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Genetic Testing in Epilepsy: Your Quick Reference Guide

Understanding the role of genetic testing in epilepsy can significantly enhance patient care. This concise one-pager, developed by the American Epilepsy Society, provides essential guidance on "WHY" genetic testing is valuable, "WHO" needs it, "WHEN" to order it, "WHERE" to obtain it, "HOW" to interpret results, and "WHAT" types of tests are available. It's designed to be a practical, printable resource for clinicians to quickly reference considerations for clinical use in their offices. 

 

Download Our Clinical Worksheet

 

 

Who & When: Epilepsy That is Unexplained

Pathologic variants resulting in epilepsy cause a variety of changes that can be broadly classified into the following categories.

 

Cause / Indication
ChannelopathiesMetabolic disorders
Childhood onset epilepsy including severe forms of childhood epilepsyNeurodegeneration
Drug-resistant epilepsy, especially of unknown causeOther neurologic findings
Family history of epilepsy in two first-degree family membersSyndromic disorder
Malformations of cortical developmentUnexplained epilepsy

 

 

Genetic Testing - Who & When


Genetic Testing in Epilepsy: Practical Considerations for Clinical Use | Who & When: Epilepsy That is Unexplained

This downloadable chart from “Genetic Testing in Epilepsy: Practical Considerations for Clinical Use” outlines when to consider genetic testing, what to test for, and how to interpret results. It summarizes common genetic causes—like channelopathies, metabolic disorders, and syndromic epilepsies—and connects them to clinical scenarios. Designed for healthcare providers, this resource supports informed decision-making in cases of unexplained, early-onset, or drug-resistant epilepsy, while also highlighting gaps in access to testing for underserved populations.

Download

 

Where: Practicalities of Testing, a Step-by-Step Guide

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Step 1: Selecting the Right Test arrow_drop_down
  • Choose the appropriate test based on the patient’s clinical picture and practice environment. See below for “Finding Information on Genetic Tests” to learn more about available tests and the purpose of each test.
  • Example: Medicaid coverage for Whole Exome Sequencing (WES) is available in certain states:
    • Covered: Arkansas, Connecticut, Iowa, Maryland, Minnesota, North Carolina, Oklahoma, Pennsylvania, Washington.
    • Not Covered: Wisconsin

     

Finding Information on Genetic Tests

The National Institutes of Health (NIH) Genetic Testing Registry (GTR) is a useful resource for finding genetic tests. It provides details on: ✅ Test purpose and validity ✅ Laboratory contacts and credentials ✅ Genes tested

How to Search for Epilepsy-Related Tests

  1. Go to the NIH Genetic Testing Registry (GTR): Home - NIH Genetic Testing Registry (GTR) - NCBI
  2. Click on the “Human Tests” tab.
  3. Use keywords like “epilepsy” or “seizures” to find tests related to epilepsy.

    For an up-to-date list of identified epilepsy-related genes, visit: Genes4Epilepsy – Bahlo Lab

 

 

Step 2: Obtain Informed Consent From your Patient arrow_drop_down
Ensure they understand the full range of potential risks, including the possibility of being denied life insurance, uncovering non-paternity, and the emotional impact of either a positive or negative result, among other considerations.
Step 3: Choosing a Testing Provider arrow_drop_down
  • Select a laboratory or organization for testing.

 

Example of CLIA Certified Laboratories Who Offer “Epilepsy Panel” Genetic Testing

(Updated as of May 2025)

