Abstracts

Rationale: In 2014, the Epilepsy Genetics Initiative (EGI) established a mechanism to transfer exome sequence data obtained as part of clinical care to a centralized database, with the permission of the physician and patient/family. This database allows for (1) EGI to systematically reanalyze the data to identify and report back to the physician genetic diagnoses that were not possible at the time of initial testing, and (2) a resource for researchers to facilitate the discovery of novel epilepsy genes. Here we provide an update on the progress of EGI to date. Methods: Two hundred thirty-seven individuals with epilepsy who previously underwent diagnostic exome sequencing were enrolled in EGI at one of several enrollment sites worldwide; the majority of these did not receive a definitive genetic diagnosis at the time of clinical testing. Exome sequence data were transferred to Columbia University Medical Center and re-interrogated on a research basis to identify genetic variants responsible for the individual’s epilepsy. Candidate variants were reviewed at a multidisciplinary team meeting comprised of genetic counselors, geneticists, bioinformaticians and physicians. New genetic diagnoses were returned to the referring provider for clinical confirmation and return to the family. Results: Reanalysis of 139 individuals without a known genetic diagnosis by EGI identified eight new diagnoses. The new diagnoses were based on new information of the genetic causes of epilepsy and improved knowledge of the protein coding sequences in the genome. The database was also used in conjunction with exome sequence data generated for research purposes to identify a novel epilepsy gene, PPP3CA. Ongoing analyses of exome sequence data from another 70 individuals has revealed multiple additional diagnoses, including a pathogenic variant in the newly discovery PPP3CA, and a variant in RORA, a gene discovered in 2018. Conclusions: The work of EGI continues to show the value of periodic reanalysis of exome sequence data and data centralization to facilitate gene discovery. Funding: Citizens United for Research in Epilepsy and National Institute for Neurological Disorders and Stroke (U01-NS077303-04S1)