A study published in *Nature* (2013) investigated de novo mutations in two severe childhood epilepsy disorders, infantile spasms (IS) and Lennox-Gastaut Syndrome (LGS). Researchers sequenced the exomes of 264 patients and their parents, identifying 329 de novo mutations. These mutations were significantly enriched in genes that are intolerant to functional variation, with GABRB3 and ALG13 showing strong associations. The study found that de novo mutations in these genes are highly unlikely to occur by chance, suggesting they may be causative in these conditions. Other genes, including CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HDAC4, HNRNPU, IQSEC2, MTOR, and NEDD4L, were also implicated. The study highlights the role of de novo mutations in epilepsy, particularly in genes involved in ion channels, synaptic function, and neurodevelopmental pathways. It also shows that these mutations are enriched in genes regulated by the Fragile X protein, similar to findings in autism spectrum disorders. The study emphasizes the importance of considering the entire genome rather than single genes for genetic diagnostics in epilepsy. The results suggest that de novo mutations in specific genes may converge on shared biological pathways, offering new insights into the genetic basis of epileptic encephalopathies and potential targets for treatment. The study also underscores the need for larger sample sizes to confirm the role of inherited variants in these conditions. Overall, the findings highlight the significance of de novo mutations in the pathogenesis of severe childhood epilepsy and the importance of genomic approaches in understanding and treating these disorders.A study published in *Nature* (2013) investigated de novo mutations in two severe childhood epilepsy disorders, infantile spasms (IS) and Lennox-Gastaut Syndrome (LGS). Researchers sequenced the exomes of 264 patients and their parents, identifying 329 de novo mutations. These mutations were significantly enriched in genes that are intolerant to functional variation, with GABRB3 and ALG13 showing strong associations. The study found that de novo mutations in these genes are highly unlikely to occur by chance, suggesting they may be causative in these conditions. Other genes, including CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HDAC4, HNRNPU, IQSEC2, MTOR, and NEDD4L, were also implicated. The study highlights the role of de novo mutations in epilepsy, particularly in genes involved in ion channels, synaptic function, and neurodevelopmental pathways. It also shows that these mutations are enriched in genes regulated by the Fragile X protein, similar to findings in autism spectrum disorders. The study emphasizes the importance of considering the entire genome rather than single genes for genetic diagnostics in epilepsy. The results suggest that de novo mutations in specific genes may converge on shared biological pathways, offering new insights into the genetic basis of epileptic encephalopathies and potential targets for treatment. The study also underscores the need for larger sample sizes to confirm the role of inherited variants in these conditions. Overall, the findings highlight the significance of de novo mutations in the pathogenesis of severe childhood epilepsy and the importance of genomic approaches in understanding and treating these disorders.