Abstracts

Rationale: The genetic basis of epilepsy is now well established with over 100 genes implicated and 30-50% of severe early-onset pediatric epilepsies being attributed to a genetic cause. These advances have been invaluable in dissecting the genetic architecture of epilepsy, as well as enhancing our understanding of pathogenic mechanisms. However, we have yet to fully appreciate the contribution of genetic variants to more common types of epilepsy, including adult-onset epilepsies. To begin to address this challenge, here we present our experience with clinical and research genetic testing at an academic adult epilepsy center over a period of 14 months.  Methods: To date, we have performed genetic testing in 30 individuals with epilepsy (10 with adult-onset epilepsy, 20 with childhood-onset epilepsy). Testing included 9 single gene sequencing tests, 6 phenotype-based gene panels, and 15 whole exome sequencing evaluations (typically trios including parents when available). Variants were identified both by commercial analysis and by further analysis of whole exome data on a research basis. Results: In 6/30 (20%) of the cases, genetic testing identified a pathogenic variant that likely accounts for the patient’s epilepsy. These included pathogenic variants in LGI1 (2), PTEN (2), KRIT1 (1), and NPRL3 (1). The majority (5/6) of probands with a positive genetic finding had adult-onset epilepsy. In the sixth case, the proband’s seizure onset was in childhood, while other affected members of her family had seizures beginning in adulthood. In the two patients with pathogenic variants in PTEN, identification of the pathogenic variant prompted critical early cancer screening and a diagnosis of bilateral in-situ breast carcinoma in one patient.  In an additional 5/30 (17%) individuals we identified variants in genes that are likely candidates for the phenotype.  These include variants in GABRA1 and SZT2 detected in patients with a milder phenotype than previously reported, which may correlate with the specific variant and suggest novel genotype-phenotype correlations. Further genetic and functional studies are ongoing to determine the pathogenicity of candidate variants. Conclusions: While still a relatively small and carefully selected cohort, this pilot study illustrates how thorough investigation of individual adult patients with epilepsy and their families can yield important insights into the genetic architecture of more common epilepsies.  Moreover, these genetic studies can reveal new genotype-phenotype correlations in known epilepsy genes that contribute to our understanding of how alterations in these genes cause epilepsy. Finally these findings highlight the value of clinical genetic testing and genetic counseling for adults with epilepsy. The identification of pathogenic mutations plays an important role in the diagnosis and management of these patients including risk assessment, family planning and, in some cases, appropriate screening for systemic disease.  Funding: None