While not proving that severe functionally damaging mutations in human EPHB2 are sufficient to cause ASD or other NDDs, our findings support the notion that full EPHB2 function is critical, particularly in females, for typical expression of behaviors and neurological functions altered in these common NDDs and add to the growing literature that genes involved in synapse development and brain wiring play a disproportionate role in conferring NDD risk. This evidence concerns the gene EPHB2 and Neurodevelopmental delay.