Journal
ANNALS OF NEUROLOGY
Volume 76, Issue 4, Pages 529-540Publisher
WILEY
DOI: 10.1002/ana.24263
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Funding
- Scripps Genomic Medicine, an NIH National Center for Advancing Translational Sciences Clinical and Translational Science Award [5 UL1 RR025774]
- Shaffer Family Foundation
- Anne and Henry Zarrow Foundation
- NIH/NHGRI [U01 HG006476]
- NIH/NINDS [R01 NS053792, R01 NS032387, F31 NS083097]
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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 K(V)2.1 voltage-gated potassium channel. Functional studies demonstrated a deleterious effect of the mutation on K(V)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 K(V)2.1 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.
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