The Molecular Diagnostic Landscape of Children with Seizure Onset in the First Three Years of Life
Abstract number :
2.33
Submission category :
12. Genetics / 12A. Human Studies
Year :
2022
Submission ID :
2203921
Source :
www.aesnet.org
Presentation date :
12/4/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:22 AM
Authors :
Dianalee McKnight, PhD – Invitae; Heather M. McLaughlin, PhD, FACMG; Noam Butterfield, PhD, PMP – Xenon Pharmaceuticals; Swaroop Aradhya, PhD, FACMG – Invitae Corporation; Lauren DeRienzo, PsyD – Xenon Pharmaceuticals; Celene Grayson, PhD – Xenon Pharmaceuticals; Britt Johnson, PhD, FACMG – Invitae Corporation; Ana Morales, MS, CGC – Invitae Corporation; Robin Sherrington, PhD – Xenon Pharmaceuticals; Andrew Willcock, MS – Invitae Corporation
This abstract has been invited to present during the Genetics & Behavior/Neuropsychology/Language platform session
Rationale: The Behind the Seizure (BTS) program offers sponsored, no-charge genetic testing and counseling for individuals who experienced an unprovoked seizure before age 8. To better understand the molecular diagnostic landscape of individuals with early-onset epilepsy, we sought to determine the most common molecular diagnoses stratified by age at seizure onset and to ascertain the time to molecular diagnosis in children with seizure onset in the first 36 months of life.
Methods: The BTS program utilizes a next-generation sequencing panel with simultaneous exonic sequence and copy number evaluation of up to 302 genes associated with epilepsy. Ordering physicians provide a brief clinical history including seizure type, age of seizure onset, family history, developmental delays, and use of anti-seizure medications. Molecular diagnostic yield analyses were performed for various ages at seizure onset including < 1 months, 1 to 2 mos, 3 to 5 mos, 6 to 11 mos, 12 to 23 mos, and 24 to 35 mos. The time to molecular diagnosis, calculated by subtracting the age at seizure onset from the age at molecular diagnosis, was determined for the top 10 genes in each seizure onset category.
Results: A total of 15,074 individuals with seizure-onset in the first 36 mos of life were tested between February 19, 2019, to January 10, 2022. The most common molecular diagnoses varied substantially according to age at seizure onset. KCNQ2 was the predominant molecular diagnostic finding in neonates with seizure onset at < 1mo, KCNQ2 and CDKL5 predominated in infants with seizure onset between 1 and 2 mos, and PRRT2 and SCN1A were the most prevalent diagnostic findings for infants with seizure onset between both 3 and 5 mos and 6 and 11 mos. While SCN1A was the most common molecular diagnostic finding in children with seizure onset between 12 and 36 mos, a number of additional genes each provided moderate contributions to molecular diagnoses in this seizure onset group (Figure 1). The median time to molecular diagnosis varied considerably by gene (Figure 2). For example, there was no delay in the median time to molecular diagnosis for the GLDC, KCNQ2, and SCN2A genes while the median delay for the MECP2, CHD2, CACNA1A, SYNGAP1, GABRG2, and SLC2A1 genes was ≥ 12 months.
Genetics