| Coverage Policy Manual | |
| Policy #: | 2013044 |
| Category: | Medicine |
| Initiated: | November 2013 |
| Last Review: | March 2024 |
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| Genetic Test: Epilepsy | |
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| Description: |
Epilepsy is a disorder characterized by unprovoked seizures. It is a heterogenous condition that encompasses many different types of seizures and that varies in age of onset and severity. The common epilepsies, also called idiopathic epilepsy, are thought to have a complex, multifactorial genetic basis. There are also numerous rare epileptic syndromes that occur in infancy or early childhood and that may be caused by a single gene mutation. Genetic testing is commercially available for a large number of genetic mutations that may be related to epilepsy.
Epilepsy is defined as the occurrence of two or more unprovoked seizures. It is a common neurologic disorder, with approximate 3% of the population developing the disorder over their entire lifespan (Williams, 2013).
Epilepsy is heterogeneous in etiology and clinical expression and can be classified in a variety of ways. Most commonly, classification is done by the clinical phenotype, i.e., the type of seizures that occur. The International League Against Epilepsy (ILAE) developed the classification system that is widely used for clinical care and research purposes (Berg, 2010). Classification of seizures can also be done on the basis of age of onset: neonatal, infancy, childhood, and adolescent/adult.
Classification of Seizure Disorders by Type
Although genetic epilepsies are not discussed in the 2017 ILAE report, a 2010 ILAE report identified genetic epilepsies as conditions in which the seizures are a direct result of a known or presumed genetic defect(s) (Fisher, 2017; Berg, 2010). Genetic epilepsies are characterized by recurrent unprovoked seizures in patients who do not have demonstrable brain lesions or metabolic abnormalities. In addition, seizures are the core symptom of the disorder, and other symptomatology is not present, except as a direct result of seizures. This is differentiated from genetically determined conditions in which seizures are part of a larger syndrome, such as tuberous sclerosis, fragile X syndrome, or Rett syndrome.
The policy will focus on the category of genetic epilepsies in which seizures are the primary clinical manifestation. This category does not include syndromes that have multiple clinical manifestations, of which seizures may be one. Examples of syndromes that include seizures are Rett syndrome and tuberous sclerosis. Genetic testing for these syndromes will not be assessed in this policy but may be included in separate policies that specifically address genetic testing for that syndrome.
Genetic epilepsies can be further broken down by type of seizures. For example, genetic generalized epilepsy (GGE) refers to patients who have convulsive (grand mal) seizures, while genetic absence epilepsy (GAE) refers to patients with nonconvulsive (absence) seizures. The disorders are also sometimes classified by age of onset.
The category of genetic epilepsies includes a number of rare epilepsy syndromes that present in infancy or early childhood (Williams, 2013; Merwick, 2012). These syndromes are characterized by epilepsy as the primary manifestation, without associated metabolic or brain structural abnormalities. They are often severe and sometimes refractory to medication treatment. They may involve other clinical manifestations such as development delay and/or intellectual disability, which in many cases are thought to be caused by frequent uncontrolled seizures. In these cases, the epileptic syndrome may be classified as an epileptic encephalopathy, which is described by ILAE as disorders in which the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone and that these can worsen over time. A partial list of severe early-onset syndromes is as follows:
Dravet syndrome falls on a spectrum of SCN1A-related seizure disorders, which includes febrile seizures at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures at the severe end. The spectrum may be associated with multiple seizure phenotypes, with a broad spectrum of severity; more severe seizure disorders may be associated with cognitive impairment, or deterioration (Miller, 2014). Ohtahara syndrome is a severe early-onset epilepsy syndrome characterized by intractable tonic spasms, other seizures, interictal electroencephalography abnormalities, and developmental delay. It may be secondary to structural abnormalities but has been associated with variants in the STXBP1 gene in rare cases. West syndrome is an early-onset seizure disorder associated with infantile spasms and the characteristic electroencephalography finding of hypsarrhythmia. Other seizure disorders presenting early in childhood may have a genetic component but are characterized by a more benign course, including benign familial neonatal seizures and benign familial infantile seizures.
