Authors :
Presenting Author: Alexander Freibauer, MD – BC Children's Hospital
Kira Burke, BS – BC Children's Hospital
Shelin Adam, BSc, MSc – BC Children's Hospital
Mary Connolly, FRCPC, MBBCH – BC Children's Hospital
Cyrus Boelman, MD – BC Children`s Hospital
Michelle Demos, MD, FRCPC – BC Children's Hospital
Rationale:
Targeted whole-exome sequencing (WES) was implemented as a genetic diagnostic tool broadly for complex pediatric-onset epilepsy at BC Children’s Hospital, the only tertiary referral centre for childhood epilepsy in British Columbia. Over the course of the initial 6-year period of implementation, 964 children met criteria, with patients excluded from testing if they had a seizure syndrome with self-limited course, mesial temporal sclerosis or acquired epilepsy. Here we review our findings of this population-based approach, to understand and increase its utility and discovery. Methods:
WES was completed through commercial clinical testing, (Blueprint Genetics, Prevention Genetics, or Neurocode). Each company had different thresholds of reporting variant classification in epilepsy-associated genes. Follow up familial variant testing was completed opportunistically when clinically appropriate. Results:
An average of 122 children under the age of 19 years were tested annually between 2018-2025 for a total of 964 patients and overall, 415, (43%) were female. The median age at time of testing was 6.5 years (2 month – 31 years of age).
Overall, a molecular diagnosis (pathogenic / likely pathogenic variants) was achieved in 289/964 patients (29%). Subdividing this, yield based upon age of onset of epilepsy was: neonatal-onset 56/139 (40%), infant-onset 44/131 (34%), childhood-onset 111/444 (25%), and adolescent-onset 69/243 (28%). Additionally, 19/964 patients were identified to have likely pathogenic / pathogenic microdeletions / duplications.
The most common pathogenic / likely pathogenic variants identified were in PRRT2 (n=18), SCN1A (n=15) and CPT1A (n=8). Pathogenic / likely pathogenic variants were identified in 186 genes. 54/289 patients (19%) had variants identified in genes in which targeted therapy can be applied.
Variants of uncertain significance in epilepsy-associated genes were found in 413/964 patients (43%). Follow up familial variant testing was completed in 129/413 patients (31%), which impacted variant classification in 14/427 patients (3%). Results were presented by the patients’ primary neurologist with further genetic counselling as needed.
Conclusions:
Broad utilization of whole exome sequencing in a resource-rich public healthcare system is an effective approach to obtain molecular diagnoses in complex childhood-onset epilepsy, especially in younger ages and higher burden of disease. Though no analysis was performed for ethnic background yet, no founder effects were apparent in the diverse population of British Columbia. Higher yield may be seen with greater assessment of rare variants of uncertain significance, including inheritance, phenotype and potential variant impact. Funding: No funding was received in support of this abstract.