Abstracts

Rationale: Comprehensive epilepsy genetic panels have become part of routine evaluation of early childhood epilepsies.¹ These panels have evolved to cover hundreds of genes enabling evaluation of established and newly identified genetic disorders. Despite these advances, more than half of these cases remain undiagnosed.² A proportion of these undiagnosed cases have variants of uncertain significance (VUS), which can be reclassified into benign, likely benign, pathogenic, or likely pathogenic variants. Continued follow up of genetic testing results is prudent to identify reclassified variants, as this can have important clinical and prognostic implications for patients and families. We reviewed genetic variant reclassification in our single-site cohort undergoing standard epilepsy genetic panel testing._x000D_
Methods: A retrospective chart review of all patients who had undergoing epilepsy genetic testing, using a Genetic Epilepsy Panel (Invitae), was performed between 2016 and 2021. Data obtained included epilepsy phenotype,³ neurodiagnostic imaging, and diagnostic workup, including results of genetic panel variant interpretation and reinterpretation over the duration of patient follow up.

Results: A total of 1314 patients with epilepsy underwent genetic panel testing, out of which 88 (6.6%) patients had variant reclassification. The mean age at initial testing was 9.2 +/- 7.4 years. The phenotypes among the 88 patients included generalized epilepsy (n=33), focal epilepsy (n=26), mixed focal and generalized epilepsy (n=7), developmental epileptic encephalopathy (n=15), and others (n=7) (unknown epilepsy, non-syndromic, complex febrile seizures etc.). Reclassification to pathogenic or likely pathogenic variants was seen in patients with generalized epilepsy 11/33 (33%), focal epilepsy 4/26 (15%), developmental and epileptic encephalopathy 5/15 (33%), mixed focal and generalized epilepsy 3/7 (42%), and others 1/7(14%).

Conclusions: Variant reclassification to pathogenic or likely pathogenic categories occurred in a small proportion of patients in our cohort. Patients with generalized epilepsy, developmental and epileptic encephalopathy, and mixed focal and generalized epilepsy were associated with the highest rate of reclassification from VUS to pathogenic or likely pathogenic gene variants. Continued review of genetic results in clinical care is recommended.

References:
1. SoRelle JA, Thodeson DM, Arnold S, Gotway G, Park JY. Clinical utility of reinterpreting previously reported genomic epilepsy test results for pediatric patients. JAMA Pediatrics. 2019;173(1):e182302. https://doi.org/10.1001/jamapediatrics.2018.2302_x000D_ _x000D_ 2. Helbig I, Ellis CA. Personalized medicine in genetic epilepsies: possibilities, challenges, and new frontiers. Neuropharmacology. 2020;172:107970. https://doi.org/10.1016/j.neuropharm.2020.107970_x000D_ _x000D_ 3. Wirrell E. (2022). Evaluation of first seizure and newly diagnosed epilepsy. Continuum (Minneapolis, Minn.). 2022;28(2):230-260. https://doi.org/10.1212/CON.0000000000001074_x000D_
Funding: No funding was received in support of this abstract.