IMPORTANCE Clinical genomic tests that examine the DNA sequence of large numbers of genes are commonly used in the diagnosis and management of epilepsy in pediatric patients. The permanence of genomic test result interpretations is not known. OBJECTIVE To investigate the value of reinterpreting previously reported genomic test results. DESIGN, SETTING, AND PARTICIPANTS This study retrospectively reviewed and reinterpreted genomic test results from July 1, 2012, to August 31, 2015, for pediatric patients who previously underwent genomic epilepsy testing at a single tertiary care pediatric health care facility. Reinterpretation of previously reported variants was conducted in May 2017. MAIN OUTCOMES AND MEASURES Patient reports from clinical genomic epilepsy tests were reviewed, and all reported genetic variants were reinterpreted using 2015 consensus standards and guidelines for interpreting hereditary genetic variants. Three classification tiers were used in the reinterpretation: pathogenic or likely pathogenic variant, variant of uncertain significance (VUS), or benign or likely benign variant. RESULTS A total of 309 patients had genomic epilepsy tests performed (mean [SD] age, 5.6 [0.8] years; 163 [52.8%] male), and 185 patients had a genetic variant reported. The reported variants resulted in 61 patients with and 124 patients without a genetic diagnosis (VUS variants only). On reinterpretation of all reported variants, 67 of the 185 patients (36.2%) had a change in variant classification. Of the 67 patients with a genetic variant change in interpretation, 21 (31.3%) experienced a change in diagnosis. During the 5 years of the study, 19 of 61 patients (31.1%) with a genetic diagnosis and 48 of 124 patients (38.7%) with undiagnosed conditions (VUS only) had their results reclassified. Review of genomic reports issued during the final 2 years of the study identified reclassification of variants in 4 of 16 patients (25.0%) with a pathogenic or likely pathogenic variant and 11 of 41 patients (26.8%) with a VUS. CONCLUSIONS AND RELEVANCE The identified high rate of reinterpretation in this study suggests that interpretation of genomic test results has rapidly evolved during the past 5 years. These findings suggest that reinterpretation of genomic test results should be performed at least every 2 years.

Epilepsy is a disorder of the central nervous system characterized by spontaneous recurrent seizures. Although current therapies exist to control the number and severity of clinical seizures, there are no pharmacological cures or disease-modifying treatments available. Use of transgenic mouse models has allowed an understanding of neural stem cells in their relation to epileptogenesis in mesial temporal lobe epilepsy. Further, with the significant discovery of factors necessary to reprogram adult somatic cell types into pluripotent stem cells, it has become possible to study monogenic epilepsy-in-a-dish using patient-derived neurons. This discovery along with some of the newest technological advances in recapitulating brain development in a dish has brought us closer than ever to a platform in which to study and understand the mechanisms of this disease. These technologies will be critical in understanding the mechanism of epileptogenesis and ultimately lead to improved therapies and precision medicine for patients with epilepsy.

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Genomic testing has become routine in the diagnosis and management of pediatric patients with epilepsy. In a single test, hundreds to thousands of genes are examined for DNA changes that may not only explain the etiology of the patient's condition but may also inform management and seizure control. Clinical genomic testing has been in clinical practice for less than a decade, and because of this short period of time, the appropriate clinical use and interpretation of genomic testing is still evolving. Compared to the previous era of single-gene testing in epilepsy, which yielded a diagnosis in <5% of cases, many clinical genomic studies of epilepsy have demonstrated a clinically significant diagnosis in 30% or more of patients tested. This review will examine key studies of the past decade and indicate the clinical scenarios in which genomic testing should be considered standard of care.

Epilepsy and Autism Spectrum Disorder (ASD) are frequently co-morbid conditions. There are no clear testing modalities or biomarkers to distinguish children with ASD who are at risk for developing epileptic seizures from those who are not. Epileptiform electroencephalogram (EEG) abnormalities are common in children with ASD, suggesting a possible shared underlying pathophysiology with epilepsy. Our study analysed EEGs in children with ASD who underwent serial EEG studies. We show that initial EEG classification was a significant prognosticator for future EEG findings (p < 0.0001). Our study failed to demonstrate a statistically significant difference in the presence of epileptiform EEGs in children with ASD and co-morbid epilepsy as compared to those without co-morbid epilepsy. Furthermore, analysis of children with ASD and developmental regression or ASD and language impairment failed to demonstrate statistically significant differences in presence of epileptiform EEG abnormalities. Together these findings suggest that repeat EEGs should be obtained on a case-by-case basis in children with ASD and epileptiform EEG abnormalities in ASD in the absence of convincing epileptic seizures should be cautiously interpreted.