A Novel SCN1A Mutation Associated with Generalized Epilepsy with Febrile Seizures Plus—and Prevalence of Variants in Patients with Epilepsy

We recently described mutations of the neuronal sodium-channel α-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 myoc...

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Bibliographic Details
Published in:American journal of human genetics 2001-04, Vol.68 (4), p.866-873
Main Authors: Escayg, Andrew, Heils, Armin, MacDonald, Bryan T., Haug, Karsten, Sander, Thomas, Meisler, Miriam H.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Biological and medical sciences
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
Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy
Humans
Introns - genetics
Male
Medical sciences
Molecular Sequence Data
Mutation - genetics
NAV1.1 Voltage-Gated Sodium Channel
Nerve Tissue Proteins - genetics
Nervous system (semeiology, syndromes)
Neurology
Pedigree
Phosphorylation
Polymorphism, Single Nucleotide - genetics
Protein-Tyrosine Kinases - metabolism
Seizures, Febrile - genetics
Sequence Alignment
Sodium Channels - genetics
Syndrome
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Summary:We recently described mutations of the neuronal sodium-channel α-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.
ISSN:0002-9297
1537-6605
DOI:10.1086/319524