title: De novo KCNB1 mutations in epileptic encephalopathy.
abstract: OBJECTIVE
  Numerous studies have demonstrated increased load of de novo copy number variants or single nucleotide variants in individuals with neurodevelopmental disorders, including epileptic encephalopathies, intellectual disability, and autism.
  
  
  METHODS
  We searched for de novo mutations in a family quartet with a sporadic case of epileptic encephalopathy with no known etiology to determine the underlying cause using high-coverage whole exome sequencing (WES) and lower-coverage whole genome sequencing. Mutations in additional patients were identified by WES. The effect of mutations on protein function was assessed in a heterologous expression system.
  
  
  RESULTS
  We identified a de novo missense mutation in KCNB1 that encodes the KV 2.1 voltage-gated potassium channel. Functional studies demonstrated a deleterious effect of the mutation on KV 2.1 function leading to a loss of ion selectivity and gain of a depolarizing inward cation conductance. Subsequently, we identified 2 additional patients with epileptic encephalopathy and de novo KCNB1 missense mutations that cause a similar pattern of KV 2.1 dysfunction.
  
  
  CONCLUSIONS
  Our genetic and functional evidence demonstrate that KCNB1 mutation can result in early onset epileptic encephalopathy. This expands the locus heterogeneity associated with epileptic encephalopathies and suggests that clinical WES may be useful for diagnosis of epileptic encephalopathies of unknown etiology.
authors.affiliation: The Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute, San Diego, CA 92037.
authors.forename: Ali
authors.initials: A
authors.lastname: Torkamani
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bersell
authors.affiliation: Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Jorge
authors.affiliation: Pediatrics, Scripps Health, San Diego, CA 92037, USA.|Sea Breeze Pediatrics, APC, San Diego, CA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bjork
authors.affiliation: Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Friedman
authors.affiliation: The Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute, San Diego, CA 92037.
authors.forename: Cinnamon S
authors.initials: CS
authors.lastname: Bloss
authors.affiliation: Kennedy Krieger Institute, Baltimore, MD 21205.
authors.forename: Julie
authors.initials: J
authors.lastname: Cohen
authors.affiliation: Kennedy Krieger Institute, Baltimore, MD 21205.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Kennedy Krieger Institute, Baltimore, MD 21205.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
authors.forename: Sakkubai
authors.initials: S
authors.lastname: Naidu
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.|Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Vanoye
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.|Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.|Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.|Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kearney
mesh_terms: D000818:Animals; D019921:Biotinylation; D016466:CHO Cells; D002648:Child; D002675:Child, Preschool; D003412:Cricetulus; D002658:Developmental Disabilities / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D051669:Shab Potassium Channels / Q000235:genetics*; D014162:Transfection
chemical_list: C496988:KCNB1 protein, human; D051669:Shab Potassium Channels