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Study Description

Epilepsy is one of the most common neurologic disorders, affecting approximately 4% of individuals at some time in their lives. More than 30% of people with epilepsy continue to have seizures despite treatment, and improved approaches to treatment and prevention are sorely needed. In the search for new strategies to reduce the burden of disease, the discovery of specific genes that influence risk offers a novel opportunity to clarify pathogenic mechanisms, identify susceptible individuals prior to seizure onset, and treat and prevent seizures in people at risk. Despite clear evidence of the importance of genetics in susceptibility to epilepsy, only limited progress has been made in identifying the specific genes that influence risk. One of the greatest challenges for genetic research on this disorder is its extreme clinical and genetic heterogeneity. Although epilepsy is broadly defined by recurrent unprovoked seizures, it is so variable in its clinical manifestations, natural history, and treatment response that most epileptologists view it as a collection of different syndromes ("epilepsies") with distinct etiologies. The genetic effects on susceptibility are also likely to be extremely variable, ranging from rare variants with high penetrance (some of which produce Mendelian patterns of inheritance) to common variants with low penetrance. Recent findings strongly suggest that rare gene variants play a major role in the genetic architecture of the epilepsies.

The purpose of this study was to discover new genetic risk factors for epilepsy. The primary approach was to use whole-genome sequencing to interrogate classes of genetic variants, including very rare variants, in multiplex families. Our main hypothesis was that, in at least some proportion of these families, a single variant would explain all instances of epilepsy. Variants identified within the families could then be tested for cosegregation within the family and also validated by seeing enrichment in sporadic epilepsy cases. Furthermore, understanding the impact of rare variation in epilepsy also has the potential to provide insight into the genetic architecture of other complex human diseases.

Our analysis focused on families containing multiple individuals with non-acquired (idiopathic or unknown cause) epilepsy under the hypothesis that these would be enriched for genetic control. The families studied had been previously collected and phenotyped in detail, and contain an average of 3.8 individuals per family with a range of different types of epilepsy. We selected one or two affected individuals from each family for sequencing. This work has generated NGS data on 60 samples from 29 multiplex epilepsy families. We have established that, under a monogenic model of inheritance, sequencing pairs of distantly related relatives is an effective method for reducing the number of candidate variants. Critically, we have found that no single variant can explain a large proportion of these epilepsy families. This work emphasizes that identifying causal variants among the many genetic candidates found in this work will require very large sample sizes and gene-based analyses.

  • Study Type: Family
  • Number of study subjects that have individual level data available through Authorized Access: 60

Authorized Access
Publicly Available Data (Public ftp)

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Study Inclusion/Exclusion Criteria

The selected multiplex epilepsy families contained an average of 3.8 (range 2-8) individuals per family with non-acquired (idiopathic or unknown cause) epilepsy, and an average of 3.9 (range 2-9) individuals with non-acquired epilepsy or isolated unprovoked seizures. Genome-wide linkage analysis was carried out in each family using a panel of microsatellite markers; no significant linkage peaks (LOD >3.0) were identified in any individual family. We selected a total of 29 families, including 6 families with focal epilepsy, 13 families with idiopathic generalized epilepsy (IGE) and 10 families with a mix of IGE and focal epilepsy. For the majority of families we sequenced multiple distantly related family members (usually 2) and for the IGE only families we sequenced just a single affected family member for 12 of these 13 families.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Exome Sequencing Illumina TruSeq Exome Enrichment Kit N/A N/A
Whole Genome Sequencing Illumina HiSeq 2000 N/A N/A
Whole Genome Sequencing Illumina Genome Analyzer IIX N/A N/A
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