A novel locus for generalized epilepsy with febrile seizures plus in French families.
BACKGROUND
Generalized epilepsy with febrile seizures plus (GEFS(+)) is a familial autosomal dominant entity characterized by the association of febrile and afebrile seizures. Mutations in 3 genes--the sodium channel alpha1 subunit gene (SCN1A), the sodium channel beta1 subunit gene (SCN1B), and the gamma2 GABA receptor subunit gene (GABRG2)--and linkage to 2 other loci on 2p24 and 21q22 have been identified in families with GEFS(+), indicating genetic heterogeneity.


OBJECTIVE
To localize by means of linkage analysis a new gene for GEFS(+) in a large family with 11 affected members and to test the new locus in 4 additional families with GEFS(+).


METHODS
Family-based linkage analysis.


METHODS
University hospital.


METHODS
Five French families with GEFS(+) and at least 7 available affected members with autosomal dominant transmission. All the patients had febrile seizures and/or afebrile generalized tonic-clonic seizures or absence epilepsy.


METHODS
We analyzed 380 microsatellite markers and conducted linkage analysis.


RESULTS
In the largest family, a 10-cM-density genomewide scan revealed linkage to a 13-Mb (megabase) interval on chromosome 8p23-p21 with a maximum pairwise logarithm of odds (LOD) score of 3.00 (at Theta = 0) for markers D8S351 and D8S550 and a multipoint LOD score of 3.23. A second family with GEFS(+) was also possibly linked to chromosome 8p23-p21 and the region was narrowed to a 7.3-Mb candidate interval, flanked by markers D8S1706 and D8S549. We have not, so far, identified mutations in the coding exons of 6 candidate genes (MTMR9, MTMR7, CTSB, SGCZ, SG223, and ATP6V1B2) located in the genetic interval.


CONCLUSIONS
We report a sixth locus for GEFS(+) on chromosome 8p23-p21. Because no ion channel genes are located in this interval, identification of the responsible gene will probably uncover a new mechanism of pathogenesis for GEFS(+).
Baulac
Stéphanie
S
INSERM, UMR679, Neurologie and Thérapeutique Expérimentale, UPMC Univ Paris 06, Groupe Hospitalier Pitié-Salpêtrière, 47 boulevard de l'hôpital, 75013 Paris, France. baulac@ccr.jussieu.fr
Gourfinkel-An
Isabelle
I
Couarch
Philippe
P
Depienne
Christel
C
Kaminska
Anna
A
Dulac
Olivier
O
Baulac
Michel
M
LeGuern
Eric
E
Nabbout
Rima
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D004829:Epilepsy, Generalized / Q000150:complications / Q000235:genetics*; D005260:Female; D005602:France; D008040:Genetic Linkage / Q000235:genetics; D005819:Genetic Markers; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D040641:Quantitative Trait Loci / Q000235:genetics*; D003294:Seizures, Febrile / Q000150:complications / Q000235:genetics*
D005819:Genetic Markers