BlueCross BlueShield of Tennessee Medical Policy Manual

Genetic Testing for Epilepsy


Epilepsy is a disorder characterized by unprovoked seizures. It is a condition that has many different types of seizures and varies in age of onset and severity. Classification is typically based on seizure type (e.g., simple partial, complex partial, generalized, convulsive, non-convulsive) or age of onset (i.e. neonatal, infancy, childhood, adolescent/adult). The most recent proposal by the Commission on Classification and Terminology of the International League Against Epilepsy (ILAE) proposes using terms with specific etiologic categories such as genetic, structural/metabolic, and unknown.

The common epilepsy syndromes, also known as idiopathic epilepsy, generally present in childhood, adolescence or early adulthood. They include generalized or focal in nature and may be convulsant (grand mal) or absence type. There is a lack of evidence on the clinical utility of genetic testing for the common genetic epilepsies

Epilepsy syndromes that present in infancy or early childhood are usually severe and characterized by seizures as the primary manifestation, without associated metabolic or structural brain abnormalities. Mutations in a large number of genes have been associated with early onset epilepsies. Specific clinical syndromes based on the ILAE classification and their associated genes are demonstrated in the following table:

Single-Gene Mutations Associated with Epileptic Syndromes


Associated Genes

Dravet syndrome (presents between 4 and 15 months with prolonged convulsive seizures; severe developmental delay also known as myoclonic epilepsy in infancy [SMEI] or polymorphic myoclonic epilepsy in infancy [PMEI]))


Early infantile epileptic encephalopathy STXBP1
EFMR syndrome (epilepsy limited to females with mental retardation) PCDH19
Nocturnal frontal lobe epilepsy (epileptic encephalopathy with continuous spike-and-wave during sleep) CHRNA4, CHRNB2, CHRNA2, GRIN2A
GEFS+ syndrome (generalized epilepsies with febrile seizures plus) SCN1A, SCN2A, SCN1B, SCN9A, GABRG2
Ohtahara syndrome (Early infantile epileptic encephalopathy with suppression burst) KCNQ2, SLC25A22, STXBP1, CDKL5, ARX
Landau-Kleffner syndrome (aphasia with convulsions) GRIN2A
West syndrome (the most common with onset within the first 2 years; hypsarrhythmia on interictal EEG, and developmental delay; also known as X-linked infantile spasm syndrome)


Glucose transporter type 1 deficiency syndrome SLC2A1
Less commonly reported single gene mutations: ASAH1, FOLR1, GRIN2A, SCN8A, SYNGAP1, SYNJ1, SLC13A5

Another area of interest for epilepsy research is the pharmacogenomics of anti-epileptic medications.  It has been proposed that by identifying genetic markers in individuals who are likely to be refractory to common medications that a more efficient process for medication selection, and more effective control of symptoms could be developed.  However, how genetic information might be used to tailor medication management is not yet well-defined.

While there are multiple commercial pre-curated genetic panels available (e.g. GeneDx) there are also companies that will allow a customized genetic test to be built for each individual (e.g. INVITAE at ).

Note: This policy does not address testing for genetic syndromes that have a wider range of symptomatology; the intent is to address epilepsy syndromes that present in infancy or early childhood, are severe, and are characterized by epilepsy as the primary manifestation, without associated metabolic or brain structural abnormalities.


See also: Responsive Neurostimulation for the Treatment of Refractory Partial Epilepsy




For epilepsy pharmacogenomics, the body of evidence does not show consistent or strong relationships between genetic variants and response to medications. Therefore, the clinical utility of pharmacogenomics in epilepsy has not been demonstrated and genetic testing for anti-epileptic medication tolerance remains investigational.  

No regulations are required by The U.S. Food and Drug Administration (FDA) for this type of testing.  Genetic testing is considered laboratory-developed services and subject only to the general laboratory operational regulation under the Clinical Laboratory Improvement Amendments (CLIA) of 1988.


