Abstracts

Rationale: Genetic testing for epilepsy of is rapidly expanding. Testing yields vary depending on the sample and the type of test. Moreover, differences in testing strategies and methods affect results. Next generation sequencing (NGS) epilepsy panels have allowed for screening of multiple genes simultaneously, however, the interpretation of these results is complex and evolving. We present the UT Southwestern experience in utilizing NGS epilepsy panels. Methods: Patients seen at Children’s Medical Center from April 2012 – August 2015 who underwent NGS epilepsy panel were identified. Information was systematically extracted from the medical record including date of genetic test, result of genetic testing, gender, and age of seizure onset. Yield was defined as number of variants identified per patient tested.  The pathogenicity of the variant was assigned by the testing laboratory as pathogenic, likely pathogenic, and variant of unknown significance (VUS).  Benign variants were not included in the analysis. Results: 308 patients were identified (See table 1). In total, 60.4% (186/308) of patients had an identified genetic variant. Of these 186 patients, there was a total of 315 genetic variants identified. For each patient tested, 50.5% (94/186) had 1 genetic variant, 36.5% (68/186) had 2 genetic variants, and the remaining 13.0% (24/186) had 3-6 genetic variants. The detection rate of a pathogenic/likely pathogenic variant was 20.5% (63/308), of which 45 patients (14.6%) had variants expected to cause disease and 18 patients (5.8%) had variants which were expected to be carrier states. The most common pathogenic/likely pathogenic variants were SCN1A (13), KCNQ2 (7), MECP2 (3), PCDH19 (3), TSC2 (2), CDKL5 (2), and SCN2A (2). There were single identified pathogenic/likely pathogenic variants of ARX, ATP1A2, CHRNA7, CHRNB2, EFHC1, GABRG2, PNPO, POLG, PPT1, PRRT2, STXBP1, SYN1, TCF4, and UBE3A (Figure 1). Patients with identified pathogenic/likely pathogenic variants had a trended to have a lower median age of seizure onset of 6 months (IQR 2-24 months) compared to patients with VUS, which had a median age of seizure onset of 12 months (IQR 5-39.5 months). There was a trend for higher rates of pathogenic/likely pathogenic variants which were expected to cause disease  identified in 2012 compared to 2013 – 2015, 20% vs 13% - 14% respectively.  There were comparable rates of VUS identification throughout the study period. Conclusions: At our center, the yield of NGS epilepsy panels identifying pathogenic/likely pathogenic variants was 20.5% (63/308). Of these cases, 14.6% (45/308) had pathogenic/likely pathogenic variants which were expected to cause disease. There was a trend for patients with pathogenic/likely pathogenic variants to have an earlier age of seizure onset compared to patients with VUS, median of 6 months and 12 months respectively. There was also a slightly higher yield in the first year of NGS testing. This may be due to broadening use and more liberal testing criteria as NGS testing has become more commonplace in clinical practice.  Our experience illustrates the complex and evolving field of genetic testing in epilepsy. Further characterization of VUS and methods of studying pathogenicity are needed to help clinicians navigate the complicated landscape of NGS testing in epilepsy. Funding: Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award Number UL1TR001105. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.