Abstracts

Rationale: Up to 70-80% of children with epilepsy are thought to have an underlying genetic etiology.  Even with recent advances in genetic testing, up to 75% of children never obtain a genetic diagnosis despite extensive testing with single nucleotide polymorphism (SNP) microarrays, next generation panels (NGPs), and whole exome sequencing (WES).  Challenges include test selection, interpretation of variants of unknown significance (VOUS), and lack of standard testing practices . An epilepsy genetics clinic staffed by neurogeneticists, genetic counselors, and epileptologists was established to address these issues.  We outline the details of the clinic and report the initial results of our testing strategies. Methods: Beginning in April of 2016, epileptologists were able to refer children into this monthly clinic.  Children were required to have a diagnosis of intractable epilepsy and some degree of developmental impairment, with an emphasis on children who had onset of seizures early in life.  Prior negative testing with a SNP microarray was also required.  Epileptologists provided detailed phenotyping of the childhood epilepsy syndrome (early onset epileptic encephalopathy, myoclonic astatic epilepsy, etc.) in a pre-clinic conference. Neurogeneticists and genetic counselors discussed a testing strategy based on this information to determine highest yield and financially responsible testing with epileptologists prior to discussion of testing with families.  Initial testing included commercially available NGPs, tailored NGPs with 100 gene slices, designed by the neurogeneticist to best represent the highest yield for the individual patients, as well as WES.  Test results were then discussed at the conference, with the ability to make decisions on the pathogenicity of VOUS and relevance to the syndrome. Results: There have been 38 children evaluated to this point, yielding recommendations for 12 NGPs, eight tailored gene slices, and four whole exome sequences. Results from the first ten studies completed show nine genetic abnormalities, including three known pathogenic mutations and six VOUS. Reviewing these variants with our geneticists, three were de novo mutations with likely pathogenesis (SCN1A, CASK, and KCNA2), while two were detected in parental studies and one was likely nonpathogenic based on modeling. Both tailored exome slices uncovered pathogenic detections, while commercially available NGPs were above 50% (4/7). Overall, 6 in 10 studies have revealed genetic etiologies underlying the epilepsy. Conclusions: Early clinic results show a high rate of pathogenic detections, far exceeding the expected detection rate and that previously seen at our institution, and often is able to narrow down the genes of interest. This clinic has also been successful in streamlining the acquisition of testing as well, verifying results, and addressing the likely relevance of VOUS, thus increasing the likelihood of meaningful and actionable results. These findings support the added benefit of improved phenotypic descriptions and interdepartmental collaboration to inform genetic testing, Funding: none