Abstracts

Rationale: Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous underscoring the need for large cohorts of well-characterized patients to further define the genetic landscape. Methods: Through a collaboration between two consortia, we analyzed exome sequencing data of 356 trios with the "classical" epileptic encephalopathies infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. Results: In this expanded cohort, we find a total of 429 de novo mutations, including de novo mutations in DNM1 in five patients, and de novo mutations in GABBR2, FASN, and RYR3 in two patients each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy patients compared to the general population (p=8·2x10^-4) using a likelihood analysis, supporting a prominent role for de novo mutations in epileptic encephalopathies. We statistically consolidate DNM1 as a gene for epileptic encephalopathy, and show that at least 11% of analyzed patients have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these patients are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. Conclusions: Our analyses show that with increasing sample sizes we are able to provide statistical evidence for DNM1 as an epileptic encephalopathy gene and suggestive evidence for at least three additional genes. In addition, our findings emphasize an important role for synaptic dysregulation, above and beyond that caused by ion channel dysfunction in epileptic encephalopathies.