Genetic Architecture of Idiopathic Generalized Epilepsy: Clinical Genetic Analysis of 55 Multiplex Families

Carla Marini, Ingrid E. Scheffer, Kathryn M. Crossland, Bronwyn E. Grinton, Fiona L. Phillips, Jacinta M. McMahon, Samantha J. Turner, Joanne T. Dean, Sara Kivity, Aziz Mazarib, Miriam Y. Neufeld, Amos D. Korczyn, Louise A. Harkin, Leanne M. Dibbens, Robyn H. Wallace, John C. Mulley, Samuel F. Berkovic*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

123 Scopus citations


Purpose: In families with idiopathic generalized epilepsy (IGE), multiple IGE subsyndromes may occur. We performed a genetic study of IGE families to clarify the genetic relation of the IGE subsyndromes and to improve understanding of the mode(s) of inheritance. Methods: Clinical and genealogic data were obtained on probands with IGE and family members with a history of seizures. Families were grouped according to the probands' IGE subsyndrome: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with tonic-clonic seizures only (IGE-TCS). The subsyndromes in the relatives were analyzed. Mutations in genes encoding α1 and γ2 γ-aminobutyric acid (GABA)-receptor subunits, α1 and β1 sodium channel subunits, and the chloride channel CLC-2 were sought. Results: Fifty-five families were studied. 122 (13%) of 937 first- and second-degree relatives had seizures. Phenotypic concordance within families of CAE and JME probands was 28 and 27%, respectively. JAE and IGE-TCS families had a much lower concordance (10 and 13%), and in the JAE group, 31% of relatives had CAE. JME was rare among affected relatives of CAE and JAE probands and vice versa. Mothers were more frequently affected than fathers. No GABA-receptor or sodium or chloride channel gene mutations were identified. Conclusions: The clinical genetic analysis of this set of families suggests that CAE and JAE share a close genetic relation, whereas JME is a more distinct entity. Febrile seizures and epilepsy with unclassified tonic-clonic seizures were frequent in affected relatives of all IGE individuals, perhaps representing a nonspecific susceptibility to seizures. A maternal effect also was seen. Our findings are consistent with an oligogenic model of inheritance.

Original languageEnglish
Pages (from-to)467-478
Number of pages12
Issue number5
StatePublished - May 2004


  • Family studies
  • Genetics
  • Idiopathic generalized epilepsy


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