title: Complex SCN8A DNA-abnormalities in an individual with therapy resistant absence epilepsy.
abstract: BACKGROUND
  De novo SCN8A missense mutations have been identified as a rare dominant cause of epileptic encephalopathy. We described a person with epileptic encephalopathy associated with a mosaic deletion of the SCN8A gene.
  
  
  METHODS
  Array comparative genome hybridization was used to identify chromosomal abnormalities. Next Generation Sequencing was used to screen for variants in known and candidate epilepsy genes. A single nucleotide polymorphism array was used to test whether the SCN8A variants were in cis or in trans.
  
  
  RESULTS
  We identified a de novo mosaic deletion of exons 2-14 of SCN8A, and a rare maternally inherited missense variant on the other allele in a woman presenting with absence seizures, challenging behavior, intellectual disability and QRS-fragmentation on the ECG. We also found a variant in SCN5A.
  
  
  CONCLUSIONS
  The combination of a rare missense variant with a de novo mosaic deletion of a large part of the SCN8A gene suggests that other possible mechanisms for SCN8A mutations may cause epilepsy; loss of function, genetic modifiers and cellular interference may play a role. This case expands the phenotype associated with SCN8A mutations, with absence epilepsy and regression in language and memory skills.
authors.affiliation: Stichting Epilepsie Instellingen Nederland SEIN, Zwolle, The Netherlands. Electronic address: bberghuis@sein.nl.
authors.forename: Bianca
authors.initials: B
authors.lastname: Berghuis
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Carolien G F
authors.initials: CG
authors.lastname: de Kovel
authors.affiliation: Stichting Epilepsie Instellingen Nederland SEIN, Zwolle, The Netherlands; De Waterlelie School, Expertisecentrum voor Onderwijs en Epilepsie, Cruquius, The Netherlands.
authors.forename: Loretta
authors.initials: L
authors.lastname: van Iterson
authors.affiliation: Stichting Epilepsie Instellingen Nederland SEIN, Zwolle, The Netherlands.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lamberts
authors.affiliation: Stichting Epilepsie Instellingen Nederland SEIN, Zwolle, The Netherlands; NIHR UCL Hospitals Biomedical Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom; Epilepsy Society, Chalfont St Peter SL9 0RJ, United Kingdom.
authors.forename: Josemir W
authors.initials: JW
authors.lastname: Sander
authors.affiliation: Stichting Epilepsie Instellingen Nederland SEIN, Zwolle, The Netherlands; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Lindhout
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
mesh_terms: D000069279:Drug Resistant Epilepsy / Q000235:genetics*; D004832:Epilepsy, Absence / Q000235:genetics* / Q000503:physiopathology; D005091:Exons; D005260:Female; D006801:Humans; D059645:Mutation Rate; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C100681:SCN8A protein, human
keywords: Epileptic encephalopathy; Mosaicism; SCN5A; SCN8A; fQRS