Linkage and association analysis of CACNG3 in childhood absence epilepsy.

Everett, Kate V; Chioza, Barry; Aicardi, Jean; Aschauer, Harald; Brouwer, Oebele; Callenbach, Petra; Covanis, Athanasios; Dulac, Olivier; Eeg-Olofsson, Orvar; Feucht, Martha; +16 more...Friis, Mogens; Goutieres, Françoise; Guerrini, Renzo; Heils, Armin; Kjeldsen, Marianne; Lehesjoki, Anna-Elina; Makoff, Andrew; Nabbout, Rima; Olsson, Ingrid; Sander, Thomas; Sirén, Auli; McKeigue, Paul; Robinson, Robert; Taske, Nichole; Rees, Michele; and Gardiner, Mark (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: 10.1038/sj.ejhg.5201783
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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, 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 < or = 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.

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