Abstracts

Rationale: Most seizures in the neonatal period are related to acute brain injury including structural, infectious, metabolic and immune causes. However, for some patients, neonatal seizures are the first symptom of a genetic epilepsy syndrome. The objective of this analysis was to determine the molecular diagnostic yield of neonatal patients with unprovoked seizures, identified through a sponsored, targeted testing program for children suspected to have genetic epilepsy.

Methods: The no-charge testing program used a next-generation sequencing panel with simultaneous exonic sequence and copy number variant detection in up to 302 genes. Patients eligible for testing had an unprovoked seizure and were 0-48 months (Feb 19-Jan 20) and 0-96 months of age (Jan 20-Oct 22). Ordering clinicians provided a brief medical history including seizure type, age of seizure onset, family history, developmental delays, and use of antiseizure medications. A positive molecular diagnosis (PosMD) was defined as a patient harboring pathogenic or likely pathogenic variant(s) with the expected inheritance pattern match for the gene-condition. Variants of uncertain significance (VUS) were also returned on clinical reports.

Results: Of the 1276 patients with a seizure-onset reported in the first month of life, 24% (309/1276) had a PosMD. The most common genetic etiology was KCNQ2; accounting for 13.6% (174/1276) of all tests performed and 56.3% (174/309) of the PosMD. KCNQ2 variants were approximately 8-times more frequent than the next most common PosMD, SCN2A (6.8%). The other most common PosMD were KCNQ3 (3.6%), STXBP1 (3.6%) and CDKL5 (2.6%). To confirm age of onset trends, analysis was also performed for patients who were tested in the first month of life. Of the 801 patients tested < 1 month of age, 29% (233/801) had a PosMD. Variants in KCNQ2 predominated and accounted for 19.1% (153/801) of all tests performed and 65.7% (153/233) of the PosMD, followed again by SCN2A (7.7%). VUS resolution testing was offered to solve the interpretation of VUS. Family member testing was performed for 68% (44/65) of patients who harbored a KCNQ2 VUS with seizure onset < 1 month of age, leading to VUS reclassification to pathogenic or likely pathogenic in 39% (17/44) of patients. In contrast, only 9% (7/77) of patients with seizure onset >1 month had a KCNQ2 VUS reclassified.

Conclusions: Variants in KCNQ2 were the most frequent molecular diagnosis in neonates, accounting for approximately 1/5 of all genetic tests ordered in the first month of life and almost 2/3 of the PosMD. Maximizing the diagnostic yield in neonates by access to genetic testing early in the diagnostic pathway, including VUS resolution testing, is important as obtaining a molecular diagnosis is vital to facilitate early intervention, avoid unnecessary specialist evaluation and to inform treatment strategies and prognosis, including access to potential precision therapies currently in clinical development.

Funding: Xenon Pharmaceuticals Inc.