High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

F.F. Hamdan, C.T. Myers, P. Cossette, P. Lemay, D. Spiegelman, A.D. Laporte, C. Nassif, O. Diallo, J. Monlong, M. Cadieux-Dion, S. Dobrzeniecka, C. Meloche, K. Retterer, M.T. Cho, J.A. Rosenfeld, W. Bi, C. Massicotte, M. Miguet, L. Brunga, B.M. ReganK. Mo, C. Tam, A. Schneider, G. Hollingsworth, D.R. FitzPatrick, A. Donaldson, N. Canham, E. Blair, B. Kerr, A.E. Fry, R.H. Thomas, J. Shelagh, J.A. Hurst, H. Brittain, M. Blyth, R.R. Lebel, E.H. Gerkes, L. Davis-Keppen, Q. Stein, W.K. Chung, S.J. Dorison, P.J. Benke, E. Fassi, N. Corsten-Janssen, E.-J. Kamsteeg, F.T. Mau-Them, S. Martinelli, B. Dallapiccola, M. Tartaglia, C. Nava

Research output: Contribution to journalArticlepeer-review


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. © 2017 American Society of Human Genetics
Original languageEnglish
Pages (from-to)664-685
Number of pages22
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - 2017


  • CLTC
  • epileptic encephalopathy
  • GABBR2
  • GABRB2
  • NTRK2
  • NUS1
  • RAB11
  • SNAP25
  • adolescent
  • adult
  • Article
  • Canada
  • child
  • CLTC gene
  • data mining
  • developmental and epileptic encephalopathy
  • developmental delay
  • DHDDS gene
  • epilepsy
  • female
  • frameshift mutation
  • GABBR2 gene
  • GABRB2 gene
  • gene
  • gene deletion
  • gene duplication
  • gene identification
  • gene mutation
  • gene sequence
  • gene targeting
  • genetic association
  • genetic linkage
  • genetic variability
  • human
  • intellectual impairment
  • major clinical study
  • male
  • missense mutation
  • molecular diagnosis
  • mutational analysis
  • nonsense mutation
  • NTRK2 gene
  • NUS1 gene
  • preschool child
  • priority journal
  • RAB11A gene
  • school child
  • SNAP25 gene
  • whole genome sequencing
  • young adult
  • brain disease
  • genetics
  • genome-wide association study
  • human genome
  • meta analysis
  • mutation
  • procedures
  • recurrent disease
  • seizure
  • Brain Diseases
  • Child
  • Child, Preschool
  • Epilepsy
  • Female
  • Genome, Human
  • Genome-Wide Association Study
  • Humans
  • Intellectual Disability
  • Male
  • Mutation
  • Recurrence
  • Seizures


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