Article (Scientific journals)
De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies
Appenzeller, Silke; Balling, Rudi; Barisic, Nina et al.
2014In American Journal of Human Genetics, 4, p. 360-370
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Keywords :
Epilepsy; Genetics
Abstract :
[en] 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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Appenzeller, Silke
Balling, Rudi ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Barisic, Nina
Baulac, Stephanie
Caglayan, Hande
Craiu, Dana
De Jonghe, Peter
Depienne, Christel
Dimova, Petia
Djemie, Tania
Gormly, Padhraig
Guerrini, Renzo
Helbig, Ingo
Hjalgrim, Helle
Hoffman-Zacharska, Dorota
Jähn
Klein, Karl Martin
Koeleman, Bobby
Komarek, Vladimir
Krause, Roland  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Kuhlenbäumer, Gregor
Leguern, Eric
Lehesjoki, Anna-Elina
Lemke, Johannes R.
Lerche, Holger
Linnankivi, Tarja
Marini, Carla
May, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Møller, Rikke S.
Muhle, Hiltrud
Pal, Deb
Palotie, Aarno
Pendziwitat, Manuela
Robbiano, Angela
Roelens, Filip
Rosenow, Felix
Selmer, Kaja
Serratosa, Jose M.
Sisodiya, Sanjay
Stephani, Ulrich
Sterbova, Katalin
Striano, Pasquale
Suls, Arvid
Talvik, Tiina
von Spizak, Sarah
Weber, Yvonne
Weckhuysen, Sarah
Zara, Frederico
Epilepsy Phenome/Genome Project
Epi4K Consortium
More authors (40 more) Less
External co-authors :
yes
Language :
English
Title :
De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies
Publication date :
25 September 2014
Journal title :
American Journal of Human Genetics
ISSN :
1537-6605
Publisher :
University of Chicago Press, Chicago, United States - Illinois
Volume :
4
Pages :
360-370
Peer reviewed :
Peer Reviewed verified by ORBi
Name of the research project :
EuroEPINOMICS RES consortium
Available on ORBilu :
since 04 October 2014

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