Abstracts

Rationale: Given the enormous success of next-generation sequencing in identifying disease-causing mutations, a large number of patients are now being sequenced as part of their clinical care. While patients often receive a genetic diagnosis from exome sequencing, many patients remain genetically unsolved because the causal variant lies in a gene or region of the genome about which little is known, or that heretofore has never been reported to be associated with any type of disease. The mission of EGI is to assemble a database of clinically generated sequence data that will be analyzed every six months to identify epilepsy-causing mutations based on recently published literature, and, leveraging the large sample sizes made possible through nationwide recruitment, to identify novel genes. Methods: With the support of CURE, we assembled a team of researchers and clinicians at six institutions and developed an implementation plan for EGI. Results: Since its initiation in May 2014, six inaugural sites are participating in the assembly of sequence data as part of the EGI initiative, including Duke University, Children's Hospital-Boston, University of California-San Francisco, Children's Hospital of Philadelphia, University of Melbourne, and New York University. Physicians at these sites ordering exome sequencing as part of a patient's clinical care may consent the patient to participate in the initiative and submit basic phenotypic information related to the epilepsy condition. An EGI Genetic Counselor will then work with the enrolling physician to obtain the patient's sequence data, and that of thier parents if available. Once the raw sequence data are depositied into the EGI database, we will align the sequence reads to the reference genome and call mutations. Every six months, the data will then be genetically analyzed to look for disease-causing mutations and to identify novel epilepsy genes. If disease-causing mutations are identified, the findings will be reported back to the treating physician who will communicate these results to the patient. The database of sequence data, including access for other research purposes, will be managed by CURE. Conclusions: The EGI repository is unique in its design and has immense potential to propel epilepsy research and patient care forward. This endeavor will not only provide a key mechanism for expanded genetic discovery in epilepsy, but will also provide patients with an avenue for obtaining a potential genetic cause of their epilepsy based on the most recent research. Such information may influence treatment options as the molecular underpinnings of epilepsy are revealed.