Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Hamdan FF

PROVIDER: S-EPMC5673604 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Hamdan Fadi F FF Myers Candace T CT Cossette Patrick P Lemay Philippe P Spiegelman Dan D Laporte Alexandre Dionne AD Nassif Christina C Diallo Ousmane O Monlong Jean J Cadieux-Dion Maxime M Dobrzeniecka Sylvia S Meloche Caroline C Retterer Kyle K Cho Megan T MT Rosenfeld Jill A JA Bi Weimin W Massicotte Christine C Miguet Marguerite M Brunga Ledia L Regan Brigid M BM Mo Kelly K Tam Cory C Schneider Amy A Hollingsworth Georgie G FitzPatrick David R DR Donaldson Alan A Canham Natalie N Blair Edward E Kerr Bronwyn B Fry Andrew E AE Thomas Rhys H RH Shelagh Joss J Hurst Jane A JA Brittain Helen H Blyth Moira M Lebel Robert Roger RR Gerkes Erica H EH Davis-Keppen Laura L Stein Quinn Q Chung Wendy K WK Dorison Sara J SJ Benke Paul J PJ Fassi Emily E Corsten-Janssen Nicole N Kamsteeg Erik-Jan EJ Mau-Them Frederic T FT Bruel Ange-Line AL Verloes Alain A Õunap Katrin K Wojcik Monica H MH Albert Dara V F DVF Venkateswaran Sunita S Ware Tyson T Jones Dean D Liu Yu-Chi YC Mohammad Shekeeb S SS Bizargity Peyman P Bacino Carlos A CA Leuzzi Vincenzo V Martinelli Simone S Dallapiccola Bruno B Tartaglia Marco M Blumkin Lubov L Wierenga Klaas J KJ Purcarin Gabriela G O'Byrne James J JJ Stockler Sylvia S Lehman Anna A Keren Boris B Nougues Marie-Christine MC Mignot Cyril C Auvin Stéphane S Nava Caroline C Hiatt Susan M SM Bebin Martina M Shao Yunru Y Scaglia Fernando F Lalani Seema R SR Frye Richard E RE Jarjour Imad T IT Jacques Stéphanie S Boucher Renee-Myriam RM Riou Emilie E Srour Myriam M Carmant Lionel L Lortie Anne A Major Philippe P Diadori Paola P Dubeau François F D'Anjou Guy G Bourque Guillaume G Berkovic Samuel F SF Sadleir Lynette G LG Campeau Philippe M PM Kibar Zoha Z Lafrenière Ronald G RG Girard Simon L SL Mercimek-Mahmutoglu Saadet S Boelman Cyrus C Rouleau Guy A GA Scheffer Ingrid E IE Mefford Heather C HC Andrade Danielle M DM Rossignol Elsa E Minassian Berge A BA Michaud Jacques L JL

American journal of human genetics 20171101 5

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 ...[more]

PMID: 29100083

Similar Datasets

Project description:FZR1, which encodes the Cdh1 subunit of the anaphase-promoting complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Whole-exome sequencing in 39 patient-parent trios and subsequent targeted sequencing in an additional cohort of 211 patients was performed to identify novel genes involved in developmental and epileptic encephalopathy. Functional studies in Drosophila were performed using three different mutant alleles of the Drosophila homologue of FZR1 fzr. All three individuals carrying de novo variants in FZR1 had childhood-onset generalized epilepsy, intellectual disability, mild ataxia and normal head circumference. Two individuals were diagnosed with the developmental and epileptic encephalopathy subtype myoclonic atonic epilepsy. We provide genetic-association testing using two independent statistical tests to support FZR1 association with developmental and epileptic encephalopathies. Further, we provide functional evidence that the missense variants are loss-of-function alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homologue fzr and overexpression studies, we show that patient variants can affect proper neurodevelopment. With the recent report of a patient with neonatal-onset with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and developmental and epileptic encephalopathy and expands the associated phenotype. We conclude that heterozygous loss-of-function of FZR1 leads to developmental and epileptic encephalopathies associated with a spectrum of neonatal to childhood-onset seizure types, developmental delay and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed myoclonic atonic epilepsy or developmental and epileptic encephalopathy cases.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets