Abstracts

Rationale: 2 years ago, a genetic counselor was added (0.2 FTE) to our Complex Epilepsy Clinic (CEC) at Nationwide Children's Hospital, a freestanding academic Children's Hospital. Patients with treatment resistant epilepsy can be referred to the CEC for further evaluation of medical management and treatment options. Etiologies for each referral are categorized using the 2010 ILAE Epilepsy Etiology Classification criteria. Genetic testing of patients followed is routinely performed since the addition of the genetic counselor. Genetic testing offered includes baseline metabolic studies, microarray, single gene testing, next generation sequencing (NGS) epilepsy panels, and whole exome sequencing (WES) analysis. Consistent with medical genetics practice guidelines, patients had an initial microarray and baseline metabolic studies if they had epilepsy, dysmorphic features, autism spectrum disorder and/or developmental delay. Our analysis of the test results has allowed an assessment of our diagnostic approach and facilitates the design of a more consistent, streamlined, and cost-effective approach to genetic testing considerations for complex epilepsy patients. Methods: We performed a retrospective analysis of all patients who received genetic testing through the CEC in the past two years. Analysis included review of what testing was obtained prior to the being seen in the CEC, if a diagnosis was made as a result of testing, which diagnosis made if obtained, which test led to a diagnosis, and if further testing was indicated. Results: Overall 111 patients had genetic testing in the past two years when seen in the CEC. We report the results in 86 patients. In 25 cases, prior authorization/testing is currently in process. Of the 52 microarray studies completed, 5 were diagnostic (~10%), 42 non-diagnostic, 4 had variants of unclear significance (VUS) with associated neurodevelopmental concerns and 1 had a variant of unknown significance with a significant reported region of homozygosity (VUS ~10%). Baseline or initial metabolic studies were performed in 61 of the 111 cases, typically including one or more of the following: acylcarnitine profile, serum amino acids, urine organic acids, serum lactate, CSF studies and in several cases additional screening for congenital disorders of glycosylation and creatine metabolism disorders. Biochemical analyses were essentially uninformative in our patient population. For patients without a conclusive diagnosis and treatment resistant epilepsy, either single gene or next generation sequencing (NGS) panel analysis was performed. Of the 19 Epilepsy NGS Panels completed, 5 were diagnostic (26%) and two reported findings possibly related to clinical concerns with additional studies recommended. 22 patients did not have a diagnosis based on genetic testing or MRI. These patients had WES performed. Of the non-diagnostic studies which proceeded to WES, 8 of 22 cases were diagnostic (36%), 5 had results which may be clinically significant (~23%) and 9 were non-diagnostic. Overall, 25.6% (22) patients had a definitive diagnosis with variants of unclear significance found in 40.7% (35) patients. Conclusions: Our experience demonstrates that genetic testing can be useful to obtain for patients with treatment resistant epilepsy presenting with an unknown etiology. The technological advances in molecular diagnostics have made significant changes in the evaluation and management of patients with complex epilepsy. Accurate diagnostics allow for more appropriate genetic counseling, treatment options, medical management and better outcomes, clinically and psychosocially. Further work is ongoing to determine the usefulness and treatment changes as a result of obtaining a diagnostic genetic test. Funding: None