Abstracts

Rationale: Variants in the KCNQ2 gene underlie a spectrum of neonatal-onset epilepsies with varying severity, including severe developmental and epileptic encephalopathy to a milder self-limited form. KCNQ2-related epilepsy typically presents during the first week of life, with multiple, daily seizures, caused by loss of Kv7.2 mediated potassium current. The objective of this analysis was to determine the molecular diagnostic yield and age of diagnosis of patients with KCNQ2-related epilepsy, identified through a sponsored pediatric genetic testing program.

Methods: The no-cost testing program uses a next-generation sequencing panel with simultaneous sequence and exonic copy number variant detection in up to 186 genes previously associated with epilepsy. Patients eligible for testing have unprovoked seizures and were 0-48 (Feb/19-Jan/20) or 0-96 months of age (Jan/20-present). Ordering physicians provided a brief clinical history including seizure type, age of seizure onset, family history, developmental delays and use of antiseizure medications.

Results: As KCNQ2-related epilepsy presents early in life, we analyzed the available data in children < 24 months at the time of testing. When stratified by age, causal variants in KCNQ2 were by far the most frequently identified genetic etiology accounting for 69.9% (n=109/156) of the positive molecular diagnoses (PosMD) in neonates tested ( < 1 month of age), and 19% (n=109/573) of all neonates tested. KCNQ2 variants were also the most frequent molecular diagnosis in patients < 6 months of age at testing, accounting for 32.8% (n=156/475) of the PosMD, and 8.6% of the infants tested < 6 months of age (n=156/1820). In patients tested < 24 months of age, the most frequent PosMD were for PRRT2 (23.7%), KCNQ2 (15.5%), SCN1A (13.9%), SCN2A (3.9%), CDKL5 and PCDH19 (2.9%). The average age at molecular diagnosis of KCNQ2-related epilepsy in patients tested at < 24 months of age (n=176) was 1.9 months. The average time to diagnosis was 1 month between onset of seizures and time of testing in 189 patients with a reported seizure onset < 24 months. These data demonstrate the value of a sponsored testing program supporting the early detection of KCNQ2 variants.

Conclusions: Variants in KCNQ2 are the most common cause of genetic epilepsy during early infancy. These data support the early genetic testing of neonates and infants with seizure onset < 6 months of age, as the diagnostic yield for KCNQ2 variants is high. By 24 months of age, the diagnostic yield of KCNQ2-related epilepsy is similar to SCN1A-related disorders, including Dravet Syndrome. Unlike Dravet Syndrome, no drug has been tested or is approved in KCNQ2-related epilepsy. Early diagnosis has important implications in informing prognosis and treatment strategies and to enable early access to potential precision therapies in clinical development, such as XEN496 in the Phase 3 “EPIK” study. Broader access to early in life genetic testing will enable the rapid identification of additional children with KCNQ2-related epilepsy.

Funding: Please list any funding that was received in support of this abstract.: Xenon Pharmaceuticals Inc.