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

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.

Figure 1. Diagnostic Yield and Genes With Positive Findings

(A) Individuals in the study population were categorized according to their genetic test results. A definitive molecular diagnosis was defined as 1 pathogenic/likely pathogenic (P/LP) variant in a gene with autosomal dominant or X-linked inheritance or 2 P/LP variants (or a single homozygous variant) in a gene with autosomal recessive (AR) inheritance. A nondiagnostic finding was any combination of reported variant(s) that did not meet the definition of a definitive molecular diagnosis; this included variant(s) of uncertain significance (VUS), a single P/LP variant in an AR gene, and a heterozygous P/LP variant and heterozygous VUS in the same AR gene. A negative finding occurred when no variants were reported, although benign or likely benign variants may have been detected. (B) Among those with a diagnostic finding, frequency was calculated by gene. The number of individuals with a diagnostic finding in a gene is indicated in parentheses along the x-axis. Each of the genes in the Other 44 events group individually accounted for <1% of the total diagnostic findings. A full summary of the genes with diagnostic findings can be found in eTable 2 (links.lww.com/NXG/A505). (C) Among those with a diagnostic finding, a box and whisker plot reporting age at the time of testing was constructed. Line indicates the inclusive median; X indicates the average; bottom of box indicates the first quartile; top of box indicates the third quartile; whiskers indicate the minimum and maximum ages; dots indicate outliers. ^aA pathogenic copy number variant spanning both genes was observed as a single event.

Figure 2. Diagnostic Yield and Distribution of Genes With Molecular Diagnoses by Age at Seizure Onset

(A) The proportion of individuals with a definitive molecular diagnosis was calculated based on age at seizure onset (age groups defined in x-axis). (B) Among those with a definitive molecular diagnosis, the number of individuals with diagnostic findings in each gene was stratified according to age at seizure onset (age groups defined in the legend). These analyses included only individuals with a noted numerical age at onset. ^aA pathogenic copy number variant spanning both genes was observed as a single event.

Figure 3. Diagnostic Yield by Demographic and Clinical Features

(A) The proportion of individuals with a diagnostic finding with each clinician-reported feature was calculated based on the number of individuals for whom that feature was noted (total indicated above each feature). (B) The overall diagnostic yield and diagnostic yield for clinician-reported ID/DD were calculated separately for female and male individuals. (C) Among individuals with seizure onset reported in childhood, adolescence, and adulthood, the diagnostic yield was calculated overall and for clinician-reported ID/DD, family history of epilepsy, and sex. The number of individuals with each clinical feature reported is noted below each bar. Individuals with ID/DD were those with any of the following reported symptoms: ID, cognitive issues, or developmental delay. Statistical differences were calculated when appropriate by χ² tests. Statistically significant differences (p ≤ 0.05) are indicated with an asterisk. ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability.

Figure 4. Clinically Actionable Genetic Findings, Overall and Among Individuals With Pharmacoresistant Seizures

(A) All definitive molecular diagnoses and (B) definitive molecular diagnoses with pharmacoresistant seizures were categorized according to whether the diagnostic finding was in a gene with a published clinical action and if so, the type (ASM indications, ASM contraindications, metabolic treatments, possible surgical indications, or surgical contraindications). Individuals with clinically actionable findings in more than 1 category were counted more than once. A full list of clinically actionable genetic findings can be found in eTable 3 (links.lww.com/NXG/A505). ASM = antiseizure medication.