Exome-Based Testing for Patients with Seizures: Advantages over Panel-Based Testing
Abstract number :
1.204
Submission category :
4. Clinical Epilepsy / 4B. Clinical Diagnosis
Year :
2023
Submission ID :
251
Source :
www.aesnet.org
Presentation date :
12/2/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Elizabeth Butler, MS, CGC – GeneDx
Annabelle Tuttle, BS – GeneDx; Lindsay Havens Dyer, MS – GeneDx; Paul Kruszka, MD, MPH, FACMG – GeneDx; Kirsty McWalter, MS, CGC – GeneDx; Michelle Morrow, PhD, MS, LCGC – GeneDx; Melanie Napier, MSc, CGC, CCGC – GeneDx; Karen Wain, MS, CGC – GeneDx
Rationale:
The National Society of Genetic Counselors and the American Epilepsy Society endorse genetic testing for patients with unexplained epilepsy; as a first tier test, they recommend exome sequencing or a panel test with more than 25 genes (J Genet Couns. 2022; 32:266-280). We examined a large genetic testing dataset and identified advantages of exome-based testing over panel-based testing.
Methods:
We reviewed the diagnostic outcomes of exome-based testing (ES) from a large commercial laboratory (GeneDx database for 22,500 individuals with a clinical history of seizures or suspected seizures. Analysis was performed under IRB approval. We compared the genes with likely pathogenic or pathogenic (L/PATH) findings to lists of genes included on commercially available epilepsy gene panels (EP) to identify diagnoses potentially missed by panel testing. We also analyzed the subset of cases with documented previous EP testing to determine if ES performed subsequent to EP added diagnostic information.
Results:
ES dentified L/PATH variants in 725 seizure-related genes for 24% of individuals with seizures. EP included just 210 (29%) of these genes. Clinically relevant ES results unlikely to be identified via EP included variants in genes not on EP (39%), variants in genes associated with neurodevelopmental concerns but without a well-established seizure association at the time of ES (2%), and findings unrelated to seizures or neurodevelopmental concerns (5%). Additionally, nondiagnostic ES findings included candidate genes having potential for future reclassification to disease-associated (26%). Over 4,600 cases (~20% of our cohort) diagnosed by ES had previous EP, indicating the EP did not yield a satisfactory genetic diagnosis. Diagnostic findings by ES in this subcohort included variants in genes not on EP and variants classified as L/PATH that were classified as VUS by EP, including variants with immediate implications for medical management.
Conclusions:
Nearly 25% of patients with seizures received a genetic diagnosis through ES, compared to a previously reported 19% diagnostic yield for EP Epilepsia. 2022;63:375-387). Seventy-one percent of genes with L/PATH variants reported via ES would not have been identified by EP. Among patients with previous EP, 20% received a genetic diagnosis through ES. In summary, the advantages of ES over EP included a higher diagnostic rate, identification of variants with treatment implications, the identification of clinically relevant findings unrelated to seizures, and the identification of potentially contributory candidate gene findings that may lead to future diagnoses through re-classification. These data further support the use of exome sequencing as a first-tier test for patients with unexplained seizures.
Funding: None
Clinical Epilepsy