Abstracts

Rationale: The genetic (idiopathic) generalized epilepsies (GGEs) account for 40 to 60% of the etiologies of epilepsy. Most of these syndromes have a complex transmission with phenotypic and genetic heterogeneity as well as incomplete penetrance of the causative mutations. However, despite this complexity, many genes and loci responsible for epilepsies have been identified. The identification of these loci, genes and associated mutations has been possible by genetic linkage studies and recently by Whole Exome Sequencing. The advents of Next Generation Sequencing technologies, such as whole genome and exome sequencing, is very promising for the identification of new genes of epilepsy. Methods: To identify novel GGEs causative genes, we clinically characterized three consanguineous families from Morocco with juvenile myoclonic epilepsy (JME) and autosomal recessive inheritance. All available family members were genotyped using Illumina Human Omni-express SNP chips. Multipoint linkage analysis was carried out with Merlin using an autosomal-recessive model with complete penetrance. Exome sequencing was performed for 8 patients from the three families. Exome capture was done using the Agilent SureSelect V4 and the sequencing on Illumina HiSeq2000. The annotation and the calling of the variants was done using an in-house data pipeline with the GATK software. Results: Linkage analysis led to the identification of one candidate region per family. Using Exome sequencing, we have identified a total of 116 835, 143 404 and 115 593 shared variants in family 1, 2 and 3 respectively. In order to identify the homozygous variants segregating with the disease, we prioritized the variants identified within intervals of homozygosity. All variants with an allelic frequency greater to 1% in public databases as well as in our in-house database (1500 exomes) were excluded from the analysis. Some of the remaining variants segregate well with the disease phenotype and were validated by Sanger sequencing. Conclusions: The combination of Linkage analysis, homozyosity mapping, and whole exome sequencing in consanguineous families with juvenile myoclonic epilepsy has great potential to identify the causative genes of this disease which in turn could provide novel therapeutic targets for epilepsy. The most promising variants segregating with the diseases in the consanguineous families described here will be validated by functional studies.