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Linkage and association analysis of CACNG3 in childhood absence epilepsy

Item Type:Article
Title:Linkage and association analysis of CACNG3 in childhood absence epilepsy
Creators Name:Everett, K.V. and Chioza, B. and Aicardi, J. and Aschauer, H. and Brouwer, O. and Callenbach, P. and Covanis, A. and Dulac, O. and Eeg-Olofsson, O. and Feucht, M. and Friis, M. and Goutieres, F. and Guerrini, R. and Heils, A. and Kjeldsen, M. and Lehesjoki, A.E. and Makoff, A. and Nabbout, R. and Olsson, I. and Sander, T. and Siren, A. and McKeigue, P. and Robinson, R. and Taske, N. and Rees, M. and Gardiner, M.
Abstract: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, alpha=0.62) was obtained for markers encompassing CACNG3 in 65 nuclear families with a proband with CAE. The maximum non-parametric 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 approximately 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.
Keywords:Absence epilepsy, Linkage, Association, CACNG3, Splice variants
Source:European Journal of Human Genetics
Publisher:Nature Publishing Group
Page Range:463-472
Date:April 2007
Official Publication:https://doi.org/10.1038/sj.ejhg.5201783
PubMed:View item in PubMed

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