A Second Locus for Familial Generalized Epilepsy with Febrile Seizures Plus Maps to Chromosome 2q21-q33

Abstract

We report a clinical and genetic study of a family with a phenotype resembling generalized epilepsy with febrile seizures plus (GEFS+), described by Berkovic and colleagues. Patients express a very variable phenotype combining febrile seizures, generalized seizures often precipitated by fever at age >6 years, and partial seizures, with a variable degree of severity. Linkage analysis has excluded both the beta 1 subunit gene (SCN1B) of a voltage-gated sodium (Na+) channel responsible for GEFS+ and the two loci, FEB1 and FEB2, previously implicated in febrile seizures. A genomewide search, under the assumption of incomplete penetrance at 85% and a phenocopy rate of 5%, permitted identification of a new locus on chromosome 2q21-q33. The maximum pairwise LOD score was 3.00 at recombination fraction 0 for marker D2S2330. Haplotype reconstruction defined a large (22-cM) candidate interval flanked by markers D2S156 and D2S2314. Four genes coding for different isoforms of the alpha-subunit voltage-gated sodium channels (SCN1A, SCN2A1, SCN2A2, and SCN3A) located in this region are strong candidates for the disease gene.

Sodium channel mutations in epilepsy and other neurological disorders

“…In 1999, linkage analysis in 2 large families localized a second GEFS+ locus to an interval of chromosome 2q24 that includes a sodium channel gene cluster (12,13). Sequencing of SCN1A demonstrated that affected individuals are heterozygous for missense mutations in highly evolutionarily conserved amino acid residues, T875M in 1 family and R1648H in the other (14).…”

A Missense Mutation of the Gene Encoding Voltage-Dependent Sodium Channel (Nav1.1) Confers Susceptibility to Febrile Seizures in Rats

“…The most common symptoms of GEFSϩ are FS and FS plus, in which the seizures are triggered by hyperthermia and occur after 6 years of age (Scheffer and Berkovic, 1997;Baulac et al, 1999). To investigate whether Scn1a mutant rats are susceptible to thermal stimuli, we used a hot water bath to induce FS (Klauenberg and Sparber, 1984)…”

Identification of Epilepsy Genes in Human and Mouse

“…A second locus, GEFS+2, was mapped in 1999 to a 20-cM interval of chromosome 2q24 that contained the α subunit genes SCN1A, SCN2A, and SCN3A by analysis of two large families (6,50). Screening affected individuals from both families using conformation sensitive gel electrophoresis of amplified exons identified two missense mutations in the SCN1A gene, R1648H and T875M (27).…”