Abstracts

Rationale: Genetic Generalized Epilepsies (GGEs) are characterized by generalized seizure types and generalized spike-wave or polyspike wave discharges on EEG. Studies of twins and multiplex families demonstrate high heritability; the clinical genetics of GGE suggest complex inheritance involving two or more genes and high-density pedigrees are rare exceptions. We describe the clinical characteristics and linkage analysis of a large consanguineous family from south-eastern region of Turkey with GGE and a pedigree consistent with Mendelian inheritance. Methods: All family members underwent extensive electro-clinical phenotyping; for an individual to be considered affected, a diagnostic EEG was required. 19 family members (14 affected and 5 unaffected) were chosen for SNP genotyping using the Illumina Infinium HumanOmniExpress BeadChip array at the Australian Genome Research Facility (Melbourne, VIC, Australia). Approximate multipoint linkage analysis was performed on this large pedigree with MORGAN. 3 affected individuals were subsequently chosen for whole-exome sequencing (WES) at Otogenetics (Norcross, USA). ? Results: Affected individuals (n=14) exhibited fairly homogenous GGE phenotypic manifestations (Figure), although the age of onset was relatively broad ranging between 6-19 years (mean = 12 years). 13 affected family members experienced myoclonic limb jerking upon wakening or soon after falling asleep; in 11, myoclonus was associated with eyelid blinking and in 10, interspersed with absences. Generalized tonic-clonic seizures (GTCS) were seen in 11. One individual had GTCS alone. EEGs demonstrated generalized polyspike and wave discharges that were not associated with photoparoxysmal response or eye-closure abnormalities. Two additional family members were clinically affected, but in the absence of a diagnostic EEG remained unclassified and were excluded from genetic analyses (Figure). Despite consanguinity within this family, the GGE phenotype appeared to segregate in a dominant fashion. Linkage analysis revealed a region on chromosome 5 where 12/14 genotyped affected family members and a single unaffected family member shared one or two copies of the putative disease haplotypes; homozygous versus heterozygous state was not associated with phenotypic severity or age of seizure onset. The 5p13.2-q13.3 locus encompasses about 40 Mb of the genomic region and harbors 345 genes containing no proven epilepsy genes; WES analysis was negative. Conclusions: The phenotype in this family most closely resembled juvenile myoclonic epilepsy, although there was some variation in seizure types between individuals and 4 subjects had onset under the age of 10 years. Our results suggest that inbreeding can enrich for disease alleles resulting in dominant inheritance and that mutations in the heterozygous versus homozygous state may result in similar phenotypes. Most importantly, we have identified a strong candidate region with the opportunity now for novel gene discovery in a common form of epilepsy. Funding: No funding