Abstract 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.