title: Mutation screening of SCN2A in schizophrenia and identification of a novel loss-of-function mutation.
abstract: OBJECTIVE
  There is a growing body of evidence suggesting a shared genetic susceptibility between many neuropsychiatric disorders, including schizophrenia, autism, intellectual disability (ID) and epilepsy. The sodium channel, voltage-gated type II α subunit gene SCN2A has been shown to exhibit loss-of-function (LoF) mutations in individuals with seizure disorders, ID, autism and schizophrenia. The role of LoF mutations in schizophrenia is still uncertain with only one such mutation identified to date.
  
  
  METHODS
  To seek additional evidence for a role for LoF mutations at SCN2A in schizophrenia we performed mutation screening of the entire coding sequence in 980 schizophrenia cases. Given an absence of LoF mutations in a public exome cohort (ESP6500, N=6503), we did not additionally sequence controls.
  
  
  RESULTS
  We identified a novel, nonsense (i.e. stop codon) mutation in one case (E169X) that is absent in 4300 European-American and 2203 African-American individuals from the NHLBI Exome Sequencing Project. This is the second LoF allele identified in a schizophrenia case to date. We also show a novel, missense variant, V1282F, that occurs in two cases and is absent in the control dataset.
  
  
  CONCLUSIONS
  We argue that very rare, LoF mutations at SCN2A act in a moderately penetrant manner to increase the risk of developing several neuropsychiatric disorders including seizure disorders, ID, autism and schizophrenia.
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine & Neurology, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: Liam S
authors.initials: LS
authors.lastname: Carroll
authors.forename: Rebecca
authors.initials: R
authors.lastname: Woolf
authors.forename: Yousef
authors.initials: Y
authors.lastname: Ibrahim
authors.forename: Hywel J
authors.initials: HJ
authors.lastname: Williams
authors.forename: Sarah
authors.initials: S
authors.lastname: Dwyer
authors.forename: James
authors.initials: J
authors.lastname: Walters
authors.forename: George
authors.initials: G
authors.lastname: Kirov
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
mesh_terms: D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D006113:United Kingdom
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; C568251:SCN2A protein, human