6533b852fe1ef96bd12ab6de
RESEARCH PRODUCT
High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies
Patrick CossetteZoha KibarZoha KibarMaxime Cadieux-dionMaxime Cadieux-dionHelen BrittainAndrew E. FryEmily FassiEdward BlairSimone MartinelliPaul J. BenkeGuy D'anjouAlexandre D. LaporteBerge A. MinassianBerge A. MinassianSylvia StocklerTyson L WareDavid R. FitzpatrickWeimin BiAmy L SchneiderJill A. RosenfeldShekeeb S. MohammadJacques L. MichaudJacques L. MichaudCarlos A. BacinoCarlos A. BacinoJoss ShelaghSamuel F. BerkovicStéphane AuvinYunru ShaoSylvia DobrzenieckaKelly MoCory TamNicole Corsten-janssenWendy K. ChungRenee-myriam BoucherAlain VerloesFadi F. HamdanBronwyn KerrFrédéric Tran Mau-themMartina BebinPhilippe M. CampeauPhilippe M. CampeauDara V.f. AlbertGuy A. RouleauQuinn SteinAnne LortieSusan M. HiattLubov BlumkinBoris KerenDan SpiegelmanSaadet Mercimek-mahmutogluRonald G. LafrenièreMarie-christine NouguesRhys H. ThomasErica H. GerkesElsa RossignolElsa RossignolBruno DallapiccolaKlaas J. WierengaNatalie CanhamMonica H. WojcikMonica H. WojcikCaroline MelocheMoira BlythCyril MignotHeather C MeffordLedia BrungaD. L. JonesFrançois DubeauKyle RettererJames J. O'byrneChristine MassicotteVincenzo LeuzziCaroline NavaIngrid E. SchefferIngrid E. SchefferIngrid E. SchefferErik-jan KamsteegCyrus BoelmanMegan T. ChoGabriela PurcarinBrigid M. ReganJean MonlongSimon GirardSimon GirardSimon GirardPhilippe MajorMarguerite MiguetKatrin ÕUnapYu Chi LiuYu Chi LiuGuillaume BourqueMyriam SrourOusmane DialloEmilie RiouLionel CarmantLionel CarmantSeema R. LalaniChristina NassifRobert Roger LebelAnna LehmanGeorgie HollingsworthStéphanie JacquesSunita VenkateswaranMarco TartagliaCandace T. MyersAnge-line BruelDanielle M. AndradeImad JarjourPeyman BizargitySara J. DorisonJane A. HurstRichard E. FryeLynette G. SadleirAlan DonaldsonFernando ScagliaPhilippe LemayPaola DiadoriLaura Davis-keppensubject
Male0301 basic medicineCandidate genemedicine.medical_specialtymedical geneticsglycosylationNonsense mutationGenome-wide association studyGene mutationBiologySensory disorders Donders Center for Medical Neuroscience [Radboudumc 12]Articlesevere intellectual disability03 medical and health sciencesEpilepsy0302 clinical medicinechildrenRecurrenceSeizuresGenetic linkageIntellectual Disability[ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathologyJournal ArticleGeneticsmedicineHumansChilddisordersGenetics (clinical)Genetic associationGeneticsBrain DiseasesdiseaseEpilepsycis-prenyltransferaseGenome Humanstructural basismedicine.diseasediphosphate synthase030104 developmental biologyChild PreschoolMutationMedical geneticsFemalenogo-b receptor030217 neurology & neurosurgery[SDV.MHEP]Life Sciences [q-bio]/Human health and pathologyGenome-Wide Association StudyMeta-Analysisdescription
Item does not contain fulltext Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-11-01 |