritic morphology. We also found differential effects of ASH1L between C57BL/6 and CD-1 strains on a number of different measures identifying aspects of ASH1L function that may be influenced by genetic background. When we analyzed human subjects based on biological sex, for epilepsy, intellectual disability, and ASD, we found sex differences in epilepsy and autism, with epilepsy predominantly in female and ASD in male subjects. Functional evaluation by whole cell patch clamp electrophysiology in mice demonstrated hyperexcitability female compared with male hippocampal CA1 neurons. Thus, the role of ASH1L in specific circuits may be sex-dependent leading to sexual dimorphic effects from haploinsufficiency of this gene.