Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature.

2019-09-12

Bar, Claire

Barcia, Giulia

Jennesson, Mélanie

Le Guyader, Gwenaël

Schneider, Amy L

Mignot, Cyril

Lesca, Gaetan

Breuillard, Delphine

Montomoli, Martino

Keren, Boris

Doummar, Diane

de Villemeur, Thierry Billette

Afenjar, Alexandra

Marey, Isabelle

Gerard, Marion

Isnard, Hervé

Poisson, Alice

Dupont, Sophie

Berquin, Patrick

Meyer, Pierre

Genevieve, David

De Saint Martin, Anne

El Chehadeh, Salima

Chelly, Jamel

Guët, Agnès

Scalais, Emmanuel

Dorison, Nathalie

Myers, Candace T

Mefford, Heather C

Howell, Katherine B

Marini, Carla

Freeman, Jeremy L

Nica, Anca

Terrone, Gaetano

Sekhara, Tayeb

Lebre, Anne-Sophie

Odent, Sylvie

Sadleir, Lynette G

Munnich, Arnold

Guerrini, Renzo

Scheffer, Ingrid E

Kabashi, Edor

Nabbout, Rima

KCNB1

developmental and epileptic encephalopathy

epilepsy

potassium channel

Journal Article

0000-0003-1489-0211

10.1002/humu.23915

Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the alpha subunit of the delayed-rectifier voltage-dependent potassium channel Kv 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of Kv 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms. This article is protected by copyright. All rights reserved.

link

Human Mutation 2020; 41(1): 69-80

Human mutation