De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP

Am J Hum Genet. 2012 Mar 9;90(3):502-10. doi: 10.1016/j.ajhg.2012.01.006. Epub 2012 Feb 23.


Individuals with severe, sporadic disorders of infantile onset represent an important class of disease for which discovery of the underlying genetic architecture is not amenable to traditional genetic analysis. Full-genome sequencing of affected individuals and their parents provides a powerful alternative strategy for gene discovery. We performed whole-genome sequencing (WGS) on a family quartet containing an affected proband and her unaffected parents and sibling. The 15-year-old female proband had a severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. We discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. This mutation alters an evolutionarily conserved residue in Nav1.6, one of the most abundant sodium channels in the brain. Analysis of the biophysical properties of the mutant channel demonstrated a dramatic increase in persistent sodium current, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in hippocampal neurons transfected with p.Asn1768Asp channels revealed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype in the heterozygous proband. This work identifies SCN8A as the fifth sodium-channel gene to be mutated in epilepsy and demonstrates the value of WGS for the identification of pathogenic mutations causing severe, sporadic neurological disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Death, Sudden / etiology*
  • Epilepsy / complications*
  • Epilepsy / genetics*
  • Exons
  • Female
  • Gene Frequency / genetics
  • Genome-Wide Association Study / methods
  • Genomic Structural Variation
  • Heterozygote
  • Humans
  • Male
  • Mutation, Missense*
  • NAV1.6 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins / genetics*
  • Neurons / metabolism
  • Phenotype
  • Sequence Analysis, DNA / methods
  • Sodium Channels / genetics*


  • NAV1.6 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins
  • SCN8A protein, human
  • Sodium Channels