We first established the IQSEC2 gene [NM_001111125] (MIM 300522) as a genetic cause of ID due to missense variants in X-linked familial cases.18 Since this report, high-throughput sequencing in ID or epilepsy cohorts has identified de novo loss-of-function IQSEC2 mutations in males and increasingly in females.19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 Abolition of enzymatic activity of IQSEC2 typically leads to a more severe phenotype including epileptic encephalopathy in both sexes. This evidence concerns the gene IQSEC2 and Epileptic encephalopathy.