Exploration of the genetic architecture of idiopathic generalized epilepsies.
OBJECTIVE
Idiopathic generalized epilepsy (IGE) accounts for approximately 20% of all epilepsies and affects about 0.2% of the general population. The etiology of IGE is genetically determined, but the complex pattern of inheritance suggests an involvement of a large number of susceptibility genes. The objective of the present study was to explore the genetic architecture of common IGE syndromes and to dissect out susceptibility loci predisposing to absence or myoclonic seizures.


METHODS
Genome-wide linkage scans were performed in 126 IGE-multiplex families of European origin ascertained through a proband with idiopathic absence epilepsy or juvenile myoclonic epilepsy. Each family had at least two siblings affected by IGE. To search for seizure type-related susceptibility loci, linkage analyses were carried out in family subgroups segregating either typical absence seizures or myoclonic and generalized tonic-clonic seizures on awakening.


RESULTS
Nonparametric linkage scans revealed evidence for complex and heterogeneous genetic architectures involving linkage signals at 5q34, 6p12, 11q13, 13q22-q31, and 19q13. The signal patterns differed in their composition, depending on the predominant seizure type in the families.


CONCLUSIONS
Our results are consistent with heterogeneous configurations of susceptibility loci associated with different IGE subtypes. Genetic determinants on 11q13 and 13q22-q31 seem to predispose preferentially to absence seizures, whereas loci on 5q34, 6p12, and 19q13 confer susceptibility to myoclonic and generalized tonic-clonic seizures on awakening.
Hempelmann
Anne
A
Gene Mapping Center, Max-Delbrück Center, Berlin, Germany.
Taylor
Kirsten P
KP
Heils
Armin
A
Lorenz
Susanne
S
Prud'homme
Jean-Francois
JF
Nabbout
Rima
R
Dulac
Olivier
O
Rudolf
Gabrielle
G
Zara
Federico
F
Bianchi
Amedeo
A
Robinson
Robert
R
Gardiner
R Mark
RM
Covanis
Athanasios
A
Lindhout
Dick
D
Stephani
Ulrich
U
Elger
Christian E
CE
Weber
Yvonne G
YG
Lerche
Holger
H
Nürnberg
Peter
P
Kron
Katherine L
KL
Scheffer
Ingrid E
IE
Mulley
John C
JC
Berkovic
Samuel F
SF
Sander
Thomas
T
D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004831:Epilepsies, Myoclonic / Q000235:genetics; D004832:Epilepsy, Absence / Q000235:genetics; D004829:Epilepsy, Generalized / Q000235:genetics*; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D044465:White People / Q000235:genetics