A novel locus for Idiopathic Generalized Epilepsy in French
Canadian families maps to 10p11
Peter Kinirons, Dominique J. Verlaan, Marie-Pierre Dubé, Josée Poirier, Charles Deacon,
Anne Lortie, Jean-François Clément, Richard Desbiens, Lionel Carmant, Cecile CieutaWalti, Michael Shevell, Guy A. Rouleau, Patrick Cossette
Center for the Study of Brain Disease, University of Montreal, Canada
Presenting author : Peter Kinirons
Abstract
Introduction. Idiopathic generalized epilepsy (IGE) is a common form of epilepsy with evidence of a
strong genetic etiology. Although the underlying genetic architecture appears complex for a large
proportion of patients, Mendelian forms of the disease do exist. Taking advantage of the welldocumented founder effect in Quebec, we set out to conduct genomewide linkage analysis for genes
responsible for familial IGE in French-Canadian pedigrees.
Materials and Methods. 20 French-Canadian families segregating apparent autosomal dominant
disease were collected. Four larger IGE families sufficiently powerful for independent linkage analysis
were genome scanned at 10 cM density. Follow-up fine mapping was performed over regions with
LOD scores >3.0 for validation and haplotype analysis. The genotyping of 16 smaller families was
carried out at significantly linked loci for supportive linkage analysis and haplotype comparisons.
Results. Of the four genome scanned families, only one, EG-21, provided a significant linkage result
at marker D10S1426 on chromosome 10 (two-point LOD score =3.05, theta = 0; multipoint LOD
score =3.18.). Fine mapping in EG-21 revealed a segregating haplotype and key recombination
breakpoints, suggesting a candidate gene interval of approximately 6.5Mb. Genotyping of the
additional 16 smaller pedigrees was performed across the region and further multipoint linkage
analysis using these provided a maximum LOD score under heterogeneity (HLOD)of 4.23 (alpha=
0.34). Seven of these families appeared to be linked to the region. Evaluation of recombination
breakpoints in these smaller families narrowed the candidate region to 1.7 Mb. The two known genes
contained in this region, NRP1 and PARD3, were sequenced over coding regions and found to be
negative for mutation.
Discussion. We report the finding of a novel locus for IGE, located on chromosome 10p11. The
dominant phenotype associated with linkage to the region was IGE with tonic-clonic seizures only
(IGE-TCS). The gene neuropilin-1 (NRP-1) represents the best candidate for epilepsy within the
region and although screening of the coding regions were negative for mutation, it is possible that
variation in copy number or regulatory regions may underlie the disease.