Journal
NEUROLOGY-GENETICS
Volume 1, Issue 4, Pages -Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/NXG.0000000000000035
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Funding
- French program Investissements d'avenir [ANR-10-IAIHU-06]
- Fondation Francaise pour la Recherche sur l'Epilepsie (FFRE)
- Association de Recherche sur la Genetique des Epilepsies (ARGE)
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Objective: To identify the genetic cause in a large family with febrile seizures (FS) and temporal lobe epilepsy (TLE) and subsequently search for additional mutations in a cohort of 107 families with FS, with or without epilepsy. Methods: The cohort consisted of 1 large family with FS and TLE, 64 smaller French families recruited through a national French campaign, and 43 Italian families. Molecular analyses consisted of whole-exome sequencing and mutational screening. Results: Exome sequencing revealed a p.Glu402fs*3 mutation in the gamma 2 subunit of the GABA(A) receptor gene (GABRG2) in the large family with FS and TLE. Three additional nonsense and frameshift GABRG2 mutations (p.Arg136*, p.Val462fs*33, and p.Pro59fs*12), 1 missense mutation (p.Met199Val), and 1 exonic deletion were subsequently identified in 5 families of the follow-up cohort. Conclusions: We report GABRG2 mutations in 5.6% (6/108) of families with FS, with or without associated epilepsy. This study provides evidence that GABRG2 mutations are linked to the FS phenotype, rather than epilepsy, and that loss-of-function of GABA(A) receptor gamma 2 subunit is the probable underlying pathogenic mechanism.
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