Company / OrganizationCountry
ARUP Laboratories, Molecular Genetics and GenomicsUnited States
Asper Biogene, Asper Biogene LLCEstonia
Baylor GeneticsUnited States
Blueprint GeneticsFinland
CeGaT GmbHGermany
Center for Human Genetics, IncUnited States
Centogene AG - the Rare Disease CompanyGermany
Children's Hospital Colorado Precision Diagnostics LaboratoryUnited States
Children's Hospital of Los Angeles, Center for Personalized MedicineUnited States
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaUnited States
Molecular Diagnostics, Children's Hospital of WisconsinUnited States
CNH Molecular Diagnostics Laboratory, Children's National HospitalUnited States
Cincinnati Children's Hospital Medical Center Genetics and Genomics Diagnostic LaboratoryUnited States
Fulgent GeneticsUnited States
GeneDxUnited States
Greenwood Genetic Center Diagnostic LaboratoriesUnited States
HNL Genomics Connective Tissue Gene TestsUnited States
Integrated Genetics Westborough, LabCorpUnited States
Labcorp Genetics (formerly Invitae)United States
Mayo Clinic LaboratoriesUnited States
MendelicsBrazil
MNG Laboratories (Medical Neurogenetics, LLC.)United States
Molecular Vision LaboratoryUnited States
NxGen MDxUnited States
OtogeneticsUnited States
PreventionGenetics, part of Exact SciencesUnited States
Revvity OmicsUnited States
CGC Genetics, UnilabsPortugal
Genetic Services Laboratory, University of ChicagoUnited States
Molecular Otolaryngology and Renal Research Laboratories, University of Iowa Hospital and ClinicsUnited States
Variantyx, Inc.United States
Clinical Genomics Laboratory, Washington University in St. LouisUnited States
Step 4: Ordering & Billing Considerations arrow_drop_down

Prior Authorization: Most genetic tests require approval from insurance.

  • Some institutions do not allow genetic testing during inpatient admissions or restrict it to certain cases (e.g., NICU). Review institutional policies before ordering.
  • In some states, prior authorization is not required if a geneticist orders the test, which may help patients facing insurance denials.
  • Some states require genetic counseling before testing.

Typical Prior Authorization Requirements:

  • Requisition paperwork (varies by testing provider, available on their website).
  • Consent forms (often included in requisition paperwork, but some providers require additional forms).
  • Clinical notes supporting medical necessity.
  • More details on prior authorization and medical necessity: Genetics Policy Hub

If Insurance Denies Coverage:

  • Testing can still be offered, but patients should be informed of potential out-of-pocket costs.
Step 5: Sample Collection arrow_drop_down
  • Most labs accept blood (serum) samples and provide buccal swab collection kits for at-home sample collection.
  • If a collection kit is needed for a patient, indicate this in the requisition paperwork.
  • Many labs offer provider-held test kits for easier sample collection.
Step 6: Results & Follow-Up arrow_drop_down
  • The requisition form may allow providers to include patient contact details so that both the clinician and patient receive results.
  • For unexpected or complex results, additional support is available:

 

Find a Genetics Clinic

Find a Genetic Counselor

 

What: Description of Types of Tests

Overview of Most Commonly Used Genetic Testing Options for People with Epilepsy

 

Test NameRegion of Genome AnalyzedAdvantagesDisadvantages
NGS Multi-Gene Panel (MGP)Specific genes currently recognized to be associated with epilepsy (range in 2024: 20 to >1,000 genes depending on panel) • A curated and focused set of genes, so least likely to get incidental findings
• High NGS depth of coverage
• Easiest for a neurologist without genetics expertise and/or limited access to medical geneticists to interpret and act upon
• Typically, the least expensive and fast turnaround
• Easy to order and get covered by insurance 		• Causative gene may not be included (yet)
• Limited options for reanalysis, may require repeat WES or WGS if suspicion remains high
• Will likely miss actionable secondary findings (e.g., BRCA, Lynch syndrome) unrelated to epilepsy
• No coverage of non-coding variants implicated in generalized genetic epilepsy risk
Whole Exome Sequencing (WES)Coding regions (exons) and exon/intron boundaries (~1–2% of genome) • Comprehensive coverage of coding regions and actionable gene findings
• Effective for heterogeneous neurological conditions & comorbidities
• Able to identify mutations in novel genes
• Reanalysis is possible 		• More likely than MGP to result in incidental or secondary findings requiring medical geneticist interpretation
• Depth of coverage is not uniform
• Unable to detect non-coding (intronic) variants
• Limited ability to identify CNVs or structural variants
Whole Genome Sequencing (WGS)Entire genome • Detects coding and noncoding variants (unlike other 2 options)
• Uniform coverage
• Able to identify mutations in novel genes as well as non-coding (e.g., presumed regulatory) regions
• Reanalysis is possible
• Allows detection of copy number variants (CNV) and some smaller structural variants 		• Most expensive and longest turnaround
• More challenging to get covered by insurance
• Most likely to result in incidental findings that are difficult to interpret
• Requires medical geneticist for full interpretation
Chromosomal Microarray (CGH)Genome-wide copy number variants (CNV) & structural variants (e.g., deletions, translocations) • Cost effective in people with epilepsy PLUS comorbid developmental delay (DD), intellectual disability (ID), or birth defects
• Often considered as second-line testing if previous testing was unrevealing
• Detects structural variants that may be undetectable on other NGS-based tests 		• Not cost-effective as first-line test unless DD/ID or birth defect comorbidities
• Cannot detect balanced translocations and some structural rearrangements (chromosome analysis needed)

