Analysis of 141 Epilepsy Related Genes Using Next Generation Sequencing in 390 Patients (P5.154)

OBJECTIVE: To assess the frequency and type of mutations of 141 epilepsy related genes in 390 individuals referred to a commercial clinical laboratory for testing. BACKGROUND : Epilepsy is a common, clinically and genetically heterogeneous disease characterized by recurrent seizures. The molecular diagnosis of epilepsy is critical for assessing recurrence risk in subsequent pregnancies and may guide antiepileptic therapies. Next-generation DNA sequencing (NGS) allows for the simultaneous evaluation of many relevant epilepsy genes and may aid in the identification of a genetic etiology. DESIGN/METHODS: In-solution hybridization and NGS was used to analyze 141 epilepsy related genes (panel 1) in a cohort of 187 specimens and 36 genes (panel 2) associated with generalized or partial seizures, myoclonic, absence or recurrent febrile seizures in another cohort of 203 specimens. NGS results were analyzed with a threshold of a mean per-base coverage depth of ≥30X and per-base minimum coverage depth of ≥20X. Pathogenicity assessments of detected variants were performed using a published, rules-based DNA variant scoring system. RESULTS: Dominant pathogenic variants across 12 genes (panel 1) were identified in 10.2[percnt] (n=19/187) of specimens. The majority of specimens (85.6[percnt]; 160/187) harbored variants of uncertain significance (VUS). 4.3[percnt] (8/187) were carrier of a recessive pathogenic variant. Additionally, pathogenic variants (dominant and recessive) from 8 genes (panel 2) were identified in 9.9[percnt] (20/203) of specimens. Again, the majority of specimens (66.0[percnt]; 134/203) had VUS or benign/likely benign variants (23.7[percnt]; 48/203) with only one carrying a recessive pathogenic variant (0.5[percnt]; 1/203). The majority of pathogenic variants were found in pediatric cases in both genetic panels. CONCLUSIONS: Phenotype-driven multigene panels for epilepsy identified a genetic etiology in a substantial number of cases. The high frequency of VUS underscores the need for pre- and post-test genetic counseling for patients and their families. Disclosure: Dr. Wang has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Jaremko has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Batish has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Meservey has received personal compensation for activities with Quest Diagnostics as an employee. Dr. McCarthy has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Medeiros has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Walsh has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Allen has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Rochibaud has received personal compensation for activities with Quest Diagnostics. Dr. DiVincenzo has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Thomas Casiello has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Bazinet has received personal compensation for activities with Quest Diagnostic as an employee. Dr. Doan has received personal compensation for activities with Quest Diagnostics as an employee. Dr. McCarthy has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Karbassi has received research support from Quest Diagnostics. Dr. Storozuk has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Kacprzyk has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Liaquat has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Hoffman has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Krasner has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Dodge has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Evans has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Elzinga has received personal compensation for activities with Quest Diagnostics as an employee. Dr. York has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Braastad has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Higgins has received personal compensation for activities with Quest Diagnostics.