Commentary
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Insights From the Pediatric Epilepsy Research Consortium on Advancing Genetic Testing
A duo of experts discussed the importance of addressing barriers such as provider comfort, access to genetic counselors, and insurance coverage to reduce diagnostic latency and standardize genetic testing for epilepsy. [WATCH TIME: 5 minutes]
Julie Ziobro, MD, PhD
(Credit: University of Michigan)
Recent advancements in genetic testing, particularly next-generation sequencing (NGS), have greatly enhanced the ability to pinpoint genetic causes of pediatric epilepsy. At the 2024 American Epilepsy Society Annual Meeting, held December 6-10, in Los Angeles, 2 studies leveraging data from the Pediatric Epilepsy Research Consortium (PERC) database provided critical insights into genetic testing. These included findings on diagnostic delays, disparities in access, and the role of genetic factors in drug-resistant epilepsy (DRE).1,2
The first study, led by Julie Ziobro, MD, PhD, analyzed data from 323 pediatric patients to assess the time between seizure onset and genetic testing.1 All told, the median delay was 69 months, with shorter testing latency in patients with early seizure onset, infantile spasms, and developmental delay or intellectual disability (DD/ID). Encouragingly, the study identified no significant differences in latency based on race, language, or socioeconomic status, indicating relatively equitable access within the cohort. These findings underscored the importance of raising awareness and implementing earlier interventions to streamline diagnostic and treatment processes.
The second study, presented by John Schreiber, MD, explored the genetic and clinical characteristics of pediatric patients with DRE.2 Among 288 patients with identified pathogenic or likely pathogenic genetic variants, those with DRE experienced earlier seizure onset, a higher prevalence of DD/ID and autism, and longer epilepsy duration compared to non-DRE patients. While diagnostic rates were comparable between gene panels and whole exome sequencing, the study highlighted ongoing challenges in integrating genetic findings into clinical care, including their application in treatment strategies and prognostication.
John Schreiber, MD
(Credit: Children’s National Hospital)
In a discussion with NeurologyLive® at AES 2024, Schreiber, director of epilepsy genetics at Children’s National Hospital, and Ziobro, an assistant professor of pediatrics at the University of Michigan, delved deeper into the challenges and opportunities surrounding genetic testing in pediatric epilepsy. They emphasized the importance of addressing barriers to equitable access, particularly in underserved regions, and highlighted strategies to bolster neurologists' confidence in ordering and interpreting genetic tests. Both experts underscored the critical role of interdisciplinary collaboration in reducing delays and optimizing outcomes, advocating for enhanced partnerships to streamline the diagnostic process for rare epilepsies.
NeurologyLive: Could you provide an overview of your presentations and explain why this topic is important to you?
John Schreiber, MD: The PERC Genetics Database has been a long time in the making. Our goal is to collect data on people with rare genetic epilepsies. While some genetic epilepsies are well-researched, hundreds of genes associated with epilepsy lack sufficient study and innovation. The database pools resources and patient data to address these less-researched genes, representing thousands of patients. PERC facilitates collaboration between institutions, which is especially vital for rare disorders.
Julie Ziobro, MD, PhD: We started developing the Epilepsy Genetics Database in 2021. At the time of our analysis, 9 centers were contributing patients, creating a database of 413 individuals. We examined factors associated with the latency—the time from the first seizure to the first genetic test. While our database is still relatively small, it provided valuable insights into our population, which sparked these initial studies.
What were the key findings from the study? And what should clinicians, neurologists, and epileptologists take away from your work?
John Schreiber, MD: As Dr. Ziobro mentioned, our database captures a range of information, including demographics, seizure characteristics, comorbidities, medications, and genetic testing outcomes. This initial analysis focused on two areas: factors affecting latency to genetic testing and factors associated with drug-resistant epilepsy.
Regarding latency, we know many clinical and demographic factors can contribute, such as ethnicity, location, or seizure characteristics. For drug resistance, we found that younger age at seizure onset, longer epilepsy duration, and comorbidities like intellectual disability, developmental delay, or autism were associated with a higher likelihood of drug resistance. Interestingly, in our cohort, 151 of 351 patients with available data were not drug-resistant. Additionally, we found no significant difference in the likelihood of having a pathogenic or likely pathogenic genetic variant between those with and without drug-resistant epilepsy.
Julie Ziobro, MD, PhD: For latency to genetic testing, we examined sociodemographic factors like race, language, distance to testing centers, and whether patients lived in rural or urban areas. Encouragingly, we didn’t find significant differences, suggesting limited bias among our centers. However, clinically, patients with earlier epilepsy onset had shorter latency to testing, which aligns with the understanding that genetic testing is most effective in children under three.
Conversely, patients with developmental delay, intellectual disability, or autism spectrum disorder experienced longer delays to genetic testing. This finding raises questions about why these delays occur. Many clinicians shared hypotheses, such as neurologists deferring testing until patients see a geneticist, which can add months to the process.
Why isn’t genetic testing always integrated into clinical practice? What are the barriers, and how can we address them?
Julie Ziobro, MD, PhD: There are several reasons. Neurologists may feel uncomfortable ordering genetic tests if they’re unsure how to interpret or act on the results. Education is helping to address this, with more neurologists testing earlier in epilepsy diagnoses.
Some clinicians question whether a genetic diagnosis will change the patient’s course or management. However, even when no diagnosis is found, families often report value in undergoing testing. Moreover, newer data shows that positive results can influence treatment about half the time.
The imperfections of genetic testing also contribute. Many patients with likely genetic epilepsies don’t receive a diagnosis, but this shouldn’t deter us from testing—it’s a reason to keep pushing for advancements.
John Schreiber, MD: The National Society of Genetic Counselors recommends genetic testing for all patients with unexplained epilepsy. While a definitive answer isn’t guaranteed, even negative results provide useful information. Our findings reinforce this guidance, showing no significant difference in testing outcomes between drug-resistant and non-drug-resistant patients.
What steps can we take to reduce latency to genetic testing?
John Schreiber, MD: Reducing latency is critical for equity and care. PERC aims to elevate the standard of care nationwide, ensuring all patients have equal access to genetic testing regardless of location.
Julie Ziobro, MD, PhD: Barriers include insurance coverage and access to genetic counselors. Insurance policies have improved, and guidelines now recommend whole exome sequencing as a first-line test in pediatric epilepsy. However, more genetic counselors are needed to support neurologists, and fair reimbursement for these professionals is essential to expanding care.
Is genetic testing standardized across institutions, or is there variability?
Julie Ziobro, MD, PhD: There’s significant variability because of differences in resources, education, and insurance policies. For instance, some institutions require preliminary tests with lower yields before whole exome sequencing, delaying diagnosis. Guidelines help reduce variability, but challenges remain. We hope to use our database to track progress in reducing latency over time.
John Schreiber, MD: Genetic testing is a vast topic deserving its own discussion. However, the emergence of guidelines is encouraging, as they help clinicians navigate testing decisions and improve access to care.
Transcript edited for clarity. Click here for more AES 2024 coverage.
