Linkage and mutational analysis of CLCN2 in childhood absence epilepsy.
In order to assess the chloride channel gene CLCN2 as a candidate susceptibility gene for childhood absence epilepsy, parametric and non-parametric linkage analysis was performed in 65 nuclear pedigrees. This provided suggestive evidence for linkage with heterogeneity: NPL score=2.3, p<0.009; HLOD=1.5, alpha=0.44. Mutational analysis of the entire genomic sequence of CLCN2 was performed in 24 unrelated patients from pedigrees consistent with linkage, identifying 45 sequence variants including the known non-synonymous polymorphism rs2228292 (G2154C, Glu718Asp) and a novel variant IVS4+12G>A. Intra-familial association analysis using the pedigrees and a further 308 parent-child trios showed suggestive evidence for transmission disequilibrium of the G2154C minor allele: AVE-PDT chi(1)2 = 5.17, p<0.03. Case-control analysis provided evidence for a protective effect of the IVS4+12G>A minor allele: chi(1)2 = 7.27, p<0.008. The 65 nuclear pedigrees were screened for three previously identified mutations shown to segregate with a variety of idiopathic generalised epilepsy phenotypes (597insG, IVS2-14del11 and G2144A) but none were found. We conclude that CLCN2 may be a susceptibility locus in a subset of cases of childhood absence epilepsy.
Everett
Kate
K
General and Adolescent Paediatric Unit, Centre for Human Molecular Genetics, UCL Institute Child Health, University College London, The Rayne Building, 5 University Street, London WC1E 6JJ, UK.
Chioza
Barry
B
Aicardi
Jean
J
Aschauer
Harald
H
Brouwer
Oebele
O
Callenbach
Petra
P
Covanis
Athanasios
A
Dooley
Joseph
J
Dulac
Olivier
O
Durner
Martina
M
Eeg-Olofsson
Orvar
O
Feucht
Martha
M
Friis
Mogens
M
Guerrini
Renzo
R
Heils
Armin
A
Kjeldsen
Marianne
M
Nabbout
Rima
R
Sander
Thomas
T
Wirrell
Elaine
E
McKeigue
Paul
P
Robinson
Robert
R
Taske
Nichole
N
Gardiner
Mark
M
D000483:Alleles; D000090007:CLC-2 Chloride Channels; D002648:Child; D018118:Chloride Channels / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000235:genetics*; D005787:Gene Frequency; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D007073:Immunoglobulin E / Q000235:genetics / Q000502:physiology; D018895:Microsatellite Repeats; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics
D000090007:CLC-2 Chloride Channels; D018118:Chloride Channels; D007073:Immunoglobulin E; D004247:DNA