Genetics of epilepsy
The common genetic epilepsies are primarily believed to involve multifactorial inheritance patterns. This follows the concept of a threshold effect, in which any particular genetic defect may increase the risk of epilepsy, but is not by itself causative (Petrovski, 2013). A combination of risk-associated genes, together with environmental factors, determines whether the clinical phenotype of epilepsy occurs. In this model, individual genes that increase the susceptibility to epilepsy have a relatively weak impact. Multiple genetic defects, and/or particular combination of genes, probably increase the risk by a greater amount. However, it is not well understood how many abnormal genes are required to exceed the threshold to cause clinical epilepsy, nor is it understood which combination of genes may increase the risk more than others.
Early-onset epilepsy syndromes may be single-gene disorders. Because of the small amount of research available, the evidence base for these rare syndromes is incomplete, and new mutations are currently being discovered frequently (Helbig, 2013).
Some of the most common genes that have been associated with genetic epileptic syndromes are: KCNQ2 (Potassium channel), KCNQ3 (Potassium channel), SCN1A (Sodium channel α-subunit), SCN2A (Sodium channel α-subunit), SCN1B (Sodium channel α-subunit), GABRG2 (γ-aminobutyrate A-type subunit), GABRRA1 (γ-aminobutyrate A-type subunit), GABRD (γ-aminobutyrate subunit), CHRNA2 (Acetylcholine receptor α2 subunit), CHRNA4 (Acetylcholine receptor α4 subunit), CHRNB2 (Acetylcholine receptor β2 subunit), STXBP1 (Synaptic vesicle release), ARX (Homeobox gene), PCDH19 (Protocadherin cell-cell adhesion), EFHC1 (Calcium homeostasis), CACNB4 (Calcium channel subunit), CLCN2 (Chloride channel), and LGI1 (G-protein component) (Williams, 2013).
For the severe early epilepsy syndromes, the disorders most frequently reported to be associated with single-gene variants include generalized epilepsies with febrile seizures plus syndrome (associated with SCN1A, SCN1B, and GABRG2 variants), Dravet syndrome (associated with SCN1A variants, possibly modified by SCN9A variants), and epilepsy and intellectual disability limited to females (associated with PCDH19 variants). Ohtahara syndrome has been associated with variants in STXBP1 in cases where patients have no structural or metabolic abnormalities. West syndrome is often associated with chromosomal abnormalities or tuberous sclerosis or may be secondary to an identifiable infectious or metabolic cause, but when there is no underlying cause identified, it is thought to be due to a multifactorial genetic predisposition (Deprez, 2009).
Targeted testing for individual genes is available. Several commercial epilepsy genetic panels are also available. The number of genes included in the tests varies widely, from about 50 to over 450. The panels frequently include genes for other disorders such as neural tube defects, lysosomal storage disorders, cardiac channelopathies, congenital disorders of glycosylation, metabolic disorders, neurologic syndromes, and multisystemic genetic syndromes. Some panels are designed to be comprehensive while other panels target specific subtypes of epilepsy. Chambers et al reviewed comprehensive epilepsy panels from 7 U.S.-based clinical laboratories and found that between 1% and 4% of panel contents were genes not known to be associated with primary epilepsy (Chambers, 2016). Between 1% and 70% of the genes included on an individual panel were not on any other panel.
Treatment
The condition is generally chronic, requiring treatment with 1 or more medications to adequately control symptoms. Seizures can be controlled by antiepileptic medications in most cases, but some patients are resistant to medications, and further options such as surgery, vagus nerve stimulation, and/or the ketogenic diet can be used (Kwan, 2000).
Pharmacogenomics of epilepsy
Another area of interest for epilepsy is the pharmacogenomics of anti-epileptic medications. There are a wide variety of these medications, from numerous different classes. The choice of medications, and the combinations of medications for patients who require treatment with more than one agent, is complex. Approximately one-third of patients are considered refractory to medications, defined as inadequate control of symptoms with a single medication (Cavalleri, 2011). These patients often require escalating doses and/or combinations of different medications. At present, selection of agents is driven by the clinical phenotype of seizures but has a large trial and error component in many refractory cases. The current focus of epilepsy pharmogenomics is in identifying genetic markers that identify patients who are likely to be refractory to the most common medications. This may lead to directed treatment that will result in a more efficient process for medication selection, and potentially more effective control of symptoms.
