Abstracts

Rationale: Until recently, molecular diagnosis of clinical presentations involving seizure disorders depended tremendously upon a recognizable pattern of phenotypic features. Physicians often engaged in extensive physical, biochemical, and genetic testing processes over lengthy periods of time, often failing to produce an underlying genetic explanation for their patient s symptoms. With the introduction of Next Generation sequencing options for diagnostic utilization, physicians are now able to identify rare genetic mutations associated with conditions that present with a wide range of phenotypic variability including seizures/epilepsy. Methods: The introduction of diagnostic exome sequencing (DES) in the clinical realm has revolutionized the way in which heterogeneous seizure/epilepsy disorders are now being diagnosed. Instead of employing lengthy and often step-wise genetic testing strategies to identify the single gene responsible for a patient s condition, DES can provide a single, effective, and cost-efficient option for diagnosing syndromes with daunting clinical overlap. DES is the most comprehensive option clinically available for genetic testing on the market. This test includes analysis and interpretation of coding regions (exons) of over 20,000 genes in the human genome. DES includes whole exome sequencing for family trios and analysis, reporting of novel gene discoveries, and co-segregation analysis for the most informative results. Results: Among the first 200 DES cases referred to our institution, we have 73 patients with positive exome findings. Here we present 22 individual cases referred to Ambry Genetics who were found to carry pathogenic mutations in genes reported to be associated with seizure/epilepsy phenotypes. Additionally, 3 patients carried likely pathogenic variants and 8 had uncertain results in genes also associated with seizures/epilepsy features. As expected, almost all of these cases include documentation of vast, unsuccessful testing strategies undertaken prior to their DES referral. A retrospective analysis of each individual s clinical presentation compared to previously reported patients in the literature revealed significant phenotypic overlap and/or expansion in all cases.Conclusions: With the increased usage of Next Generation sequencing in mainstream clinical practice, advanced testing options such as DES will continue to identify significantly increasing numbers of rare single-gene alterations in individuals affected by phenotypically variable seizure disorders. Ultimately, mainstream clinical usage of this technology as well as reporting of these clinical correlations will facilitate an expeditious diagnostic process for optimal patient care.