Linkage and association analysis of CACNG3 in childhood absence epilepsy.
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.
Everett
Kate V
KV
Department of Paediatrics and Child Health, Royal Free and University College Medical School, University College London, London, UK. kate.everett@ucl.ac.uk
Chioza
Barry
B
Aicardi
Jean
J
Aschauer
Harald
H
Brouwer
Oebele
O
Callenbach
Petra
P
Covanis
Athanasios
A
Dulac
Olivier
O
Eeg-Olofsson
Orvar
O
Feucht
Martha
M
Friis
Mogens
M
Goutieres
Françoise
F
Guerrini
Renzo
R
Heils
Armin
A
Kjeldsen
Marianne
M
Lehesjoki
Anna-Elina
AE
Makoff
Andrew
A
Nabbout
Rima
R
Olsson
Ingrid
I
Sander
Thomas
T
Sirén
Auli
A
McKeigue
Paul
P
Robinson
Robert
R
Taske
Nichole
N
Rees
Michele
M
Gardiner
Mark
M
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
C520579:CACNG3 protein, human; D015220:Calcium Channels; D020747:Calcium Channels, T-Type; D005819:Genetic Markers