Of note, genotyping for the HLA-B*1502 allelic variant in patients of Asian ancestry, prior to considering drug treatment with carbamazepine due to risks of severe dermatologic reactions, is recommended by the U.S. Food and Drug Administration (FDA) labeling for carbamazepine (FDA, 2018).
Genetic testing for epilepsy
Commercial testing is available from numerous companies. Testing for individual genes is available for most, or all, or the genes listed above, as well as for a wider range of genes. Because of the large number of potential genes, panel testing is available from a number of genetic companies. These panels typically include large numbers of genes that have been implicated in diverse disorders.
GeneDx® offers a number of different epilepsy panels that have overlapping genes in varying combinations. The GeneDx® Comprehensive Epilepsy Panel lists 71 genes. They also offer a Childhood Onset epilepsy panel and an Infancy Panel. The GeneDx® infantile epilepsy panel includes the following 50 genes:
ADSL, ALDH7A1, ARX, ATP6AP2, CDKL5, CHRNA7, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CTSD, FOLR1, FOXG1, GABRG2, GAMT, GRIN2A, KANSL1, KCNJ10, KCNQ2, KCNQ3, KCTD7, LIAS, MAGI2, MBD5, MECP2, MEF2C, MFSD8, NRXN1, PCDH19, PNKP, PNPO, POLG, PPT1, SCN1A, SCN1B, SCN2A, SCN8A, SLC25A22, SLC2A1, SLC9A6, SPTAN1, STXBP1, TBC1D24, TCF4, TPP1 (CLN2), TSC1, TSC2, UBE3A, ZEB2
The Courtagen epiSEEK® gene panel includes over 200 genes in its panel.
Emory Genetics® Epilepsy and Seizure Disorders panel offers testing of 123 different genetic mutations by next-generation sequencing.
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Commercially available genetic tests for epilepsy are available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.
Coding
If the specific gene being tested has been codified in CPT, the appropriate CPT code would be reported. If the specific gene has not been codified in CPT, the unlisted molecular pathology code 81479 would be reported.
Category 1 CPT codes:
CPT code 81419
Epilepsy genomic sequence analysis panel, must include analyses for ALDH7A1, CACNA1A, CDKL5, CHD2, GABRG2, GRIN2A, KCNQ2, MECP2, PCDH19, POLG, PRRT2, SCN1A, SCN1B, SCN2A, SCN8A, SLC2A1, SLC9A6, STXBP1, SYNGAP1, TCF4, TPP1, TSC1, TSC2, and ZEB2) and 0232U (CSTB [cystatin B] [e.g., progressive myoclonic epilepsy type 1A, Unverricht Lundborg disease], full gene analysis, including small sequence changes in exonic and intronic regions, deletions, duplications, short tandem repeat [STR] expansions, mobile element insertions, and variants in non uniquely mappable regions) (Effective 1/1/2021)
The following is a list of some of the tests related to epilepsy that are listed under CPT Tier 2 codes:
Under CPT code 81401:
MT-TK (mitochondrially encoded tRNA lysine) (e.g., myoclonic epilepsy with ragged-red fibers [MERRF]), common variants (e.g., m.8344A>G, m.8356T>C)
Under CPT code 81403:
NHLRC1 (NHL repeat containing 1) (e.g., progressive myoclonus epilepsy), full gene sequence
Under CPT code 81404:
ARX (aristaless related homeobox) (e.g., X-linked lissencephaly with ambiguous genitalia, X-linked mental retardation), full gene sequence
EPM2A (epilepsy, progressive myoclonus type 2A, Lafora disease [laforin]) (e.g., progressive myoclonus epilepsy), full gene sequence
Under CPT code 81405:
CHRNA4 (cholinergic receptor, nicotinic, alpha 4) (e.g., nocturnal frontal lobe epilepsy), full gene sequence
CHRNB2 (cholinergic receptor, nicotinic, beta 2 [neuronal]) (e.g., nocturnal frontal lobe epilepsy), full gene sequence
GABRG2 (gamma-aminobutyric acid [GABA] A receptor, gamma 2) (e.g., generalized epilepsy with febrile seizures), full gene sequence
Under CPT code 81406:
ALDH7A1 (aldehyde dehydrogenase 7 family, member A1) (e.g., pyridoxine-dependent epilepsy), full gene sequence
CDKL5 (cyclin-dependent kinase-like 5) (e.g., early infantile epileptic encephalopathy), full gene sequence
EFHC1 (EF-hand domain [C-terminal] containing 1) (e.g., juvenile myoclonic epilepsy), full gene sequence
Under CPT code 81407:
SCN1A (sodium channel, voltage-gated, type 1, alpha subunit) (e.g., generalized epilepsy with epilepsy with febrile seizures), full gene sequence
Proprietary Laboratory Analysis Codes:
0232U CSTB (cystatin B) (e.g., progressive myoclonic epilepsy type 1A, Unverricht Lundborg disease), full gene analysis, including small sequence changes in exonic and intronic regions, deletions, duplications, short tandem repeat (STR) expansions, mobile element insertions, and variants in non uniquely mappable regions (Effective 1/1/2021)
If a panel of tests that have not been codified in CPT is performed, code 81479 would be reported once.
