Journal article
De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies
American journal of human genetics, v 95(4), pp 360-370
02 Oct 2014
PMID: 25262651
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
Metrics
Details
- Title
- De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies
- Creators
- Epi4K ConsortiumSilke AppenzellerRudi BallingNina BarisicStephanie BaulacHande CaglayanDana CraiuPeter De JongheChristel DepiennePetia DimovaTania DjemiePadhraig GormleyRenzo GuerriniIngo HelbigHelle HjalgrimDorota Hoffman-ZacharskaJohanna JaehnKarl Martin KleinBobby KoelemanVladimir KomarekRoland KrauseGregor KuhlenbaeumerEric LeguernAnna-Elina LehesjokiJohannes R. LemkeHolger LercheTarja LinnankiviCarla MariniPatrick MayRikke S. MollerHiltrud MuhleDeb PalAarno PalotieManuela PendziwiatAngela RobbianoFilip RoelensFelix RosenowKaja SelmerJose M. SerratosaSanjay SisodiyaUlrich StephaniKatalin SterbovaPasquale StrianoArvid SulsTiina TalvikSarah von SpiczakYvonne WeberSarah WeckhuysenFederico ZaraBassel Abou-KhalilBrian K. AlldredgeEva AndermannFrederick AndermannDina AmronJocelyn F. BautistaSamuel F. BerkovicJudith BluvsteinAlex BoroGregory CascinoDamian ConsalvoPatricia CrumrineOrrin DevinskyDennis DlugosMichael P. EpsteinMiguel FiolNathan B. FountainJacqueline FrenchDaniel FriedmanEric B. GellerTracy GlauserSimon GlynnKevin HaasSheryl R. HautJean HaywardSandra L. HelmersSucheta JoshiAndres KannerHeidi E. KirschRobert C. KnowltonEric H. KossoffRachel KupermanDaniel H. LowensteinShannon M. McGuirePaul V. MotikaEdward J. NovotnyRuth OttmanJuliann M. PaolicchiJack ParentKristen ParkAnnapurna PoduriLynette SadleirIngrid E. SchefferRenee A. ShellhaasElliott SherrJerry J. ShihRani SinghJoseph SirvenMichael C. SmithJoe SullivanLiu Lin ThioAnu VenkatEileen P. G. ViningGretchen K. Von AllmenJudith L. WeisenbergPeter Widdess-WalshMelodie R. WinawerAndrew S. AllenPatrick CassetteNorman DelantyEvan E. EichlerTracy GlauserDavid B. GoldsteinYujun HanErin L. HeinzenMichael R. JohnsonRuben KuznieckyAnthony G. MarsonHeather C. MeffordSahar Esmaeeli NiehTerence J. O'BrienStephen PetrouSlave PetrovskiAnnapurna PoduriElizabeth K. Ruzzo
- Publication Details
- American journal of human genetics, v 95(4), pp 360-370
- Publisher
- Elsevier
- Number of pages
- 11
- Grant note
- Eurocores program EuroEPINOMICS-RES of the European Science Foundation U01NS053998 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Richard Thalheimer Philanthropic Fund Finding a Cure for Epilepsy and Seizures NS053998; Epi4K NS077364; NS077274; NS077303; NS077276 / National Institute of Neurological Disorders and Stroke (The Epilepsy Phenome/Genome Project) Andrew's Foundation
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Medicine (Graduate); Urban Health Collaborative
- Web of Science ID
- WOS:000342654300002
- Scopus ID
- 2-s2.0-84921803785
- Other Identifier
- 991021838152204721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Genetics & Heredity