De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies

Silke Appenzeller, Rudi Balling, Nina Barisic, Stephanie Baulac, Hande Caglayan, Dana Craiu, Peter De Jonghe, Christel Depienne, Petia Dimova, Tania Djemie, Padhraig Gormley, Renzo Guerrini, Ingo Helbig, Helle Hjalgrim, Dorota Hoffman-Zacharska, Johanna Jaehn, Karl Martin Klein, Bobby P. C. Koeleman, Vladimir Komarek, Roland KrauseGregor Kuhlenbaeumer, Eric Leguern, Anna-Elina Lehesjoki, Johannes R. Lemke, Holger Lerche, Tarja Linnankivi, Carla Marini, Patrick May, Rikke S. Moller, Hiltrud Muhle, Deb Pal, Aarno Palotie, Manuela Pendziwiat, Angela Robbiano, Filip Roelens, Felix Rosenow, Kaja Selmer, Jose M. Serratosa, Sanjay Sisodiya, Ulrich Stephani, Katalin Sterbova, Pasquale Striano, Arvid Suls, Tiina Talvik, Sarah von Spiczak, Yvonne Weber, Sarah Weckhuysen, Federico Zara, Bassel Abou-Khalil, Brian K. Alldredge, , , ,

Research output: Contribution to journalArticleAcademicpeer-review


Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), 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. In this expanded cohort, we find 429 de nova mutations, including de novo mutations in DNM1 in five individuals and de nova mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de nova mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 x 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de nova mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.

Original languageEnglish
Pages (from-to)360-370
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 2 Oct 2014




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