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, α=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 ∼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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Acknowledgements
This work was supported by the MRC (UK), Wellcome Trust, Action Medical Research and Epilepsy Research Foundation. We are very grateful to the families for participating in this study and to all our 142 collaborating clinicians, including Dr Lina Nashef. We thank Généthon for their assistance in collecting the French samples and Richard Sharp for his technical help. Austrian financial support came from the Austrian Research Foundation (awarded to Harald Aschauer, MD), Grant number P10460-MED. Thomas Sander, MD, was awarded a grant by the Deutsche Forschungsgemeinschaft (Sa434/3-1), the German National Genome Research Network (01GS0479). Dutch financial support came from the Netherlands Organisation for Health, Research and Development (ZonMW, 940-33-030) and the Dutch National Epilepsy Fund – ‘The power of the small’ (NEF – ‘De macht van het kleine’). Danish support (Mogens Friis, MD, and Marianne Kjeldsen, MD) came from the NINDS grant (NS-31564).
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Advanced Biotechnology Centre, Imperial College, http://bm-abc01.cx.med.ic.ac.uk/
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NCBI Nucleotide Database, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=nuccore
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ESEFinder, http://rulai.cshl.edu/tools/ESE/
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Everett, K., Chioza, B., Aicardi, J. et al. Linkage and association analysis of CACNG3 in childhood absence epilepsy. Eur J Hum Genet 15, 463–472 (2007). https://doi.org/10.1038/sj.ejhg.5201783
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DOI: https://doi.org/10.1038/sj.ejhg.5201783
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