This study investigates *de novo* mutations in two classic forms of epileptic encephalopathies: infantile spasms (IS) and Lennox-Gastaut Syndrome (LGS). Exome sequencing of 264 trios identified 329 *de novo* mutations, with a significant excess in genes highly intolerant to functional genetic variation. Notable genes include *GABRB3* and *ALG13*, which show strong statistical evidence of association. The study also reveals a genetic architecture suggesting additional causal mutations in intolerant genes. Furthermore, *de novo* mutations are enriched in specific gene sets, including those regulated by the Fragile X protein, and converge on pathways such as GABA ionotropic receptor subunits. The findings highlight the importance of considering the genome as a whole in genetic diagnostics for epileptic encephalopathies and provide insights into potential drug development and treatment personalization.This study investigates *de novo* mutations in two classic forms of epileptic encephalopathies: infantile spasms (IS) and Lennox-Gastaut Syndrome (LGS). Exome sequencing of 264 trios identified 329 *de novo* mutations, with a significant excess in genes highly intolerant to functional genetic variation. Notable genes include *GABRB3* and *ALG13*, which show strong statistical evidence of association. The study also reveals a genetic architecture suggesting additional causal mutations in intolerant genes. Furthermore, *de novo* mutations are enriched in specific gene sets, including those regulated by the Fragile X protein, and converge on pathways such as GABA ionotropic receptor subunits. The findings highlight the importance of considering the genome as a whole in genetic diagnostics for epileptic encephalopathies and provide insights into potential drug development and treatment personalization.