title: SCN1A duplications and deletions detected in Dravet syndrome: implications for molecular diagnosis.
abstract: OBJECTIVE
  We aimed to determine the type, frequency, and size of microchromosomal copy number variations (CNVs) affecting the neuronal sodium channel α 1 subunit gene (SCN1A) in Dravet syndrome (DS), other epileptic encephalopathies, and generalized epilepsy with febrile seizures plus (GEFS+).
  
  
  METHODS
  Multiplex ligation-dependent probe amplification (MLPA) was applied to detect SCN1A CNVs among 289 cases (126 DS, 97 GEFS+, and 66 with other phenotypes). CNVs extending beyond SCN1A were further characterized by comparative genome hybridization (array CGH).
  
  
  RESULTS
  Novel SCN1A CNVs were found in 12.5% of DS patients where sequence-based mutations had been excluded. We identified the first partial SCN1A duplications in two siblings with typical DS and in a patient with early-onset symptomatic generalized epilepsy. In addition, a patient with DS had a partial SCN1A amplification of 5-6 copies. The remaining CNVs abnormalities were four partial and nine whole SCN1A deletions involving contiguous genes. Two CNVs (a partial SCN1A deletion and a duplication) were inherited from a parent, in whom there was mosaicism. Array CGH showed intragenic deletions of 90 kb and larger, with the largest of 9.3 Mb deleting 49 contiguous genes and extending beyond SCN1A.
  
  
  CONCLUSIONS
  Duplication and amplification involving SCN1A are now added to molecular mechanisms of DS patients. Our findings showed that 12.5% of DS patients who are mutation negative have MLPA-detected SCN1A CNVs with an overall frequency of about 2-3%. MLPA is the established second-line testing strategy to reliably detect all CNVs of SCN1A from the megabase range down to one exon. Large CNVs extending outside SCN1A and involving contiguous genes can be precisely characterized by array CGH.
authors.affiliation: Child Neurology Unit, Children's Hospital A. Meyer, University of Florence, Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
authors.forename: Davide
authors.initials: D
authors.lastname: Mei
authors.forename: Kathy
authors.initials: K
authors.lastname: Cox
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
authors.forename: Jacinta M
authors.initials: JM
authors.lastname: McMahon
authors.forename: Xenia
authors.initials: X
authors.lastname: Iona
authors.forename: Rochio Sanchez
authors.initials: RS
authors.lastname: Carpintero
authors.forename: Maurizio
authors.initials: M
authors.lastname: Elia
authors.forename: Maria Roberta
authors.initials: MR
authors.lastname: Cilio
authors.forename: Nicola
authors.initials: N
authors.lastname: Specchio
authors.forename: Lucio
authors.initials: L
authors.lastname: Giordano
authors.forename: Pasquale
authors.initials: P
authors.lastname: Striano
authors.forename: Elena
authors.initials: E
authors.lastname: Gennaro
authors.forename: J Helen
authors.initials: JH
authors.lastname: Cross
authors.forename: Sara
authors.initials: S
authors.lastname: Kivity
authors.forename: Miriam Y
authors.initials: MY
authors.lastname: Neufeld
authors.forename: Zaid
authors.initials: Z
authors.lastname: Afawi
authors.forename: Eva
authors.initials: E
authors.lastname: Andermann
authors.forename: Daniel
authors.initials: D
authors.lastname: Keene
authors.forename: Olivier
authors.initials: O
authors.lastname: Dulac
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: John C
authors.initials: JC
authors.lastname: Mulley
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004831:Epilepsies, Myoclonic / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D005784:Gene Amplification / Q000235:genetics; D017353:Gene Deletion; D020440:Gene Duplication; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D021141:Nucleic Acid Amplification Techniques; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D015222:Sodium Channels / Q000235:genetics*; D013577:Syndrome
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels