De Novo KCNB1 Mutations in Epileptic Encephalopathy. A. Torkamani1, K. Bersell4, B. S. Jorge4, R. L. Bjork2, J. R. Friedman3, C. S. Bloss1, S. E. Topol1, G. Zhang1, J. Lee1, J. Cohen5, S. Gupta6, S. Naidu6, C. G. Vanoye7, A. L. George7, J. A. Kearney8 1) The Scripps Translational Science Institute, San Diego, CA; 2) Pediatrics, Scripps Health, San Diego, CA; 3) Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA; 4) Departments of Medicine and Pharmacology, Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN; 5) Kennedy Krieger Institute, Baltimore, MD; 6) Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD; 7) Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL; 8) Division of Genetic MedicineVanderbilt University, Nashville, TN.
Purpose: An 8-year-old female presented with a sporadic severe partial seizure disorder with an unusual pattern including intermittent lapses into stupor, tantrums, and oppositional behavior followed by cataplexy with no memory of the events. Her overall condition includes a complex neurological history of global delay, hypotonia, epileptic encephalopathy, vision impairment, poor modulation of motor movement, blood pressure and pulse lability, long QT, and potential cerebral folate deficiency. The condition did not appear to fit any diagnostic category, was deteriorating and demonstrated breakthroughs to most seizure medications. Thus, a family-based genome sequencing study was pursued in order to identify the cause of her condition. Methods: Combined whole genome sequencing (WGS) and whole exome sequencing (WES) was performed on the affected 8-year-old female and her unaffected parents and sibling in order to identify the genetic cause of her complex neurological condition. A combination of inheritance-based, population-based, functional-impact-based and variant annotation-based filters were applied to small variants and copy number variants identified in the family in order to isolate the potential molecular cause of the probands disorder. 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 two additional patients with epileptic encephalopathy and de novo KCNB1 missense mutations that result in a similar pattern of KV2.1 dysfunction. Our genetic and functional evidence demonstrate that KCNB1 mutation is a novel genetic cause of early onset epileptic encephalopathy.
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