26 Clinical Utility of Genomic Testing in Childhood Epilepsy

Genomic testing by next-generation sequencing (NGS) has been growing as a diagnostic tool in pediatric neurology. In 2015, our tertiary care pediatric institution launched a 134-gene NGS test focused on the genetic diagnosis of childhood epilepsy. In this study, we surveyed one year of data and evaluated the clinical utility of the 134-gene test in pediatric epilepsy. Previous studies have focused on the diagnostic yield of genomic testing in epilepsy. This study expands on previous work by examining the subset of patients who may have had a change in therapy or management based on the test result. A retrospective review of all NGS epilepsy gene tests for 2016 was performed. Clinical significance of the variants reported was determined by a genetic counselor and pathologist. All variants were graded according to the 2015 ACMG guideline on variant classification. Benign and likely benign variants were not included in this analysis. A literature search was performed to determine which of the pathogenic/likely pathogenic (P-LP) variants had clinically utility in the management and/or treatment of the patients. In all, 181 patients were identified in the study period. These patients had a total of 149 reported genetic variants. Pathogenic/likely pathogenic (P-LP) variants were identified in 17.1% (31 of 181) patients, variants of uncertain significance were identified in 74% (134 of 181), and no variants were reported (negative report) in 8.8% (16 of 181) of patients. Some patients had a combination of multiple P-LP and uncertain variants; these were all classified as patients with P-LP variants. Of the 31 patients with P-LP variants, there was a total of 35 P-LP variants. The most common P-LP variants were in CPA6 (n = 6), DHCR7 (n = 2), PRRT2 (n = 2), SCN1A (n = 2), and SCN5A (n = 2). In addition, there were single cases with P-LP variants in ARX, CDKL5, CTSD, EPM2A, FOXG1, KCNQ2, KCNQ3, KCNT1, MTHFR, PNKP, PNPO, POLG, SCN11A, SCN2A, SLC2A1, TCF4, and TSEN2. Of the 31 patients with P-LP variants, 32.3% (10 of 31) had potential clinical implications for changing the management and/or therapy based on the genes implicated: EPM2A, KCNQ2, KCNQ3, KCNT1, PNPO, POLG, PRRT2, and SCN1A. A one-year retrospective evaluation of pediatric epilepsy patients tested with a 134-epilepsy gene NGS panel yielded a P-LP diagnostic rate of 17.1% (31 of 181). Additionally, 32.3% (10 of 31) of the patients with P-LP variants had associated management and/or therapeutic implications from their test result. This study suggests that genomic (NGS) testing of medically refractory childhood epilepsy is not only essential for establishing a definitive etiology, but should also be considered standard of care because of the implications for management and/or therapy.