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Policy/ Coverage: |
EFFECTIVE November 2015
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Genetic testing of individuals with infantile- and early childhood-onset epilepsy syndromes in which epilepsy is the core clinical symptom meets member benefit certificate primary coverage criteria and is covered when ALL of the following criteria are met:
1. 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.
2. There is a completed consult with a pediatric neurologist
3. There is a completed an EEG
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for epilepsy does not meet member benefit certificate primary coverage criteria for all other indications.
For members with contracts without primary coverage criteria genetic testing for epilepsy for all other indications is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Note* This policy does not address the use of genotyping for the HLA-B*1502 allelic variant in patients of Asian ancestry prior to considering drug treatment with carbamazepine due to risks of severe dermatologic reactions (see policy 2007023). This testing is recommended by the Food and Drug Administration labeling for carbamazepine. (Administration FDA Label).
EFFECTIVE Prior to November 2015
Genetic testing for epilepsy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for epilepsy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
This policy was created in November 2013 with review of the literature through September 30, 2013.
The evaluation of a genetic test focuses on 3 main principles: 1) analytic validity (the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent); 2) clinical validity (the diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease); and 3) clinical utility (how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes)
The genetic epilepsies will be discussed in two categories: The rare epileptic syndromes that may be caused by a single-gene mutation and the common epilepsy syndromes that are thought to have a multifactorial genetic basis.
Rare Epilepsy Syndromes Associated with Single-Gene Mutations
There are numerous rare syndromes that have seizures as their primary symptom. These generally present in infancy or early childhood. Many of them are thought to be caused by single-gene mutations. The published literature on these syndromes generally consists of small cohorts of patients treated in tertiary care centers, with descriptions of genetic mutations that are detected in affected individuals.
Some of these syndromes are listed below, with the putative causative genetic mutations:
Dravet syndrome (severe myoclonic epilepsy of infancy)
SCN1A
Early infantile epileptic encephalopathy
STXBP1
Generalized epilepsy with febrile seizures plus (GEFS+)
SCN1A, SCN2A, SCN1B, GABRG2
Epilepsy and mental retardation limited to females (EFMR)
PCDH19
Nocturnal frontal lobe epilepsy
CHRNA4, CHRNB2, CHRNA2
Analytic validity
These syndromes can be evaluated by single-gene analysis, which is generally performed by direct sequencing. Direct sequencing is the gold standard for identifying specific mutations. This testing method has an analytic validity of greater than 99%. They can also be evaluated by genetic panel testing, which is generally done by next-generation sequencing. This method has a lower analytic validity compared to direct sequencing, but is still considered to be very accurate, in the range of 95-99%.
Clinical validity
The literature on the clinical validity of these rare syndromes is limited, and for most syndromes, the clinical sensitivity and specificity is not defined. Dravet syndrome is probably the most well-studied, and some evidence on the clinical validity of SCN1A mutations is available. The clinical sensitivity has been reported to be in the 70-80% range. (8, 9) In one series of 64 patients, 51 (79%) were found to have SCN1A mutations (Mulley, 2006). The false-positive rate and the frequency of variants of uncertain significance, is not well characterized.
For the other syndromes, the associations of the genetic mutations with the syndromes have been reported in case reports or very small numbers of patients. Therefore, it is not possible to determine the clinical validity of the putative causative genetic mutations.
