Multigene Panel Testing in a Large Cohort of Adults With Epilepsy: Diagnostic Yield and Clinically Actionable Genetic Findings

Dianalee McKnight; Sara L Bristow; Rebecca M Truty; Ana Morales; Molly Stetler; M Jody Westbrook; Kristina Robinson; Darlene Riethmaier; Felippe Borlot; Marissa Kellogg; Sean T Hwang; Anne Berg; Swaroop Aradhya

doi:10.1212/NXG.0000000000000650

Multigene Panel Testing in a Large Cohort of Adults With Epilepsy: Diagnostic Yield and Clinically Actionable Genetic Findings

Neurol Genet. 2021 Dec 16;8(1):e650. doi: 10.1212/NXG.0000000000000650. eCollection 2022 Feb.

Affiliation

¹ Invitae (D.M., S.L.B., R.M.T., A.M., M.S., M.J.W., K.R., D.R., S.A.), San Francisco, CA; Alberta Children's Hospital Research Institute, Cumming School of Medicine, (F.B.) University of Calgary, Canada; Oregon Health & Science University Comprehensive Epilepsy Center (M.K.); Department of Neurology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell (S.T.H); Epilepsy Center, Ann & Robert H. Lurie Children's Hospital of Chicago (A.B.); and Department of Neurology, Northwestern University-Feinberg School of Medicine (A.B.), Chicago, IL.

Abstract

Background and objectives: Although genetic testing among children with epilepsy has demonstrated clinical utility and become a part of routine testing, studies in adults are limited. This study reports the diagnostic yield of genetic testing in adults with epilepsy.

Methods: Unrelated individuals aged 18 years and older who underwent diagnostic genetic testing for epilepsy using a comprehensive, next-generation sequencing-based, targeted gene panel (range 89-189 genes) were included in this cross-sectional study. Clinical information, provided at the discretion of the ordering clinician, was reviewed and analyzed. Diagnostic yield was calculated for all individuals including by age at seizure onset and comorbidities based on clinician-reported information. The proportion of individuals with clinically actionable genetic findings, including instances when a specific treatment would be indicated or contraindicated due to a diagnostic finding, was calculated.

Results: Among 2,008 individuals, a diagnostic finding was returned for 218 adults (10.9%), with clinically actionable findings in 55.5% of diagnoses. The highest diagnostic yield was in adults with seizure onset during infancy (29.6%, 0-1 year), followed by in early childhood (13.6%, 2-4 years), late childhood (7.0%, 5-10 years), adolescence (2.4%, 11-17 years), and adulthood (3.7%, ≥18 years). Comorbid intellectual disability (ID) or developmental delay resulted in a high diagnostic yield (16.0%), most notably for females (19.6% in females vs 12.3% in males). Among individuals with pharmacoresistant epilepsy, 13.5% had a diagnostic finding, and of these, 57.4% were clinically actionable genetic findings.

Discussion: These data reinforce the utility of genetic testing for adults with epilepsy, particularly for those with childhood-onset seizures, ID, and pharmacoresistance. This is an important consideration due to longer survival and the complexity of the transition from pediatric to adult care. In addition, more than half of diagnostic findings in this study were considered clinically actionable, suggesting that genetic testing could have a direct impact on clinical management and outcomes.