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

2017-11-02

Hamdan, Fadi F

Myers, Candace T

Cossette, Patrick

Lemay, Philippe

Spiegelman, Dan

Laporte, Alexandre Dionne

Nassif, Christina

Diallo, Ousmane

Monlong, Jean

Cadieux-Dion, Maxime

Dobrzeniecka, Sylvia

Riou, Emilie

Srour, Myriam

Carmant, Lionel

Lortie, Anne

Major, Philippe

Diadori, Paola

Dubeau, François

D'Anjou, Guy

Bourque, Guillaume

Berkovic, Samuel F

Sadleir, Lynette G

Campeau, Philippe M

Kibar, Zoha

Lafrenière, Ronald G

Girard, Simon L

Mercimek-Mahmutoglu, Saadet

Boelman, Cyrus

Rouleau, Guy A

Scheffer, Ingrid E

Mefford, Heather C

Andrade, Danielle M

Rossignol, Elsa

Minassian, Berge A

Michaud, Jacques L

Meloche, Caroline

Retterer, Kyle

Cho, Megan T

Rosenfeld, Jill A

Bi, Weimin

Massicotte, Christine

Miguet, Marguerite

Brunga, Ledia

Regan, Brigid M

Mo, Kelly

Tam, Cory

Schneider, Amy

Hollingsworth, Georgie

FitzPatrick, David R

Donaldson, Alan

Canham, Natalie

Blair, Edward

Kerr, Bronwyn

Fry, Andrew E

Thomas, Rhys H

Shelagh, Joss

Hurst, Jane A

Brittain, Helen

Blyth, Moira

Lebel, Robert Roger

Gerkes, Erica H

Davis-Keppen, Laura

Stein, Quinn

Chung, Wendy K

Dorison, Sara J

Benke, Paul J

Fassi, Emily

Corsten-Janssen, Nicole

Kamsteeg, Erik-Jan

Mau-Them, Frederic T

Bruel, Ange-Line

Verloes, Alain

Õunap, Katrin

Wojcik, Monica H

Albert, Dara V F

Venkateswaran, Sunita

Ware, Tyson

Jones, Dean

Liu, Yu-Chi

Mohammad, Shekeeb S

Bizargity, Peyman

Bacino, Carlos A

Leuzzi, Vincenzo

Martinelli, Simone

Dallapiccola, Bruno

Tartaglia, Marco

Blumkin, Lubov

Wierenga, Klaas J

Purcarin, Gabriela

O'Byrne, James J

Stockler, Sylvia

Lehman, Anna

Keren, Boris

Nougues, Marie-Christine

Mignot, Cyril

Auvin, Stéphane

Nava, Caroline

Hiatt, Susan M

Bebin, Martina

Shao, Yunru

Scaglia, Fernando

Lalani, Seema R

Frye, Richard E

Jarjour, Imad T

Jacques, Stéphanie

Boucher, Renee-Myriam

CLTC

DHDDS

GABBR2

GABRB2

NTRK2

NUS1

RAB11

SNAP25

epileptic encephalopathy

Journal Article

0000-0002-2311-2174

0000-0003-4580-841X

10.1016/j.ajhg.2017.09.008

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.

link

American journal of human genetics 2017; 101(5): 664-685

American journal of human genetics