Abstracts

Rationale: In patients with familial epilepsy, the yield and results of diagnostic molecular genetic testing may vary across centers due to differences in tested populations and the availability of testing. There is currently no data on the overall diagnostic yield and overall genetic architecture of familial epilepsies seen at modern US medical centers in the era of widespread genetic testing. Hence, the overall spectrum of familial epilepsy may differ significantly from descriptions in the literature. We report our first findings from an ongoing study of familial epilepsy at the pediatric and adult neurogenetics programs at our institutions. Methods: We identified patients seen in our pediatric and adult neurogenetics clinics with familial epilepsy (defined as proband and at least 1 first-degree family member with epilepsy) who had diagnostic molecular genetic testing performed. Genetic testing qualifying for our study consisted of either commercially-available comprehensive epilepsy panels or whole exome sequencing. Families were grouped into epilepsy syndromes for analysis and variants were reviewed and re-interpreted by ACMG criteria if required. Results: Thirty-three families ascertained within a time period of 12 months met inclusion criteria. Age at time of testing range 4 months to 66 years. Known pathogenic mutations were identified in 3/33 families (9%) overall. When grouped by epilepsy syndrome, pathogenic mutations occurred in 2/7 families (29%) with focal epilepsy (DEPDC5 and GRIN2A) and in 1/4 families (25%) with benign familial neonatal epilepsy (KCNQ2). There were no pathogenic or likely pathogenic findings in any families with genetic generalized epilepsy (GGE, 0/17) or generalized epilepsy with febrile seizures plus (GEFS+, 0/5). Conclusions: In our initial findings from this ongoing study, we see two emerging trends in our epilepsy families. First, in patients with familial focal epilepsy and benign familial neonatal epilepsy we identified mutations in established pathogenic genes at expected rates. Second, in families with GGE and GEFS+ the diagnostic rate is virtually zero, a significant difference to prior findings and assumptions about the genetic architecture of these familial epilepsies. Differences in clinical ascertainment and the widespread availability of genetic testing may account for these differences, which have implications for testing strategies and genetic counseling in epilepsy families. Funding: None.