Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature
Human Mutation. 2019-10-04; 41(1): 69-80
DOI: 10.1002/humu.23915
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1. Hum Mutat. 2020 Jan;41(1):69-80. doi: 10.1002/humu.23915. Epub 2019 Oct 4.
Expanding the genetic and phenotypic relevance of KCNB1 variants in
developmental and epileptic encephalopathies: 27 new patients and overview of
the literature.
Bar C(1)(2)(3), Barcia G(2)(3)(4), Jennesson M(5), Le Guyader G(6)(7), Schneider
A(8), Mignot C(9)(10), Lesca G(11)(12), Breuillard D(1), Montomoli M(13), Keren
B(10), Doummar D(14), Billette de Villemeur T(14), Afenjar A(15), Marey I(10),
Gerard M(16), Isnard H(17), Poisson A(18), Dupont S(9)(19), Berquin P(20), Meyer
P(21)(22), Genevieve D(23), De Saint Martin A(24), El Chehadeh S(25), Chelly
J(25), Guët A(26), Scalais E(27), Dorison N(28), Myers CT(29), Mefford HC(30),
Howell KB(31)(32), Marini C(13), Freeman JL(31)(32), Nica A(33), Terrone G(34),
Sekhara T(35), Lebre AS(36), Odent S(37)(38), Sadleir LG(39), Munnich A(3)(4),
Guerrini R(13), Scheffer IE(8)(31)(40), Kabashi E(2)(3), Nabbout R(1)(2)(3).
Author information:
(1)Department of Pediatric Neurology, Reference Centre for Rare Epilepsies,
Hôpital Necker-Enfants Malades, Paris, France.
(2)Imagine institute, laboratory of Translational Research for Neurological
Disorders, INSERM UMR 1163, Imagine Institute, Paris, France.
(3)Université Paris Descartes-Sorbonne Paris Cité, Paris, France.
(4)Department of genetics, Necker Enfants Malades hospital, Assistance
Publique-Hôpitaux de Paris, Paris, France.
(5)Department of Pediatrics, American Memorial Hospital, Reims, France.
(6)Department of genetics, University hospital Poitiers, Poitiers Cedex, France.
(7)EA3808-NEUVACOD Unité Neurovasculaire et Troubles Cognitifs, Pôle Biologie
Santé, Université de Poitiers, Poitiers, France.
(8)Department of Medicine, Epilepsy Research Centre, Austin Health, The
University of Melbourne, Heidelberg, Victoria, Australia.
(9)Institut du Cerveau et de la Moelle épinière, INSERM, U 1127, CNRS UMR 7225,
Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Paris, France.
(10)Département de Génétique et de Cytogénétique, Centre de Reference Déficience
Intellectuelle de Causes Rares, APHP, Hôpital Pitié-Salpêtrière, GRC UPMC
(Déficience Intellectuelle et Autisme), Paris, France.
(11)Department of genetics, Hospices Civils de Lyon, Lyon, France.
(12)Neurosciences centre of Lyon, INSERM U1028, UMR CNRS 5292, Université Claude
Bernard Lyon 1, Bron Cedex, France.
(13)Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories,
Department of Neuroscience, A Meyer Children’s Hospital, University of Florence,
Florence, Italy.
(14)Department of Pediatric Neurology, Hôpital Armand Trousseau, AP-HP, Paris,
France.
(15)Département de Génétique et Embryologie Médicale, Pathologies Congénitales
du Cervelet-LeucoDystrophies, Centre de Référence déficiences intellectuelles de
causes rares, AP-HP, Hôpital Armand Trousseau, GRC n°19, Sorbonne Université,
Paris, France.
(16)Department of genetics, CHU Côte de Nacre, Caen, France.
(17)Neurology clinic, Lyon, France.
(18)Reference Center for Diagnosis and Management of Genetic Psychiatric
Disorders, Centre Hospitalier le Vinatier and EDR-Psy Team, Centre National de
la Recherche Scientifique & Lyon 1 Claude Bernard University, Villeurbanne,
France.
(19)Epileptology and Rehabilitation department, GH Pitie-Salpêtrière-Charles
Foix, AP-HP, Paris, France.
(20)Department of pediatric neurology Amiens-Picardie university hospital,
Université de Picardie Jules Verne, Amiens, France.
(21)Department of pediatric neurology, Montpellier university hospital,
Montpellier, France.
(22)PhyMedExp, U1046 INSERM, UMR9214 CNRS, Montpellier, France.
(23)Service de génétique clinique et du Département de Génétique Médicale,
Maladies Rares et Médecine Personnalisée, Centre de référence maladies rares
anomalies du développement, CHU Montpellier, Montpellier, France.
(24)Department of Pediatric Neurology, Strasbourg University Hospital,
Strasbourg, France.
(25)Department of genetics, Hôpital de Hautepierre, Hôpitaux Universitaires de
Strasbourg, Strasbourg, France.
(26)Department of Pediatric, Louis-Mourier Hospital, Colombes, France.
(27)Department of Pediatric Neurology, Centre Hospitalier de Luxembourg,
Luxembourg City, Luxembourg City, Luxembourg.
(28)Department of pediatric Neurosurgery, Rothschild Foundation Hospital, Paris,
France.
(29)Department of Pediatrics, University of Washington, Seattle, Washington.
(30)Department of Pediatrics, Division of Genetic Medicine, University of
Washington, Seattle, Washington.
(31)Departments of Neurology and Paediatrics, Royal Children’s Hospital,
University of Melbourne, Melbourne, Victoria, Australia.
(32)Murdoch Children’s Research Institute, Melbourne, Victoria, Australia.
(33)Department of Neurology, Center for Clinical Research (CIC 1414), Rennes
University Hospital, Rennes, France.
(34)Department of Translational Medical Sciences, Section of Pediatrics-Child
Neurology Unit, Federico II University, Naples, Italy.
(35)Department of Pediatric Neurology, C.H.I.R.E.C, Brussels, Belgium.
(36)Department of genetics, Maison Blanche hospital, University hospital, Reims,
Reims, France.
(37)Reference Centre for Rare Developmental Abnormalities, CLAD-Ouest, CHU
Rennes, Rennes, France.
(38)Institute of genetics and development, CNRS UMR 6290, Rennes university,
Rennes, France.
(39)Department of Paediatrics and Child Health, University of Otago, Wellington,
New Zealand.
(40)The Florey Institute of Neurosciences and Mental Health, Heidelberg,
Victoria, Australia.
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 α 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.
© 2019 Wiley Periodicals, Inc.
DOI: 10.1002/humu.23915
PMID: 31513310 [Indexed for MEDLINE]