Epilepsy Benchmark IB2
Benchmark Area I: Understanding basic mechanisms of epileptogenesis
Section B: Continue the progress of identifying the genes predisposing to epilepsy
Specific Benchmark 2: Create a national consortium aimed at identifying new epilepsy susceptibility genes through a large-scale genotype:phenotype
screen. Initiate this effort with a consensus conference that prioritizes phenotypes, develops implementation strategies,
and defines endpoints.
2005 Report submitted by Benchmark Steward(s):
Ruth Ottman, Ph.D. (Columbia University)
Background of the benchmark goal:
Most epilepsy is not consistent with Mendelian modes of inheritance. The genes that influence risk in the majority of patients
are likely to have small effects, interacting with the effects of environmental factors. Identification of such genes requires
very large numbers of patients. Thus a collaborative study, with the highest quality of methods for phenotype and genotype
analysis, is essential to move the field forward.
Current status of field:
Allelic association studies are being performed by many separate groups, and published at a rapidly increasing rate. Most
of these studies are underpowered. Consequently, about half of the reported findings are positive, and half negative, and
no association has been consistently confirmed.
Dan Lowenstein spearheaded a multi-institutional effort to conduct a state-of-the-art study of genes in genetically complex
epilepsies. The result was a collaboration of 14 institutions throughout the U.S., and a well-designed, adequately powered
study to address the most pressing issues in epilepsy genetics (e.g., gene discovery in genetically complex epilepsies, genes
influencing treatment response, and the role of somatic mutations). The proposal for this project, which will include 5,000
superbly well-characterized patients and 15,000 controls, was submitted to NIH for review.
Top priorities for next 5-10 years:
- Identification of genetic polymorphisms that influence risk for genetically complex epilepsies and for response to treatments.
- Development and evaluation of methods to use genetic information to develop new treatments and tailor them to specific patients.
- Development of new paradigms for epilepsy classification that reflect shared and distinct genetic mechanisms.
Roadblocks to progress:
Study designs involving large numbers of patients, with state-of-the-art genomic analysis and clinical characterization, are
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