De novo KCNB1 mutations in epileptic encephalopathy

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...

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Published in:	Annals of neurology Vol. 76; no. 4; pp. 529 - 540
Main Authors:	Torkamani, Ali, Bersell, Kevin, Jorge, Benjamin S., Bjork Jr, Robert L., Friedman, Jennifer R., Bloss, Cinnamon S., Cohen, Julie, Gupta, Siddharth, Naidu, Sakkubai, Vanoye, Carlos G., George Jr, Alfred L., Kearney, Jennifer A.
Format:	Journal Article
Language:	English
Published:	United States Blackwell Publishing Ltd 01-10-2014 Wiley Subscription Services, Inc
Subjects:	Animals Biotinylation Child Child, Preschool CHO Cells Cricetulus Developmental Disabilities - genetics Epilepsy Epilepsy - genetics Female Genetic Predisposition to Disease - genetics Humans Male Medical research Membrane Potentials - genetics Mutation Mutation, Missense - genetics Patch-Clamp Techniques Phenotype Shab Potassium Channels - genetics Transfection
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Summary:	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 KV2.1 voltage‐gated potassium channel. Functional studies demonstrated a deleterious effect of the mutation on KV2.1 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 KV2.1 dysfunction. Interpretation 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. Ann Neurol 2014;76:529–540
Bibliography:	istex:90DFACA9A0A40D7CF9F9CE825AA48EA7DBAF263F ArticleID:ANA24263 ark:/67375/WNG-PS4S46DD-T ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0364-5134 1531-8249
DOI:	10.1002/ana.24263