Clinical utility
One potential area of clinical utility for genetic testing may be in making a definitive diagnosis and avoiding further testing. For most of these syndromes, the diagnosis is made by clinical criteria, and it is not known how often genetic testing leads to a definitive diagnosis when the diagnosis cannot be made by clinical criteria.
Another potential area of clinical utility may be in directing pharmacologic treatment. For Dravet syndrome, the seizures are often refractory to common medications. Some experts have suggested that diagnosis of Dravet syndrome may therefore prompt more aggressive treatment, and/or avoidance of certain medications that are known to be less effective, such as carbamazepine (Mulley, 2006; Ottman, 2010). However, there are no studies that examine the frequency with which genetic testing leads to changes in medication management, and there are no studies that report on whether the efficacy of treatment directed by genetic testing is superior to efficacy of treatment without genetic testing.
Section Summary. There are numerous rare epileptic syndromes which may be caused by single-gene mutations, but the evidence on genetic testing for these syndromes is insufficient to form conclusions on the clinical validity and clinical utility of genetic testing. The syndrome with the greatest amount of evidence is Dravet syndrome. The clinical sensitivity of testing patients with clinically defined Dravet syndrome is relatively high in small cohorts of patients. There may be clinical utility in avoiding further testing and directing treatment, but there is only a small amount of evidence to suggest this and no evidence demonstrating that outcomes are improved.
Common Epilepsies
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. They are generally thought to have a multifactorial genetic component.
Analytic validity
The common epilepsies are generally evaluated by genetic panel testing. The larger, commercially available panels that include many mutations are generally performed by next-generation sequencing. This method has a lower analytic validity compared to direct sequencing, but is still considered to be very accurate, in the range of 95-99%. Less commonly, deletion/duplication analysis may be performed; this method is also considered to have an analytic validity of greater than 95%.
Clinical validity
The literature on clinical validity includes many studies that report the association of various genetic variants with the common epilepsies. There are a large number of case-control studies that compare the frequency of genetic variants in patients with epilepsy to the frequency in patients without epilepsy. There are a smaller number of genome-wide association studies (GWAS) that evaluate the presence of single-nucleotide polymorphisms (SNPs) associated with epilepsy across the entire genome. No studies were identified that reported the clinical sensitivity and specificity of genetic mutations in various clinically defined groups of patients with epilepsy. In addition to these studies on the association of genetic variants with the diagnosis of epilepsy, there are numerous other studies that evaluate the association of genetic variants with pharmacogenomics of anti-epileptic medications.
Diagnosis of Epilepsy. The Epilepsy Genetic Association Database (epiGAD) published an overview of genetic association studies in 2010 (Tan, 2010). This review identified 165 case-control studies published between 1985 and 2008. There were 133 studies that examined the association of 77 different genetic variants with the diagnosis of epilepsy. Approximately half of these studies (65/133) focused on patients with genetic generalized epilepsy. Most of these studies had relatively small sample sizes, with a median of 104 cases (range 8-1,361) and 126 controls (range 22-1,390). There were less than 200 case patients in 80% of the studies. The majority of the studies did not show a statistically significant association. Using a cutoff of p<0.01 as the threshold for significance, there were 35 studies (21.2%) that reported a statistically significant association. According to standard definitions for genetic association, all of the associations were in the weak to moderate range, with no associations reported that were considered strong.
The EPICURE Consortium published one of the larger GWAS of genetic generalized epilepsy in 2012 (Epicure Consortium, 2012). This study included 3,020 patients with genetic generalized epilepsy (GGE) and 3,954 control patients, all of European ancestry. A 2-stage approach was used, with a discovery phase and a replication phase, to evaluate a total of 4.56 million single-nucleotide polymorphisms (SNPs). In the discovery phase, 40 candidate SNPs were identified that exceeded the significance for the screening threshold (1 x 10-5), although none of these reached the threshold defined as statistically significant for genome-wide association (1 x 10-8). After stage 2 analysis, there were 4 SNPs identified that had suggestive associations with GGE on genes SCN1A, CHRM3, ZEB2, and NLE2F1.
A second GWAS with a relative large sample size of Chinese patients was also published in 2012 (Guo, 2012). Using a similar 2-stage methodology, this study evaluated 1,087 patients with epilepsy and 3,444 matched controls. Two variants were determined to have the strongest association with epilepsy. One of these was on the CAMSAP1L1 gene and the second was on the GRIK2 gene. There were several other loci on genes that were suggestive of an association on genes that coded for neurotransmitters or other neuron function.
