Erin Johnson-Venkatesh and Hisashi Umemori share their work trying to understand why X-linked PCDH19-related disorder occurs only in females, and not males – when the opposite is typical for most disorders emanating from mutations on the X-chromosome. They find that inactivation of one copy of Pcdh19 results in a molecular mismatch at hippocampal synapses, leading to functional impairments in female, but not male mice.