OBJECTIVES: Clinical guidelines and expert consensus agree on the importance of a molecular diagnosis that identifies the underlying genetic etiology of epilepsy. While close to 1000 genes have been linked to epilepsy (Wang et al. Seizure. 2016), payer coverage policies support testing only a small number of epilepsy genes. To evaluate the potential for missing the underlying molecular diagnosis in patients affected with epilepsy, we reviewed positive results from patients tested with large next generation sequencing (NGS) panels. Our goal was to identify diagnoses that would have been missed if only epilepsy genes supported by payer coverage policies had been tested. METHODS: We evaluated pathogenic variants in genes identified in 714 epilepsy patients tested in our lab with consent using comprehensive epilepsy gene panels ranging from 471 to 1000 genes. Pathogenic variants were classified according to ACMG guidelines (Richards et al., 2015). The cohort included patients with phenotypes ranging from simple epilepsy to complex epilepsy syndromes. We compared pathogenic genes identified in the cohort against a set of 35 epilepsy genes identified as covered in a review of published US payer policies. Deletion and duplication variants were not analyzed in this study. RESULTS: Eighty-eight patients who tested positive using comprehensive panels had variants identified in 41 different genes. Fifty-five percent (48 of 88) had variants in genes with established drug and dietary treatments, or avoidance (Hani and Mikati, 2016; Pearl, 2016; Balestrini and Sisodiya, 2017). When compared with the set of payer-covered epilepsy genes, diagnoses would have been missed in 35% of patients (31 of 88). Furthermore, 6% of these patients (2 of 31) had variants in genes with established treatments options. CONCLUSIONS: Our data suggest clinical utility associated with testing epilepsy patients using a large gene panel approach, and support the extension of payer coverage to many more epilepsy-associated genes.