 

Other genetic testing considerations:

  • Trio testing can be done with WES vs WGS if both biological parents are available.
  • Quad testing feasible if there is an affected sibling + above
    • Pros: identifies de novo mutations, Family/pregnancy planning
    • Cons: risk of unexpected familial implications such as consanguinity or non-paternity

 

 

Download the Table

 

How: Example Test Report

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Positive Result arrow_drop_down

Documentation

  • Include the gene, specific mutation, inheritance pattern, and whether de novo (if known)
  • Note details about the specific test (lab, test name, date of report)

 

Literature Review

  • What has been reported before? What is the prognosis? Are there specific treatment/management recommendations? Are there known genotype-phenotype correlations?
  • PubMed, GeneReviews, OMIM, Medline Plus, RareChromo.org, NORD Rare Disease Database

 

Results Disclosure

  • Review natural history of the disorder, prognosis (often variable), associated symptoms to monitor for
  • Discuss any treatment/ management implications (change in/avoidance of medication, gene-specific precision therapy available or in development, additional imaging/workup needed)
  • Discuss recurrence risks for patient, for future pregnancies, and for other family members, and coordinate testing for other family members as indicated and appropriate (genetic testing is generally not recommended for asymptomatic minors)
  • Share resources (see above or look for disorder-specific foundations/ patient advocacy groups), inform family of any relevant clinical trials/ natural history studies.
  • Patient Advocacy Groups can also help connect families with research opportunities, community contacts, resources, and information about conferences/ events.

 

Follow Up

  • Refer to Genetics or a specialty clinic if applicable for further discussion and management
  • Check for updated information about the specific disorder when patient is seen for follow-up.
  • If new symptoms arise that are not explained by the diagnosis, additional genetic testing may be warranted (1-3% of patients with a genetic diagnosis have a dual diagnosis)

 

Negative Result arrow_drop_down

Documentation

  • Document details about the specific test (lab, test name, list of genes analyzed if a panel, date of report).

 

Results Disclosure

  • Review what the negative test rules out and what it does not. A negative genetic test does not mean no genetic diagnosis.
  • A negative genetic test for a certain clinical indication does not mean the patient does not have that clinical diagnosis (i.e.. a negative autism panel does not mean the patient does not have autism).

 

Follow Up

  • Coordination of additional testing if warranted, either right away or in the future depending on the clinical course (new- onset symptoms, worsening seizures, etc.).
  • For whole exome/genome sequencing, have a plan for reanalysis. Many labs offer one free reanalysis of WES/WGS, usuall~two years after the initial testing to allow time for new gene discovery. Some labs offer "continual reanalysis" and will contact ordering provider if/when additional findings are discovered.
  • Advise families to follow up in ~two years for potential additional testing recommendations/coordination of reanalysis.
Variant of Uncertain Significance arrow_drop_down

What is a Variant of Uncertain Significance (VUS)?

  • Genetic testing laboratories consider type of variant, location within the gene (mutational hot spot/ critical functional domain), presence of the variant in symptomatic individuals, prevalence of the variant in healthy population databases, whether variant is de novo, functional studies, computational evidence, and other criteria when classifying a genetic variant
  • If there is insufficient evidence to classify the variant as pathogenic or benign, it may be reported as a VUS

 

How to Further Interpret a VUS:

  • Assess clinical correlation - does the gene/variant match with the patient's phenotype?
  • Can be difficult in disorders with nonspecific symptoms/ broad spectrum of presentation. It may help to assess for other symptoms that can be associated with the gene in question (targeted exam, metabolic testing, imaging studies, etc.)
  • Test parents for phase if original testing was proband-only. A de novo variant when there is no family history of the disorder provides additional evidence for pathogenicity. A variant inherited from an unaffected parent is more likely to be benign (although possibility of reduced penetrance/ variable expressivity should be considered)
  • Test other affected family members if applicable. If a variant segregates with other symptomatic individuals, it may be the cause of disease in the family

