De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies

Silke Appenzeller, Rudi Balling, Nina Barisic, Stéphanie Baulac, Hande Caglayan, Dana Craiu, Peter De Jonghe, Christel Depienne, Petia Dimova, Tania Djémié, Padhraig Gormley, Renzo Guerrini, Ingo Helbig, Helle Hjalgrim, Dorota Hoffman-Zacharska, Johanna Jähn, Karl Martin Klein, Bobby Koeleman, Vladimir Komarek, Roland KrauseGregor Kuhlenbäumer, Eric Leguern, Anna Elina Lehesjoki, Johannes R. Lemke, Holger Lerche, Tarja Linnankivi, Carla Marini, Patrick May, Rikke S. Møller, 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, Eva Andermann, Frederick Andermann, Dina Amron, Jocelyn F. Bautista, Samuel F. Berkovic, Judith Bluvstein, Alex Boro, Gregory Cascino, Damian Consalvo, Patricia Crumrine, Orrin Devinsky, Dennis Dlugos, Michael P. Epstein, Miguel Fiol, Nathan B. Fountain, Jacqueline French, Daniel Friedman, Eric B. Geller, Tracy Glauser, Simon Glynn, Kevin Haas, Sheryl R. Haut, Jean Hayward, Sandra L. Helmers, Sucheta Joshi, Andres Kanner, Heidi E. Kirsch, Robert C. Knowlton, Eric H. Kossoff, Rachel Kuperman, Ruben Kuzniecky, Daniel H. Lowenstein, Shannon M. McGuire, Paul V. Motika, Edward J. Novotny, Ruth Ottman, Juliann M. Paolicchi, Jack Parent, Kristen Park, Annapurna Poduri, Lynette Sadleir, Ingrid E. Scheffer, Renée A. Shellhaas, Elliott Sherr, Jerry J. Shih, Rani Singh, Joseph Sirven, Michael C. Smith, Joe Sullivan, Liu Lin Thio, Anu Venkat, Eileen P G Vining, Gretchen K. Von Allmen, Judith L. Weisenberg, Peter Widdess-Walsh, Melodie R. Winawer, Andrew S. Allen, Patrick Cossette, Norman Delanty, Evan E. Eichler, David B. Goldstein, Yujun Han, Erin L. Heinzen, Michael R. Johnson, Anthony G. Marson, Heather C. Mefford, Sahar Esmaeeli Nieh, Terence J. O'Brien, Stephen Petrou, Slavé Petrovski, Elizabeth K. Ruzzo

Research output: Contribution to journalArticlepeer-review

332 Scopus citations


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 novo mutations, including de novo mutations in DNM1 in five individuals and de novo 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 novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 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 novo 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 (US)
Pages (from-to)360-370
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - 2014

Bibliographical note

Funding Information:
This work was supported by grants from the National Institute of Neurological Disorders and Stroke (The Epilepsy Phenome/Genome Project NS053998; Epi4K NS077364, NS077274, NS077303, and NS077276), The Andrew’s Foundation, Finding a Cure for Epilepsy and Seizures, the Richard Thalheimer Philanthropic Fund, and the Eurocores program EuroEPINOMICS-RES of the European Science Foundation. Additional funding sources are summarized in the Supplemental Acknowledgments . The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Publisher Copyright:
© 2014 by The American Society of Human Genetics. All rights reserved.


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