A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy

Am J Hum Genet. 2001 Apr;68(4):866-73. doi: 10.1086/319524. Epub 2001 Mar 14.


We recently described mutations of the neuronal sodium-channel alpha-subunit gene, SCN1A, on chromosome 2q24 in two families with generalized epilepsy with febrile seizures plus (GEFS+) type 2. To assess the contribution that SCN1A makes to other types of epilepsy, 226 patients with either juvenile myoclonic epilepsy, absence epilepsy, or febrile convulsions were screened by conformation-sensitive gel electrophoresis and manual sequencing of variants; the sample included 165 probands from multiplex families and 61 sporadic cases. The novel mutation W1204R was identified in a family with GEFS+. Seven other coding changes were observed; three of these are potential disease-causing mutations. Two common haplotypes, with frequencies of .67 and .33, were defined by five single-nucleotide polymorphisms (SNPs) spanning a 14-kb region of linkage disequilibrium. An SNP located 18 bp upstream of the splice-acceptor site for exon 3 was observed in 7 of the 226 patients but was not present in 185 controls, suggesting possible association with a disease mutation. This work has confirmed the role of SCN1A in GEFS+, by identification of a novel mutation in a previously undescribed family. Although a few candidate disease alleles were identified, the patient survey suggests that SCN1A is not a major contributor to idiopathic generalized epilepsy. The SCN1A haplotypes and SNPs identified here will be useful in future association and linkage studies.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Conserved Sequence / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • DNA Mutational Analysis
  • Epilepsy / genetics*
  • Epilepsy, Generalized / genetics*
  • Exons / genetics
  • Female
  • Gene Frequency / genetics
  • Genetic Testing
  • Genetic Variation / genetics*
  • Haplotypes / genetics
  • Humans
  • Introns / genetics
  • Male
  • Molecular Sequence Data
  • Mutation / genetics*
  • NAV1.1 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins / genetics*
  • Pedigree
  • Phosphorylation
  • Polymorphism, Single Nucleotide / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Seizures, Febrile / genetics*
  • Sequence Alignment
  • Sodium Channels / genetics*
  • Syndrome


  • NAV1.1 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins
  • SCN1A protein, human
  • Sodium Channels
  • Protein-Tyrosine Kinases
  • Cyclic AMP-Dependent Protein Kinases

Associated data

  • GENBANK/AF047380
  • GENBANK/AF188679
  • GENBANK/AJ251507
  • GENBANK/D37977
  • GENBANK/M22252
  • GENBANK/M32078
  • GENBANK/M81758
  • GENBANK/M94055
  • GENBANK/X82835