Made possible by a generous contribution from the John and Barbara Vogelstein Foundation, the Epilepsy Genetics Initiative (EGI) created a centralized database that holds the genetic (whole exome sequence) data of people with epilepsy. This CURE Epilepsy initiative has advanced our understanding of the genetic causes of epilepsy with a goal of improving the ways we prevent, diagnose, and treat this devastating neurological disorder.
ABOUT THE INITIATIVE
The field of epilepsy genetics is rapidly changing, as new genes associated with epilepsy are regularly identified. People with epilepsy who have had their whole exomes sequenced in a diagnostic lab but did not receive a genetic diagnosis have their information submitted to EGI by their physician. Over a five-year period, 2015 – 2020, information including clinical and genetic data from people with epilepsy, and in many cases, their families, was submitted by physicians at EGI enrollment sites across the globe.
During the active phase of EGI, the data were analyzed every six months to determine if a previously unknown mutation (genetic variant) may be the cause of a person’s epilepsy, and any evidence of a genetic cause of a participant’s epilepsy was reported back to the person’s physician. The anonymized whole exome data will continue to be analyzed by EGI investigators at Columbia University, some enrollment sites, and for cutting-edge research projects worldwide.
Nearly 50% of people with epilepsy don’t know the cause of their epilepsy, but genetic research is changing that. What makes the EGI database unique and valuable is that it includes de-identified clinical data of a person with epilepsy along with their genetic data. It also includes a large amount of trio data, in other words, genetic information from a child with epilepsy along with that of the child’s parents.
By making this database available to epilepsy researchers around the world, EGI will continue to make a difference for people and families impacted by epilepsy well into the future.
Since 2015, EGI has produced the following results:
In total, 364 patients that did not have a clear genetic diagnosis through clinical whole exome sequencing were enrolled into EGI. EGI has provided new or modified genetic diagnoses for a total of 34 patients. In 16 of the 34 cases, EGI identified a mutation in a gene that was not initially found by the initial whole exome sequencing done at a genetic testing laboratory. The genes identified are as follows:In the remaining 18 cases, a genetic mutation was identified on the initial testing report but it was not conclusively considered disease causing at that time. Reanalysis of the whole exome sequence data through EGI combined with the additional knowledge uncovered in the field of epilepsy genetics at the time of reanalysis, clarified the pathogenicity of these gene mutations. The EGI team was able to report findings on the following genes back to the patient’s original physician:
Reanalysis due to EGI improved the diagnostic yield of the original whole exome sequencing by 9.3%. This illustrates the importance of reanalysis of genetic data over time to discover new diagnoses for individuals with epilepsy but also, to aid in identifying new evidence that some genetic mutations do not contribute to an individuals epilepsy, which may save patients from unnecessary interventions.
EGI has been governed by representatives from CURE Epilepsy and the EGI Principal Investigators Sam Berkovic (University of Melbourne), Erin Heinzen (North Carolina University), David Goldstein (Columbia University), and Daniel Lowenstein (University of San Franscico), and is in partnership with the National Institute of Neurological Disorders and Stroke (NINDS).