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Stéphanie Baulac, PhD; Isabelle Gourfinkel-An, MD, PhD; Philippe Couarch, BS; Christel Depienne, PhD; Anna Kaminska, MD; Olivier Dulac, MD; Michel Baulac, MD; Eric LeGuern, MD, PhD; Rima Nabbout, MD, PhD

Arch Neurol. 2008;65(7):943-951.

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 1 subunit gene (SCN1A), the sodium channel β1 subunit gene (SCN1B), and the 2 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.

Objectives  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⁺.

Design  Family-based linkage analysis.

Setting  University hospital.

Patients  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.

Main Outcome Measures  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  = 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⁺.

Author Affiliations: INSERM, UMR_S679 Neurologie and Thérapeutique Expérimentale (Drs S. Baulac, Gourfinkel-An, Depienne, and LeGuern and Mr Couarch), UPMC Univ Paris 06, UMR_S679 (Drs S. Baulac, Gourfinkel-An, Depienne, and LeGuern and Mr Couarch), Epileptology Unit, AP-HP, Groupe Hospitalier Pitié-Salpêtrière (Drs Gourfinkel-An and M. Baulac), Department of Paediatric Neurology, Hôpital Necker Enfants Malades, AP-HP (Drs Kaminska, Dulac, and Nabbout), INSERM, UMR_S663 and University Paris Descartes (Drs Kaminska, Dulac, and Nabbout), and AP-HP, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Département de génétique et cytogénétique (Drs Depienne and LeGuern), Paris, France.

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