Abstracts

Rationale: Next generation DNA sequencing (NGS) is now an accessible diagnostic tool in pediatric neurology. NGS panels target dozens to hundreds of genes associated with specific neurological phenotypes. The diagnostic yield of NGS used for specific disease groups or categories varies by presentation and test performed. At the Children’s Hospital of Eastern Ontario (CHEO) NGS panels are requested for specific cases of pediatric epilepsy with approval of the Provincial Ministry of Health. Most clinicians, patients and families support pursuing testing in an effort to obtain a definitive genetic diagnosis and: direct clinical management, avoid unnecessary interventions and provide recurrence risk counseling. A molecular diagnosis provides an opportunity for closure to the diagnostic uncertainties surrounding the child and often motivates clinicians and families to learn more about a specific entity. It further promotes advocacy in community and social media for funding, group support and research. We set out to assess the diagnostic yield and costs for epilepsy in our tertiary care center.Methods: We conducted a retrospective review of all the patients for which a NGS panel for epilepsy was requested over the last 2 years at our institution. We reviewed the laboratory panel requested and its results including: number of genes tested per panel, the report of a positive or negative result and a variant of unknown clinical significance (VUS). The clinical correlation was done between the neurology and genetics department by reviewing the clinical history and the corresponding NGS test results.Results: A total of 41 NGS panels were performed. A positive result was available in 15% of cases with 6 mutations identified: SLC2A1, idic(15), PCDH19, DYRK1A, STXBP1, TCF4. A seventh potential mutation was identified in SCN1A however the significance of this rare variant could not be determined as parental testing was unavailableto demonstrate de novo status. Three of the positive cases were syndromic (DYRK1A, TCF4 and idic15). All 7 individuals had some degree of developmental delay or intellectual disability associated with their epilepsy. A variant of uncertain significance was detected in 65% of cases (including those that were positive) and a completely negative result was seen on 9 occasions 21%. These 41 panels cost $169,300USDConclusions: The NGS diagnostic yield in our review mirrors that reported in the literature (15%). These costs are significant and criteria for testing is a reasonable pre-requisite. The positive cases were characterized early-onset (6/6) or dysmorphic features (3/6) and all had developmental delay to moderate intellectual disability. The positive case of an SLC2A1 mutation provided therapeutic intervention and the patient was started on a ketogenic diet with reduction in seizures. This would be expected to decrease seizure frequency and potentially reduced specialist visits, fewer trips to the emergency department, less therapy trials and improved cognitive outcome.