 

Next Steps:

  • Move to the next tier of genetic testing if applicable. If a panel was negative, consider WES/WGS, microarray, or other more specific testing (i.e.. methylation analysis for Angelman/Prader-Willi, repeat analysis for Fragile X, etc.).
  • Reassess the variant status over time. Some labs automatically issue revised reports when a VUS is reclassified. For others, you may need to reach out to the lab every few years. There are also online tools and databases you can consult to check on the status of a variant (Franklin Genoox, ClinVar)


Other/Unexpected Results arrow_drop_down

 

Secondary Findings:Disease-causing variant in an ACMG SF gene* (currently 81 genes as of 2023: version 3.2)
Medically Actionable
Only pathogenic/likely pathogenic variants reported 		Refer to an appropriate specialist
Incidental Findings:Carrier Status
Disease-causing variants in non-ACMG SF genes
Disease-causing variant in a gene with variable presentations including adult onset 		Pre-test counseling crucial
Provide appropriate family planning information & referrals
Unexpected Results:Trio/ parental testing can reveal consanguinity, non-paternity, IVF implantation error (rare)
Lab usually communicates to ordering provider before report is issued
Lab may provide a discrete report without specific mention of these findings. 		Be mindful of possible social & legal implications and patient/family safety when discussing with family

 

 

Administrative Resources

 

Example Disclosure Statement for Documentation

I have discussed the patient’s diagnosis and testing history to this point ([include list of positive or negative studies]). Given the aforementioned, I have recommended genetic testing be performed. I have discussed several types of testing and have recommended [a panel/WES/WGS/CMA]. I have discussed the purpose of this test which is to identify whether there is a genetic cause of the patient’s epilepsy. The patient agrees with this testing to be performed via a [blood draw / buccal swab]. I have discussed the risks associated with the test which may include the revelation of [non-paternity / consanguinity / risk of inability to later purchase life insurance]. I have discussed that the results of this testing may be used for future research endeavors in a manner that does not expose PHI. I have discussed that the patient may receive the results before I or a colleague can review them and if this is the case, they may be unable to discuss their results in detail which may lead to considerable emotional repercussions. Therefore, I have advised them not to review their results if informed of availability, but to contact our office. The patient has agreed to the testing and signed the [disclosure / requisition paperwork]. [No witness / A witness] was available.

 

