title: Linkage and association analysis of CACNG3 in childhood absence epilepsy.
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 < 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.
authors.affiliation: Department of Paediatrics and Child Health, Royal Free and University College Medical School, University College London, London, UK. kate.everett@ucl.ac.uk
authors.forename: Kate V
authors.initials: KV
authors.lastname: Everett
authors.forename: Barry
authors.initials: B
authors.lastname: Chioza
authors.forename: Jean
authors.initials: J
authors.lastname: Aicardi
authors.forename: Harald
authors.initials: H
authors.lastname: Aschauer
authors.forename: Oebele
authors.initials: O
authors.lastname: Brouwer
authors.forename: Petra
authors.initials: P
authors.lastname: Callenbach
authors.forename: Athanasios
authors.initials: A
authors.lastname: Covanis
authors.forename: Olivier
authors.initials: O
authors.lastname: Dulac
authors.forename: Orvar
authors.initials: O
authors.lastname: Eeg-Olofsson
authors.forename: Martha
authors.initials: M
authors.lastname: Feucht
authors.forename: Mogens
authors.initials: M
authors.lastname: Friis
authors.forename: Françoise
authors.initials: F
authors.lastname: Goutieres
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Armin
authors.initials: A
authors.lastname: Heils
authors.forename: Marianne
authors.initials: M
authors.lastname: Kjeldsen
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.forename: Andrew
authors.initials: A
authors.lastname: Makoff
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
authors.forename: Ingrid
authors.initials: I
authors.lastname: Olsson
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
authors.forename: Auli
authors.initials: A
authors.lastname: Sirén
authors.forename: Paul
authors.initials: P
authors.lastname: McKeigue
authors.forename: Robert
authors.initials: R
authors.lastname: Robinson
authors.forename: Nichole
authors.initials: N
authors.lastname: Taske
authors.forename: Michele
authors.initials: M
authors.lastname: Rees
authors.forename: Mark
authors.initials: M
authors.lastname: Gardiner
mesh_terms: D015220:Calcium Channels / Q000235:genetics*; D020747:Calcium Channels, T-Type / Q000235:genetics*; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D004832:Epilepsy, Absence / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012640:Seizures
chemical_list: C520579:CACNG3 protein, human; D015220:Calcium Channels; D020747:Calcium Channels, T-Type; D005819:Genetic Markers