Linkage and association analysis of CACNG3 in childhood absence epilepsy

Everett, KV; Chioza, B; Aicardi, J; Aschauer, H; Brouwer, O; Callenbach, P; Covanis, A; Dulac, O; Eeg-Olofsson, O; Feucht, M; Friis, M; Goutieres, F; Guerrini, R; Heils, A; Kjeldsen, M; Lehesjoki, AE; Makoff, A; Nabbout, R; Olsson, I; Sander, T; Siren, A; McKeigue, P; Robinson, R; Taske, N; Rees, M; Gardiner, M; (2007) Linkage and association analysis of CACNG3 in childhood absence epilepsy. European journal of human genetics, 15 (4). pp. 463-472. ISSN 1018-4813 DOI:

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Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy characterised by absence seizures manifested by transitory loss of awareness with 2.5 - 4 Hz spike - wave complexes on ictal EEG. A genetic component to aetiology is established but the mechanism of inheritance and the genes involved are not fully defined. Available evidence suggests that genes encoding brain expressed voltage-gated calcium channels, including CACNG3 on chromosome 16p12 - p13.1, may represent susceptibility loci for CAE. The aim of this work was to further evaluate CACNG3 as a susceptibility locus by linkage and association analysis. Assuming locus heterogeneity, a significant HLOD score (HLOD 3.54, a 0.62) was obtained for markers encompassing CACNG3 in 65 nuclear families with a proband with CAE. The maximum nonparametric linkage score was 2.87 (P > 0.002). Re-sequencing of the coding exons in 59 patients did not identify any putative causal variants. A linkage disequilibrium (LD) map of CACNG3 was constructed using 23 single nucleotide polymorphisms (SNPs). Transmission disequilibrium was sought using individual SNPs and SNP- based haplotypes with the pedigree disequilibrium test in 217 CAE trios and the 65 nuclear pedigrees. Evidence for transmission disequilibrium (P <= 0.01) was found for SNPs within a similar to 35 kb region of high LD encompassing the 5'UTR, exon 1 and part of intron 1 of CACNG3. Re-sequencing of this interval was undertaken in 24 affected individuals. Seventy-two variants were identified: 45 upstream; two 5'UTR; and 25 intronic SNPs. No coding sequence variants were identified, although four variants are predicted to affect exonic splicing. This evidence supports CACNG3 as a susceptibility locus in a subset of CAE patients.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
PubMed ID: 17264864
Web of Science ID: 245103100011


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