Rationale: The clinical recognition of genetic testing for epilepsy has been rapidly evolving in the past ten years. Multi-gene panels for epilepsy conditions are cost effective and informative when pathologic variants are identified. However, these advancements have posed new challenges and are a source of frustration when the results are variants of uncertain significance (VUSs), especially in places with limited resources for genetic counseling and when no parental testing is available. The aim of this study was to determine the rates of variants of uncertain significance in the epilepsy genetic panel results in a single tertiary care center and the rates of VUSs that fit with patients’ presentation.
Methods: We performed a retrospective chart review to identify pediatric patients who underwent clinical genetic testing with commercially available epilepsy panels and were found to have variants identified in genes associated with epilepsy. For each variant, systematic evidence review was performed by collecting information from both public and private variant databases and PubMed and see if any of the variants fits with patient presentation.
Results: A total of 60 patients were included. The mean number of genes that were tested in the panels was 332 (SD 70; median 320; IQR 1-3 302-320). Sixteen percent (10/60) of patients had pathogenic variant, another twenty percent (12/60) were carriers of one or two genes. Three patients showed negative results. More than ninety percent of patients had VUSs. Mean number of VUSs per patient was 2.5 (SD 1.9; median 2; IQR 1-3 1-3.5). On average, thirty percent of the variants qualified for complimentary family testing. Only five percent (3/60) have parental testing done, and six percent (4/60) of patients were referred to geneticist. Out of the patients who had no pathogenic variants, eleven percent (7/60) had one or two variants that fit with patient’s presentation (probable VUS).
Conclusions:
Higher rates of VUSs pose a great challenge for healthcare professionals. In our cohort, 11% of the patients studied had probable VUS. It is important to correlate the clinical phenotype to the VUS result and consider the VUS fitting with the patient’s presentation in deciding about management and choice of anti-seizure medication if applicable.
Further research is needed on how to best sub-classify VUSs. It is important to have patients connected with genetic counselor as these VUSs are updated over time.
Reference:
Krey I, Platzer K, Esterhuizen A, et al. Current practice in diagnostic genetic testing of the epilepsies. Current practice in diagnostic genetic testing of the epilepsies.
Epileptic Disord. 2022;24(5):765-786. doi:10.1684/epd.2022.1448
Hunter SE, Jalazo E, Felton TR, Heinzen EL, Shiloh-Malawsky Y. Epilepsy Genetics: Advancements in the Field and Impact on Clinical Practice. In: Czuczwar SJ, ed.
Epilepsy. Brisbane (AU): Exon Publications; April 2, 2022.
Funding: None