TY - JOUR
T1 - De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies
AU - EuroEPINOMICS-RES Consortium
AU - Epilepsy Phenome/Genome Project
AU - Epi4K Consortium
AU - Appenzeller, Silke
AU - Balling, Rudi
AU - Barisic, Nina
AU - Baulac, Stéphanie
AU - Caglayan, Hande
AU - Craiu, Dana
AU - De Jonghe, Peter
AU - Depienne, Christel
AU - Dimova, Petia
AU - Djémié, Tania
AU - Gormley, Padhraig
AU - Guerrini, Renzo
AU - Helbig, Ingo
AU - Hjalgrim, Helle
AU - Hoffman-Zacharska, Dorota
AU - Jähn, Johanna
AU - Klein, Karl Martin
AU - Koeleman, Bobby
AU - Komarek, Vladimir
AU - Krause, Roland
AU - Kuhlenbäumer, Gregor
AU - Leguern, Eric
AU - Lehesjoki, Anna Elina
AU - Lemke, Johannes R.
AU - Lerche, Holger
AU - Linnankivi, Tarja
AU - Marini, Carla
AU - May, Patrick
AU - Møller, Rikke S.
AU - Muhle, Hiltrud
AU - Pal, Deb
AU - Palotie, Aarno
AU - Pendziwiat, Manuela
AU - Robbiano, Angela
AU - Roelens, Filip
AU - Rosenow, Felix
AU - Selmer, Kaja
AU - Serratosa, Jose M.
AU - Sisodiya, Sanjay
AU - Stephani, Ulrich
AU - Sterbova, Katalin
AU - Striano, Pasquale
AU - Suls, Arvid
AU - Talvik, Tiina
AU - Von Spiczak, Sarah
AU - Weber, Yvonne
AU - Weckhuysen, Sarah
AU - Zara, Federico
AU - Thio, Liu Lin
AU - Weisenberg, Judith L.
N1 - Publisher Copyright:
© 2014 by The American Society of Human Genetics. All rights reserved.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84921803785&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2014.08.013
DO - 10.1016/j.ajhg.2014.08.013
M3 - Article
C2 - 25262651
AN - SCOPUS:84921803785
SN - 0002-9297
VL - 95
SP - 360
EP - 370
JO - American journal of human genetics
JF - American journal of human genetics
IS - 4
ER -