title: Microdeletions involving the SCN1A gene may be common in SCN1A-mutation-negative SMEI patients.
abstract: Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome is a rare epilepsy syndrome. In 30 to 70% of SMEI patients, truncating and missense mutations in the neuronal voltage-gated sodium-channel alpha-subunit gene (SCN1A) have been identified. The majority of patients have truncating mutations that are predicted to be loss-of-function alleles. Because mutation detection studies use PCR-based sequencing or conformation sensitive gel electrophoresis (CSGE), microdeletions, which are also predicted to be loss-of-function alleles, can easily escape detection. We selected 11 SMEI patients with or without additional features who had no SCN1A mutation detectable with sequencing analysis. In addition, none of the patients was heterozygous for any of the SNPs in SCN1A, indicating that they were either homozygous for all SNPs or hemizygous due to a microdeletion of the gene. We subsequently analyzed these patients for the presence of microdeletions in SCN1A using a quantitative PCR method named multiplex amplicon quantification (MAQ), and observed three patients missing one copy of the SCN1A gene. All three microdeletions were confirmed by fluorescence in situ hybridization (FISH). These findings demonstrate that a substantial percentage of SCN1A-mutation-negative SMEI patients with or without additional features carry a chromosomal microdeletion comprising the SCN1A gene and that haploinsufficiency of the SCN1A gene is a cause of SMEI.
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp, Antwerp, Belgium.
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.forename: Kristl G
authors.initials: KG
authors.lastname: Claeys
authors.forename: Dirk
authors.initials: D
authors.lastname: Goossens
authors.forename: Boris
authors.initials: B
authors.lastname: Harding
authors.forename: Rob
authors.initials: R
authors.lastname: Van Luijk
authors.forename: Stefaan
authors.initials: S
authors.lastname: Scheers
authors.forename: Liesbet
authors.initials: L
authors.lastname: Deprez
authors.forename: Dominique
authors.initials: D
authors.lastname: Audenaert
authors.forename: Tine
authors.initials: T
authors.lastname: Van Dyck
authors.forename: Sabine
authors.initials: S
authors.lastname: Beeckmans
authors.forename: Iris
authors.initials: I
authors.lastname: Smouts
authors.forename: Berten
authors.initials: B
authors.lastname: Ceulemans
authors.forename: Lieven
authors.initials: L
authors.lastname: Lagae
authors.forename: Gunnar
authors.initials: G
authors.lastname: Buyse
authors.forename: Nina
authors.initials: N
authors.lastname: Barisic
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Misson
authors.forename: Jan
authors.initials: J
authors.lastname: Wauters
authors.forename: Jurgen
authors.initials: J
authors.lastname: Del-Favero
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Lieve R F
authors.initials: LR
authors.lastname: Claes
mesh_terms: D002648:Child; D002874:Chromosome Mapping; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004831:Epilepsies, Myoclonic / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005820:Genetic Testing / Q000379:methods; D006239:Haplotypes; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels