The intent of this document is to provide guidance on the optimal coordination of epilepsy gene panels. The genetics of epilepsy is complex and rapid-evolving, making the selection of an appropriate genetic test for epilepsy challenging. The following variables should be considered prior to ordering an epilepsy gene panel, and when in doubt, consider reviewing the order with an internal expert/manager/leader.
What is Epilepsy?
Epilepsy is common – approximately 1% (750,000) of children aged 0-17 years and 1.8% (4.3 million) of adults aged 18 years or older have a diagnosis of epilepsy or seizure disorder (CDC, 2016). Studies estimate that a genetic etiology is present in more than 40% of individuals with seizures (Pong, 2011). Epilepsy can be isolated or can be part of a broader genetic syndrome. Epilepsy disorders can follow many different inheritance patterns, including autosomal dominant, autosomal recessive and X-linked. Variants in a single gene may be associated with different types of seizures (clinical heterogeneity), and conversely, variants in different genes can cause the same epilepsy presentation (genetic heterogeneity).
Although the availability and accessibility of gene panels are increasing, the impact on clinical management is changing more slowly and still rests largely on patient findings from examinations, history, and other investigations. However, since there is a great deal of clinical overlap between different epilepsy disorders, selecting a comprehensive testing approach such as an epilepsy gene panel may be the optimal test once obvious conditions have been excluded.
When is genetic testing considered for a patient with epilepsy?
Genetic testing in individuals with epilepsy is typically pursued for the following reasons:
- To guide medical interventions (e.g. medications, other treatment or surveillance)
- To avoid unnecessary testing (e.g. repeated blood tests, MRIs, invasive biopsies, intracranial electrodes)
- To inform prognosis (e.g. anticipatory guidance)
- To provide information regarding recurrence risk (guide reproductive planning)
- To end the diagnostic odyssey
Note: For the purposes of this document, the recommendations relate to diagnostic epilepsy testing, which is distinct from pharmacogenomic testing in individuals with epilepsy.
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What genetic tests are available for patients with epilepsy?
There are numerous genetic tests that help determine the underlying molecular etiology of epilepsy in an individual. Decisions about which test(s) to perform can be complex because of the extreme clinical and genetic heterogeneity of the epilepsies and the rapid pace of genetic discovery.
Selecting the optimal test depends on:
- careful review of personal and family medical histories (e.g. seizure types, age at onset, EEG patterns)
- physical exam (e.g. screen for associated comorbidities such as dysmorphic features, intellectual disability, or a movement disorder), and
- imaging (e.g. MRI to look for brain malformations)
Results of this information might suggest a syndrome associated with variants in a specific gene or set of genes; targeted testing of an individual gene or small set of genes (including both sequencing and testing for deletions and duplications within the gene) is likely to be the most appropriate option for such patients. Similarly, if a chromosome deletion or duplication syndrome is suspected, chromosomal microarray (CMA) is the appropriate first test. If the clinical features do not point to a particular syndrome or molecular etiology, CMA or a panel that includes sequencing and deletion or duplication testing for several epilepsy-associated genes is likely the best first test.
What important factors should be considered before ordering an epilepsy gene panel?
The following questions provide a helpful framework when considering ordering an epilepsy gene panel and its appropriateness for the individual:
- Does the individual have isolated epilepsy or epilepsy with other clinical features?
Depending on whether the individual has isolated epilepsy or epilepsy as part of a suspected syndrome, a single-gene test, chromosomal microarray, or targeted panel may have a sufficient diagnostic yield and would be a more appropriate first test than an epilepsy gene panel. A referral to, or consult with an expert, such as a geneticist, should be considered if there are questions about whether the individual has features suggestive of a genetic syndrome.
- Has the optimal gene panel been selected based on the individual’s features?
When considering an epilepsy gene panel, size matters. The more genes included in the panel, the greater the likelihood of detecting variants of uncertain clinical significance. And many panels include genes that have loose associations with epilepsy so there is also the possibility of an incidental result that may be unrelated to the primary reason for testing. Because of these challenges, thoughtful panel selection is strongly recommended and panels with >150 genes should be approached with caution.
- Is the patient acutely ill and will results return in time to impact care (e.g. signs of decline or regression)?
Arriving at a diagnosis more quickly for a critically ill infant in the NICU may warrant consideration of a rapid epilepsy panel as the first-tier in testing, or concurrent testing.
- Is there a specific medical intervention that is being considered?
Would testing prevent a more invasive treatment option? (E.g., we’ve tried everything, the only option left is a biopsy, etc.)
- Are there multiple individuals in the family with similar clinical features?
Testing one individual may benefit many family members. Furthermore, testing many similarly affected individuals may yield more informative results. And once a familial pathogenic variant is detected in one family member, less expensive targeted familial variant testing can typically be offered to appropriate family members instead of full gene sequencing or panel testing.
- What is the benefit of pursuing testing now versus deferring until later?
Consider that new genes are being discovered at a rapid pace requiring laboratories to frequently review and update gene panels; there will be improved understanding of the variants discovered in known genes and gene-gene interactions; symptoms & family history may evolve to guide more targeted testing and the cost of testing will likely decrease; and available treatment options may increase.
- Is there suspicion for a novel condition/gene?
If the testing is being pursued to discover the first case of something, enrolling the individual in a research study may be more appropriate.
When is it not appropriate to order an epilepsy panel?
- When there would there be no change to the individual’s management regardless of the genetic test result. In the case of epilepsy, the patient may already be on a ketogenic diet that is controlling symptoms.
- When there has been no pre-test counseling for the individual (or legal guardian) regarding risks, benefits, and potential out of pocket costs of the genetic testing.
- When the order is requested by a provider who may not have the appropriate training/expertise to select the optimal test and/or interpret the results. Generally, epilepsy gene panel testing is best coordinated by a neurologist or geneticist.
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General utilization management interventions & considerations
Utilization Management Techniques
Genetic testing for epilepsy is well-suited for strong UM interventions, including formularies, requirement for high-level approval and privileging.
- Establish a formulary for epilepsy genetic tests to limit ordering to a defined reference laboratory (or set of laboratories) to ensure quality of the test and improve ease of test coordination/logistics. This may also help with negotiating the best price.
Develop practice parameters with input from experts (e.g. neurologists, geneticists), including guidelines for evaluation and screening, as well as testing algorithms.
- Require that requests be reviewed by an expert (pathologist or laboratory genetic counselor) prior to approval.
- Privilege epilepsy gene panel ordering to the experts. Due to the complex nature of this testing, many institutions privilege this test to geneticists or neurologist only.
Provider and Patient Expectations
Set clear expectations for providers regarding the approach to epilepsy genetic testing and availability of guidelines. Providers may feel that the patient came to them for evaluation, and epilepsy gene panels are a novel but necessary “tool”, so if a test isn’t ordered, they haven’t done their job. Similarly, it is critical for providers to set clear expectations for the patient or family, particularly related to the possibility of a complex result, variant of uncertain significance and low likelihood that results may reveal a specific treatment/management change.
- Reflex testing options: In some cases, it is more efficient and cost-effective to pursue a reflexive testing approach, starting with single-gene analysis or chromosomal microarray. If negative, an epilepsy gene panel could be considered. Some reference laboratories have the option of running the whole exome, but masking the majority of genes and only reporting out on epilepsy genes of interest. If this analysis is negative, there may be an option to reflex to the whole exome.
- Size of the panel: a balance must be achieved, likely on a case-by-case basis between a broad approach (test lots of genes regardless of clinical presentation, increased risk of variants) and a targeted panel based on phenotype (risk of not finding an answer with the first tes
- Family member testing options: It is advantageous to be able to test family members to clarify the significance of uncertain variants. Some reference labs perform this targeted familial variant testing at no charge and can perform the testing using saliva or buccal specimens. Other reference labs charge a per variant fee, which can be costly if many variants are identified and warrant further investigation. When selecting the optimal reference lab/test for epilepsy gene panels, it’s critical to consider the charges and logistics of familial variant testing.
- Panel updates & variant re-interpretation: Some reference labs have policies regarding re-analysis of variants (e.g. ad-hoc, systematic at time intervals, etc). Given the rapid evolution of knowledge, there will be a need for reinterpretation and for laboratories to be nimble in expanding panels to include new genes. When considering a reference lab, inquire about how genes are included on panels and how panels are kept up to date.
Conversations regarding optimal epilepsy gene panel selection and medical necessity of testing for insurance coverage can be strengthened by examples of how epilepsy-related genetic variants could impact clinical management, examples of potential clinical validity and clinical utility for diagnostic testing in an affected Individual, and examples of potential clinical validity and clinical utility for predictive testing in an unaffected relative of an affected individual who tests positive (Poduri, 2014).
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Recommendations for responsible coordination of epilepsy gene panels
Once an epilepsy gene panel has been established as the most appropriate test, the following recommendations are suggested as a responsible approach to test coordination:
- Pre-test counseling to provide clear information regarding the benefits, limitations and results of the gene panel. The counseling approach should be tailored to the individual; the focus of counseling might differ depending on whether it involves a teenager with epilepsy, the parents of a young child with epilepsy, or an at-risk family member.
- Clear documentation of medical rationale and necessity of the epilepsy gene panel, combined with insurance pre-authorization for the testing to protect the patient/institution from avoidable financial liability.
- Results communication plan established at time of test coordination, to include post-test counseling discussion. The possibility of identifying a variant of uncertain clinical significance may be high and the family should be prepared for the potential need to test other family members to help better understand the patient’s results.
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Berkovic SF. Genetics of Epilepsy in Clinical Practice. Epilepsy Currents. 2015;15(4):192-196. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532231/)
Centers for Disease Control and Prevention, Epilepsy Fast Facts, http://www.cdc.gov/epilepsy/basics/fast-facts.htm, accessed February 25, 2016.
Ottman R, Hirose S, Jain S, et al. Genetic testing in the epilepsies—Report of the ILAE Genetics Commission. Epilepsia. 2010;51(4):655-670. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855784/)
Poduri A, Sheidley BR, Shostak S, Ottman R. Genetic testing in the epilepsies-—developments and dilemmas. Nature reviews Neurology. 2014;10(5):293-299. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090104/)
Pong AW, Pal DK, Chung WK. Developments in molecular genetic diagnostics: an update for the pediatric epilepsy specialist. Pediatr Neurol. 2011; 44:317–327. (http://www.ncbi.nlm.nih.gov/pubmed/?term=PMID%3A+21481738)
Scheffer IE. Genetic Testing in Epilepsy: What Should You Be Doing? Epilepsy Currents. 2011;11(4):107-111. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152152/)