Abstracts

Rationale: Whole exome sequencing (WES) is being utilized with increasing frequency as a diagnostic tool for individuals with severe epilepsy, such as those with epileptic encephalopathy (EE). However, less is known about the efficacy for diagnostic WES in individuals in a general epilepsy population. Here we describe our experiences employing WES in a broad epilepsy cohort and evaluate the utility of diagnostic WES in this group. Methods: We enrolled 452 individuals with epilepsy in a research study at the Institute for Genomic Medicine at Columbia University Medical Center. Patients were referred to the study through their physicians, including both pediatric and adult neurologists. Clinical diagnoses included generalized epilepsy, focal epilepsy, unclassified epilepsy, brain malformations and epileptic encephalopathy. Written informed consent was obtained as part of an IRB-approved research study. Of the 452 participants, 164 had both biological parents available and were therefore enrolled and analyzed as a trio (36.3%). The remaining 288 individuals were enrolled and analyzed as a non-trio (63.7%). Data for all participants were analyzed at the IGM using the qualifying genotype approach described in Zhu et al., 2015. Candidate variants were reviewed at multidisciplinary team meetings comprised of genetic counselors, geneticists, bioinformaticians and clinical neurologists. Variants considered to be causative by team consensus were sent for clinical confirmation in a NYS-CLIA certified laboratory prior to being returned to the participant. Results: Of the 452 probands enrolled in the study, we made a genetic diagnosis in 36 individuals (8%). This included 26 pediatric diagnoses (12.7%), 23 in trios and 3 in non-trios. Of the adult population, 4 individuals enrolled as a trio and 6 individuals enrolled as a non-trio received a diagnosis, for a total of 10 adult diagnoses (4.0%). Overall, the diagnosis rate was higher for those individuals enrolled as a trio (16.5%) compared to those enrolled as a non-trio (3.1%). Among trios in which a diagnosis was made, 77.8% (21/27) of probands had a de novo variant. Genetic diagnoses in the overall cohort include confirmed variants in TSC2, KCNT1, DEPDC5, PCDH19, CACNA1A, NSD1, SCN1A, PRRT2, COL4A1, PAFAH1B1, SCN8A, PACS1, SCN2A, JARID2, KCNQ2, EEF1A2, CLN5, TUBB4A, ARID1B, KIF1A, KCNB1, LGI1, KANSL1, MBD5, CDKL5, and KCNQ3. Several individuals who received a diagnosis were more mildly affected when compared to those described previously in the literature, including diagnoses made for participants carrying a causative variant in SCN8A and MBD5. Conclusions: Our experiences highlight the potential for genetic diagnoses in epilepsy beyond those patients who are most severely affected and therefore traditionally thought to benefit most from genetic testing. The results also demonstrate a trend of phenotype expansion across several previously established epilepsy syndromes. As precision medicine continues to expand and new treatments emerge, genetic diagnosis will become increasingly important in epilepsy across the board. Funding: Funding for support of this abstract was received by Columbia University Medical Center.