We present compelling evidence that the likely cause of XLID in the extended MRX78 pedigree with six affected males and seven affected females in four generations is a missense mutation in the known XLID gene IQSEC2 (MIM*300522; Shoubridge et al., 2010) encoding a neuronal ArfGEF (known as IQSEC2, BRAG1 and IQ-ArfGEF) involved in cytoskeletal organization, dendritic spine morphology and excitatory synaptic organization, along with a review of previously published IQSEC2-related XLID patients. This evidence concerns the gene IQSEC2 and cask-related x-linked intellectual disability.