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. 2017 Nov 2;101(5):664-685.
doi: 10.1016/j.ajhg.2017.09.008.

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

Fadi F Hamdan  1 Candace T Myers  2 Patrick Cossette  3 Philippe Lemay  1 Dan Spiegelman  4 Alexandre Dionne Laporte  4 Christina Nassif  1 Ousmane Diallo  4 Jean Monlong  5 Maxime Cadieux-Dion  6 Sylvia Dobrzeniecka  7 Caroline Meloche  7 Kyle Retterer  8 Megan T Cho  8 Jill A Rosenfeld  9 Weimin Bi  10 Christine Massicotte  1 Marguerite Miguet  1 Ledia Brunga  11 Brigid M Regan  12 Kelly Mo  12 Cory Tam  12 Amy Schneider  13 Georgie Hollingsworth  13 Deciphering Developmental Disorders StudyDavid R FitzPatrick  14 Alan Donaldson  15 Natalie Canham  16 Edward Blair  17 Bronwyn Kerr  18 Andrew E Fry  19 Rhys H Thomas  20 Joss Shelagh  21 Jane A Hurst  22 Helen Brittain  22 Moira Blyth  23 Robert Roger Lebel  24 Erica H Gerkes  25 Laura Davis-Keppen  26 Quinn Stein  27 Wendy K Chung  28 Sara J Dorison  29 Paul J Benke  30 Emily Fassi  31 Nicole Corsten-Janssen  25 Erik-Jan Kamsteeg  32 Frederic T Mau-Them  33 Ange-Line Bruel  33 Alain Verloes  34 Katrin Õunap  35 Monica H Wojcik  36 Dara V F Albert  37 Sunita Venkateswaran  38 Tyson Ware  39 Dean Jones  40 Yu-Chi Liu  41 Shekeeb S Mohammad  42 Peyman Bizargity  9 Carlos A Bacino  43 Vincenzo Leuzzi  44 Simone Martinelli  45 Bruno Dallapiccola  46 Marco Tartaglia  46 Lubov Blumkin  47 Klaas J Wierenga  48 Gabriela Purcarin  48 James J O'Byrne  49 Sylvia Stockler  49 Anna Lehman  50 Boris Keren  51 Marie-Christine Nougues  52 Cyril Mignot  51 Stéphane Auvin  53 Caroline Nava  51 Susan M Hiatt  54 Martina Bebin  55 Yunru Shao  9 Fernando Scaglia  9 Seema R Lalani  9 Richard E Frye  56 Imad T Jarjour  57 Stéphanie Jacques  58 Renee-Myriam Boucher  59 Emilie Riou  60 Myriam Srour  61 Lionel Carmant  62 Anne Lortie  63 Philippe Major  63 Paola Diadori  63 François Dubeau  4 Guy D'Anjou  63 Guillaume Bourque  5 Samuel F Berkovic  13 Lynette G Sadleir  64 Philippe M Campeau  65 Zoha Kibar  66 Ronald G Lafrenière  7 Simon L Girard  67 Saadet Mercimek-Mahmutoglu  68 Cyrus Boelman  69 Guy A Rouleau  4 Ingrid E Scheffer  70 Heather C Mefford  2 Danielle M Andrade  12 Elsa Rossignol  62 Berge A Minassian  71 Jacques L Michaud  72
Free PMC article

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

Fadi F Hamdan et al. Am J Hum Genet. .
Free PMC article


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.

Keywords: CLTC; DHDDS; GABBR2; GABRB2; NTRK2; NUS1; RAB11; SNAP25; epileptic encephalopathy.


Figure 1
Figure 1
Localization of De Novo Variants in Protein Domains Encoded by Genes of Interest GABRB2 (A), CLTC (B), NUS1 (C), NTRK2 (D), and DHDDS, SNAP25, GABBR2, and RAB11A (E). Recurrent de novo variants are in italics and red font. The transmembrane domains of GABRB2 and GABBR2 are labeled 1–4 and 1–7, respectively. Abbreviations are as follows: TM, transmembrane domain; TD, trimerization domain; SP, signal peptide; LRRNT, leucine-rich repeat N-terminal domain; LRR, leucine-rich repeat; LRRCT, leucine-rich repeat C-terminal domain; IGC2, immunoglobulin C-2 type 1 domain; IGC2-2, immunoglobulin C-2 type 2 domain; Shc, SHC1 interaction domain; IPP, isopentenyl diphosphate binding site; CD, catalytic domain; FPP, farnesyl diphosphate binding site; SW, switch domain; and CC, prenylation residue.

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