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Original article
De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy
  1. Maxime G Blanchard1,
  2. Marjolein H Willemsen2,
  3. Jaclyn B Walker3,
  4. Sulayman D Dib-Hajj4,5,
  5. Stephen G Waxman4,5,
  6. Marjolijn CJ Jongmans2,
  7. Tjitske Kleefstra2,
  8. Bart P van de Warrenburg6,
  9. Peter Praamstra6,
  10. Joost Nicolai7,8,
  11. Helger G Yntema2,
  12. René JM Bindels1,
  13. Miriam H Meisler3,
  14. Erik-Jan Kamsteeg2
  1. 1Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
  2. 2Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
  3. 3Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA
  4. 4The Center for Neuroscience & Regeneration Research, Yale School of Medicine, New Haven, Connecticut, USA
  5. 5The Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, Connecticut, USA
  6. 6Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
  7. 7Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands
  8. 8Epilepsy Center Kempenhaeghe, Heeze, The Netherlands
  1. Correspondence to Dr Erik-Jan Kamsteeg, Department of Human Genetics, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands; Erik-Jan.Kamsteeg{at}


Background Mutations of SCN8A encoding the neuronal voltage-gated sodium channel NaV1.6 are associated with early-infantile epileptic encephalopathy type 13 (EIEE13) and intellectual disability. Using clinical exome sequencing, we have detected three novel de novo SCN8A mutations in patients with intellectual disabilities, and variable clinical features including seizures in two patients. To determine the causality of these SCN8A mutations in the disease of those three patients, we aimed to study the (dys)function of the mutant sodium channels.

Methods The functional consequences of the three SCN8A mutations were assessed using electrophysiological analyses in transfected cells. Genotype–phenotype correlations of these and other cases were related to the functional analyses.

Results The first mutant displayed a 10 mV hyperpolarising shift in voltage dependence of activation (gain of function), the second did not form functional channels (loss of function), while the third mutation was functionally indistinguishable from the wildtype channel.

Conclusions Comparison of the clinical features of these patients with those in the literature suggests that gain-of-function mutations are associated with severe EIEE, while heterozygous loss-of-function mutations cause intellectual disability with or without seizures. These data demonstrate that functional analysis of missense mutations detected by clinical exome sequencing, both inherited and de novo, is valuable for clinical interpretation in the age of massive parallel sequencing.

  • Epilepsy and seizures
  • Movement disorders (other than Parkinsons)
  • intelectual disability
  • sodium channel
  • encephalopathy

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