A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33

We report a clinical and genetic study of a family with a phenotype resembl ing generalized epilepsy with febrile seizures plus (GEFS+), described by B erkovic and colleagues. Patients express a very variable phenotype combinin g febrile seizures, generalized seizures often precipitated by fever at age >6 years, and partial seizures, with a variable degree of severity. Linkag e analysis has excluded both the beta 1 subunit gene (SCN1B) of a voltage-g ated sodium (Na+) channel responsible for GEFS(+) and the two loci, FEB1 an d FEB2, previously implicated in febrile seizures. A genomewide search, und er the assumption of incomplete penetrance at 85% and a phenocopy rate of 5 %, permitted identification of a new locus on chromosome 2q21-q33. The maxi mum pairwise LOD score was 3.00 at recombination fraction 0 for marker D2S2 330. Haplotype reconstruction defined a large (22-cM) candidate interval fl anked by markers D2S156 and D2S2314. Four genes coding for different isofor ms of the cu-subunit voltage-gated sodium channels (SCN1A, SCN2A1, SCN2A2, and SCN3A) located in this region are strong candidates for the disease gen e.