Abstracts

Rationale: Various studies have shown that up to 15% - 30% of patients with epilepsy have a genetic etiology.  This study aims to evaluate how various clinical features, such as age of seizure onset, type of seizures, presence of other neurological comorbidities, influence the positive diagnostic rate (PDR) of genetic testing for patients with epilepsy. Methods: This is a retrospective study of 1021 patients ranging from 9 days to 54 years (avg 8.2 years) with epilepsy who were tested using a trio-based epilepsy panel.  This test includes concurrent sequencing and analysis of the proband and parents (trio, when available) for over 1000 genes associated with epilepsy.  A result was considered positive if one or two pathogenic or likely pathogenic variants (depending on the mode of inheritance) were identified in a single gene associated with a disorder that explained patient’s phenotype. Results: In the entire cohort, 21% (219/1021) of patients had a positive result.  Patients with early-life epilepsy (seizure onset <3 years old) had a PDR of 28% (110/395), which was significantly (p=<.001) higher compared to patients with later seizure onset (PDR 13%, 17/128). No significant difference in PDR was observed by seizure classification (focal 22%, 60/278 vs. generalized 22%, 127/574).  There was also no significant difference in obtaining a positive outcome based on the seizure type: Infantile spasm (20%, 20/100), tonic and/or clonic (18%, 70/382), febrile (22%, 25/114), and myoclonic (22%, 27/122), with the exception of absence seizures, which had a notably lower PDR (13%, 23/181).  Patients who were reported to have other neurodevelopmental features had a significantly higher PDR compared to patients with isolated seizures (26%, 173/674 vs. 13%, 46/347, p=<.00001). The PDR for some of these specific neurological comorbidities included: global delays (30%, 102/345), delayed speech/language (28%, 73/265), epileptic encephalopathy (28%, 41/148), and intellectual disability (27%, 38/142). Trio testing resulted in a significantly higher PDR (24%, 174/732, p=<.05) compared to proband-only cases (12%, 18/148).  When only a single parent was available for testing, the PDR was 19% (27/145).  The highest PDR was observed for patients tested as a trio, with seizure onset <3 years old, and who presented with additional neurological features (34%, 67/195). Conclusions: It has been suggested that all patients with early-life epilepsy should have genetic testing incorporated into their initial evaluation.  Our data shows that almost one-third of patients with early-life seizures have a positive diagnostic result from genetic testing.  While seizure classification/type alone may not influence the PDR, comorbidity with other neurological features, mainly developmental delays, encephalopathy, and/or ID, is an indication of monogenetic causes for epilepsy. Lastly, inclusion of parental samples, when available, should be considered for improved genetic testing outcomes. Funding: None