Sample Appeal Letters

Resources

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References arrow_drop_down
  1. Karlin, A., Ruggiero, S., & Fitzgerald, M. (2024). Genetic testing for unexplained epilepsy: A review of diagnostic approach, benefits, and referral algorithm. Current problems in pediatric and adolescent health care, 54(8), 101579. https://doi.org/10.1016/j.cppeds.2024.101579
  2. Smith, L., Malinowski, J., Ceulemans, S., Peck, K., Walton, N., Sheidley, B. R., & Lippa, N. (2023). Genetic testing and counseling for the unexplained epilepsies: An evidence-based practice guideline of the National Society of Genetic Counselors. Journal of genetic counseling, 32(2), 266–280. https://doi.org/10.1002/jgc4.1646
  3. Ritter, D. M., & Holland, K. (2020). Genetic Testing in Epilepsy. Seminars in neurology, 40(6), 730–738. https://doi.org/10.1055/s-0040-1719070
  4. Pickrell, W. O., & Fry, A. E. (2023). Epilepsy genetics: a practical guide for adult neurologists. Practical neurology, 23(2), 111–119. https://doi.org/10.1136/pn-2022-003623
  5. Oliver, K. L., Scheffer, I. E., Bennett, M. F., Grinton, B. E., Bahlo, M., & Berkovic, S. F. (2023). Genes4Epilepsy: An epilepsy gene resource. Epilepsia, 64(5), 1368–1375. https://doi.org/10.1111/epi.17547
  6. Habela, C. W., Schatz, K., & Kelley, S. A. (2024). Genetic Testing in Epilepsy: Improving Outcomes and Informing Gaps in Research. Epilepsy currents, 15357597241232881. Advance online publication. https://doi.org/10.1177/15357597241232881
  7. Krey, I., Platzer, K., Esterhuizen, A., Berkovic, S. F., Helbig, I., Hildebrand, M. S., Lerche, H., Lowenstein, D., Møller, R. S., Poduri, A., Sadleir, L., Sisodiya, S. M., Weckhuysen, S., Wilmshurst, J. M., Weber, Y., Lemke, J. R., Berkovic, S. F., Cross, J. H., Helbig, I., Lerche, H., … Weckhuysen, S. (2022). Current practice in diagnostic genetic testing of the epilepsies. Current practice in diagnostic genetic testing of the epilepsies. Epileptic disorders : international epilepsy journal with videotape, 24(5), 765–786. https://doi.org/10.1684/epd.2022.1448
  8. Chowdhury, S. R., Whitney, R., RamachandranNair, R., Bijarnia Mahay, S., & Sharma, S. (2024). Genetic Testing in Pediatric Epilepsy: Tools, Tips, and Navigating the Traps. Pediatric neurology, 157, 42–49. https://doi.org/10.1016/j.pediatrneurol.2024.05.008
  9. Sheidley, B. R., Malinowski, J., Bergner, A. L., Bier, L., Gloss, D. S., Mu, W., Mulhern, M. M., Partack, E. J., & Poduri, A. (2022). Genetic testing for the epilepsies: A systematic review. Epilepsia, 63(2), 375–387. https://doi.org/10.1111/epi.17141
  10. Koh, H. Y., Smith, L., Wiltrout, K. N., Podury, A., Chourasia, N., D'Gama, A. M., Park, M., Knight, D., Sexton, E. L., Koh, J. J., Oby, B., Pinsky, R., Shao, D. D., French, C. E., Shao, W., Rockowitz, S., Sliz, P., Zhang, B., Mahida, S., Moufawad El Achkar, C., … BCH Neurology Referral and Phenotyping Group (2023). Utility of Exome Sequencing for Diagnosis in Unexplained Pediatric-Onset Epilepsy. JAMA network open, 6(7), e2324380. https://doi.org/10.1001/jamanetworkopen.2023.24380





Webinars arrow_drop_down
  1. Genetic Testing in Epilepsy | FREE | 2.0 CME Leah Schust Myers; Louis Dang, MD; Anup Patel, MD; John Millichap, MD, FAAN, FAAP, FACNS, FAES; Heather Mefford, MD. This course reviews available genetic testing options for people with epilepsy and seizure disorders and discusses the diagnostic yield and role of genetic testing in improving outcomes. Link to Content
  2. Ask the Experts: Making Sense of the Alphabet Soup - Practical Tips on Genetic Testing in Patients with Epilepsy, Annapurna (Ann) Poduri, MD, MPH, FAES; and Wolfgang Muhlhofer, MD, MSHS, FAES. This webinar helps learners establish familiarity with testing modalities, identify patients who would benefit from genetic testing, determine what types of genetic changes can help to explain epilepsy syndromes, and choose the appropriate type of genetic testing for patients with suspected genetic epilepsy to improve epilepsy patient care and outcomes. Link to Content  
  3. Epilepsy Currents - Episode 9 - "Genetic Testing in Epilepsy: Improving Outcomes and Informing Gaps in Research". Join Dr. Bermeo in a conversation with Dr. Elizabeth Gerard, and Dr. Christa Habela, as they discuss the article, " Genetic Testing in Epilepsy: Improving Outcomes and Informing Gaps in Research ".  Read the article or listen to the Podcast.

Websites arrow_drop_down
  1. Find a Genetic Service - Find Genetic Clinics. (2020). Acmg.net. https://clinics.acmg.net/
  2. Home - Genetic Testing Registry (GTR) - NCBI. (2012). Nih.gov. https://www.ncbi.nlm.nih.gov/gtr/
  3. Impexium. (2025). Home. Nsgc.org. https://findageneticcounselor.nsgc.org
  4. Medical Necessity Webinar Series | Genetics Policy Hub. (2024). Nccrcg.org. https://geneticspolicy.nccrcg.org/medical-neccesity/