There is considerable genetic and phenotypic heterogeneity associated with intellectual disability (ID), specific learning disabilities and epilepsy. Increasing use of unbiased next generation screening strategies highlights that some X-linked genes display a female-specific phenotype typically associated with de novo mutations. One such gene is the IQ motif and SEC7 domain containing protein 2 (IQSEC2) gene, an X-chromosome gene known to escape X-inactivation in humans. Initially, missense mutations resulting in milder phenotypes of non-syndromic intellectual disability were reported in male patients inherited in an X-linked manner. In contrast, all nonsense or truncating mutations likely to cause loss-of-function of IQSEC2 have been reported as de novo mutation events, with early onset seizure phenotypes reported in both sexes. The pathogenesis underpinning these mutations is not known. Our investigations have focused on elucidating the mechanisms underpinning the disorders by establishing the role IQSEC2 plays in dendritic spine morphology during postnatal development. As part of these studies we have generated a novel Iqsec2 knockout (KO) mouse using a CRISPR/Cas9 approach. Interestingly, this KO model provides additional information on aspects of the female specific phenotype. Not surprisingly, 25% of Iqsec2 KO hemizygous male mice display seizures around the time of reaching sexual maturity. However, once past this period, these mice survive > 3-12 months with only infrequent seizures. In contrast to normal X-linked breeding strategies, we have had to use the hemizygous male mice to breed with wild-type females to maintain the colony due to the severe phenotype of the heterozygous KO females. This phenotype includes seizures at the time of sexual maturity (45%), with continuing seizures resulting in death (42% of those presenting with seizures, 19% of total heterozygous cohort) or occurring during pregnancy (31%) with subsequent failure to carry to term. Of the limited number of heterozygous female KO mice that have carried a pregnancy successfully, in as many as 42% of litters (80% of first litters) the mothers failed to nurture the newborn pups during the early postpartum period. We conclude that in both the human and mouse setting the loss of function of IQSEC2 / Iqsec2 in the heterozygote state causes phenotypic outcomes that are similar or more severe than the loss of function in the hemizygous state in affected males.