Abstracts

Rationale:
Advances in genetic testing in children with epilepsy have contributed to greatly expanding the genes associated with epilepsy disorders and increased the diagnostic yield significantly compared to more limited testing strategies. Genetic testing is of highest yield and often of most relevance in children with early onset epilepsy, particularly those with developmental epileptic encephalopathies (DEE). Yet timely access to next generation sequencing (NGS), such as expanded multi-gene panels and exome sequencing, is often challenging even in children where a genetic etiology is strongly suspected. In addition to cost, expanded testing also frequently leads to identification of variants of uncertain significance (VUS) which risk misinterpretation and may cloud the diagnostic odyssey.  We established an epilepsy genetics (EpiGen) clinic incorporating epileptologists, neurogeneticists, and genetic counselors to streamline the diagnostic workflows for children with early onset epilepsy including facilitating genetic testing and targeting the barriers of test initiation and interpretation that often occur. We examined whether this multidisciplinary clinic led to improved testing efficiency, interpretation abilities (e.g. reduced the VUS rate), and quality of care for epilepsy patients.
Method:
Over a 3 year period we reviewed 85 children who came to EpiGen clinic with non-diagnostic baseline genetic testing. This clinic emphasized evaluating patients with drug-resistant epilepsies, and 72% of entrants met criteria for DEE. Many had prior testing: 86% had chromosomal microarrays while 36% had previous gene panel or exome sequencing testing. Clinical genetic testing was performed in 61 children. Eligibility for genetic testing was determined based on epilepsy phenotype, and genetic counseling was performed within the clinic. If children had extensive prior testing or were denied clinical testing, they were enrolled in a research study. New results were reviewed monthly, and VUS were periodically reviewed for recharacterization. As the barriers to genetic testing vary by country and institution, we evaluated NGS testing for epilepsy done outside of EpiGen in our neurology department (n=56), as a comparison cohort.
Results:
Clinical genetic testing in EpiGen yielded pathogenic or likely pathogenic variants in 41% of children, including 33% of children who had previous genetic panels. An additional 4 de novo variants in candidate epilepsy genes were detected. The pathogenic detection rate outside of clinic was similarly robust, at 36% (20/56). Yet differences emerged with test acquisition and review. Time to testing, as determined by approval and initiation of testing, was significantly shorter in the EpiGen group, 45 days compared to 74 days (p=0.01). Initial reports showed similar VUS rate between groups, at 36% in EpiGen compared to 41% in the comparison cohort. Despite thorough phenotyping and reanalysis, we were unable to reclassify variants for 7 (11%) individuals in the EpiGen group, compared to 13 (23%) in outside clinics.
Conclusion:
The EpiGen clinic provides improved access to genetic testing in children with drug-resistant seizures in our program, expediting the process to obtain testing and more efficiently reclassify VUS. The expanding database of epilepsy genes and genetic variants requires frequent reanalysis of data, and in many cases further genotype-phenotype correlation in conjunction  with continuous review of variant databases allowed for variant reclassification. These findings support the added benefit of improved phenotyping, integrated genetic counselors, and interdisciplinary collaboration to optimize genetic testing and results.
Funding:
:None