Abstracts

Rationale: Clinical genetic testing in the pediatric patients with epilepsy is now the standard of care in most tertiary medical centers. Conversely, routine clinical genetic testing in adults is rare and the utility and yield of testing in adults is currently unknown. We aimed to determine the practicality and feasibility of genetic testing in adults with epilepsy. Methods: We report on the clinical genetic testing results for 95 consecutive patients who received clinical genetic testing by microarray and/or single gene, panel or exome sequencing. All findings returned by clinical genetic testing companies were reviewed by a multidisciplinary team, which consists of an epileptologist, genetic counselor and geneticist. Variants were given final classifications as pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign and benign based on American College of Medical Genetics and Genomics (ACMG) criteria. When possible, a VUS was further classified as a 'candidate variant' if there was strong scientific and clinical rationale that it may contribute to the patient's phenotype, and 'unlikely related' if it was not likely to be contributory. This reclassification was based on several criteria: (1) detailed review of the patient's phenotype, (2) known inheritance pattern of gene in which VUS was reported, (3) literature review, (4) identification of additional cases via matchmaker exchange networks, (5) location of VUS in protein structure and in silicomodeling, (5) presence in population databases (gnomAD, TOPMed, Iranome) and (6) segregation analysis of VUS. Our aim with this further classification was to determine those variants worth further research investigations as well as to inform further clinical genetic testing and genetic counseling.  Results: Eighteen of 95 patients (18.9%) were found to have one or more pathogenic or likely pathogenic variants that explained their clinical syndrome. Of these 18 patients, 15 carried variants in single genes, and 3 patients carried copy number variants (CNVs). One individual carried 2 pathogenic CNVs (16p13.11del, 17q12dup). An additional 9 patients (9.5%) carried variants (5 in single genes, 4 CNVs), which were classified as candidate variants based on expert review of the variant and phenotype. Of those patients with positive findings (pathogenic, likely pathogenic or candidate variants), 10 (37%) had adult-onset epilepsy. Seventeen (63%) had pediatric-onset epilepsy, but had not had a genetic cause identified prior to being seen by an adult epileptologist. Overall, clinical genetic testing reported on 100 genetic variants in 52 patients. After expert review as described above, 4 VUS were reclassified as likely pathogenic. Fourty-seven VUS and 4 pathogenic or likely pathogenic variants we classified as unlikely related. The unlikely related classification was primarily applied in cases where there was a single variant VUS in a gene with known autosomal recessive inheritance and/or with a phenotype that did not match that of thee patient's. A further 8 VUS were reclassified benign or likely benign typically with the assistance of further segregation analysis.  Conclusions: To our knowledge this is the largest reported series of genetic testing, including microarray, panel and exome sequencing performed in an adult epilepsy clinic. It demonstrates that genetic testing can serve an important role in selected adult patients with epilepsy and that a multidisciplinary approach is essential for appropriate variant interpretation and patient counseling.  Funding: No funding