Allen, N., Conroy, J., Shahwan, A., Lynch, B., Correa, R., Pena, S., et. al. (2016) Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion. Epilepsia, 57(1):e12–e17. (Level 3 evidence)

American Academy of Neurology and the American Epilepsy Society. (2015)  Evidence-based guideline: management of an unprovoked first seizure in adults. Neurology 2015; 84; 1705-1713.

American Academy of Neurology and the Practice Committee of the Child Neurology Society. (2012) Evidence-based guideline update: medical treatment of infantile spasms Neurology 2012; 78; 1974-1980.

BlueCross BlueShield Association. Medical Policy Reference Manual. (2:2017). Genetic testing for epilepsy (2.04.109). Retrieved April 4, 2017 from BlueWeb. (63 articles and/or guidelines reviewed)

Brunklaus, A., Dorris, L., Ellis, R., Reavey, E., Lee, E., Forbes, G., et al. (2012). The clinical utility of an SCN1A genetic diagnosis in infantile-onset epilepsy. Developmental Medicine & Child Neurology, 55 (2), 154-161. (Level 3 evidence)

Gonsales, M., Montenegro, M., Soler, C., Coan, A., Guerreiro, M., and Lopes-Cendes, I. (2015, July) Recent developments in the genetics of childhood epileptic encephalopathies: impact in clinical practice. Arquivos de Neuro-Psiquiatria (Journal of the Brazilian Academy of Neurology). 2015; 73(11):946-958 (Level 5 evidence)

Hirose, S., Scheffer, I., Marini, C., De Jonghe, P., Andermann, E., Goldman, A., et. al. (2013) SCN1A testing for epilepsy: application in clinical practice. Epilepsia, 54(5):946–952. (Level 4 evidence)

International League Against Epilepsy (ILAE) (2015, August) Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics. Epilepsia, 56(8):1185-1197.

Kruegar, J. and Berg, A. (2015, December) Incidence of Dravet Syndrome in a US Population. Pediatric Neurology Briefs. Vol. 29, No. 12. (Level 4 evidence)

Kwong, A., Ho, A., Fung, C., and Wong V. (2015, February) Analysis of mutations in 7 genes associated with neuronal excitability and synaptic transmission in a cohort of children with non-syndromic infantile epileptic encephalopathy. PLOS ONE e0126446. Doi: 10.1371/journal.pone.0126446. (Level 3 evidence)

Mercimek-Mahmutoglu, S.,  Patel, J.,  Cordeiro, D.,  Hewson, S.,  Callen, D., Donner, E., et. al., (2015) Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epelepsia, 56(5):707-716. (Level 3 evidence)

National Institutes of Health. (2012, August) Genetics Home Reference: X-linked infantile spasm syndrome. Retrieved April 4, 2017 from

Pellock, J., Hrachovy, R., Shinnar, S.  Baram, T., Bettis, D., Dlugos, D.,et. al. (2010) Infantile spasms: A U.S. consensus report. Epilepsia, 51(10):2175–2189. (Level 5 evidence)

Tan, N. C., & Berkovic, S. F. (2010). The Epilepsy Genetic Association Database (epiGAD):  Analysis of 165 genetic association studies, 1996-2008. Epilepsia, 51 (4), 686-689. (Level 4 evidence)

Winifred S. Hayes, Inc. Genetic Test Evaluation (GTE) Overview (2015, December) Comprehensive Epilepsy Evaluation NGS Panel. Retrieved April 4, 2017 from:

Winifred S. Hayes, Inc. Genetic Test Evaluation (GTE) Overview (2015, December) NGS Epilepsy/Seizure Panel (Greenwood Genetic Center). Retrieved April 4, 2017 from:

Wirrell, E. C., Shellhaas, R. A., Joshi, C., Keator, C., Kumar, S., Mitchell, W.G., et al. (2015). How should children with West syndrome be efficiently and accurately investigated?  Results from the national infantile spasms consortium. Epilepsia, 56 (4), 617-625. (Level 3 evidence)

Wisconsin’s National Government Services, Inc. (2017, February) Local Coverage Determination (LCD): Molecular Pathology Procedures (L35000). Retrieved April 4, 2017 from




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