In contrast to the 2 studies, a GWAS published from the UK failed to show any robust associations of SNPs with partial epilepsy (Kasperaviciute, 2010). This study included 3,445 patients with partial epilepsies and 6,935 controls of European ancestry. Using a threshold of an odds ratio greater than 1.3, the authors reported that no SNPs were identified that had a statistically significant association at that level.
In 2012, Heinzen et al. used whole exome sequencing to evaluate the association of genetic variants with genetic generalized epilepsy in 118 individuals with the disorder and 242 control patients of European origin (Heinzen, 2012). No variants were found that reached the statistical threshold for a statistical association. From this initial data, the researchers selected 3,897 candidate genetic variants. These variants were tested in a replication sample of 878 individuals with GGE and 1,830 controls. None of the tested variants showed a statistically significant association.
In addition to the individual studies, there are a number of meta-analyses that evaluate the association of particular genetic variants with different types of epilepsy. Most of these have not shown a significant association. For example, Cordoba et al. evaluated the association of SLC6A4 gene variants with temporal lobe epilepsy in a total of 991 case patients and 1,202 controls and failed to demonstrate a significant association on combined analysis (Cordoba, 2012). Nurmohamed et al. performed a meta-analysis of 9 case-control studies that evaluated the association of the ABC1 gene polymorphisms with epilepsy (Nurmohamed, 2010). There were a total of 2,454 patients with epilepsy and 1,542 control patients. No significant associations were found. One meta-analysis that did report a significant association was published by Kauffman et al. In 2008 (Kauffman, 2008). This study evaluated the association of variants in the IL1B gene with temporal lobe epilepsy and febrile seizures, using data from 13 studies of 1,866 patients with epilepsy and 1,930 controls. Combined analysis showed a significant relationship between one SNP (511T) and temporal lobe epilepsy, with a strength of association that was considered modest (odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.1-2.0, p=0.01).
Pharmacogenomics of anti-epileptic medications. Numerous case-control studies report on the association of various genetic variants with response to medications in patients with epilepsy. The epiGAD database identified 32 case-control studies of 20 different genes and their association with medication treatment (Tan, 2010). The most common comparison was between patients who were responders to medication and patients who were non-responders. Some of the larger representative studies are discussed below.
Kwan et al. compared the frequency of SNPs on the SCN1A, SCN2A, and SCN3A genes in 272 drug responsive patients and 199 drug resistant patients (Kwan, 2008). A total of 27 candidate SNPs were evaluated, selected from a large database of previously identified SNPs. There was one SNP identified on the SCN2A gene (rs2304016) that had a significant association with drug resistance (OR: 2.1, 95% CI: 1.2-3.7, p<0.007).
Jang et al. compared the frequency of variants on the SCN1A, SCN1B, and SCN2B genes in 200 patients with drug resistant epilepsy and 200 patients with drug responsive epilepsy (Jang, 2009). None of the individual variants tested showed a significant relationship with drug resistance. In further analysis of whether there were gene-gene interactions that were associated with drug resistance, the authors reported that there was a possible interaction of 2 variants, one on the SCN2A gene and the other on the SCN1B gene, that were of borderline statistical significance (p=0.055).
One meta-analysis evaluating pharmacogenomics was identified (Haerian, 2010). This study examined the association between SNPs on the ABCB1 gene and drug resistance in 3,231 drug resistant patients and 3,524 controls from 22 studies. The authors reported no significant relationship between variants of this gene and drug resistance (combined OR: 1.06, 95% CI: 0.98-1.14, p=0.12). There was also no significant association between on subgroup analysis by ethnicity.
Clinical utility
There is a lack of evidence on the clinical utility of genetic testing for the common genetic epilepsies. Association studies are not sufficient evidence to determine whether genetic testing can improve the clinical diagnosis of GGE. There are no studies that report the accuracy in terms of sensitivity, specificity, or predictive value; therefore it is not possible to determine the impact of genetic testing on diagnostic decision making.
The evidence on pharmacogenomics suggests that genetic factors may play a role in the pharmacokinetics of anti-epileptic medications. However, this evidence does not provide guidance on how genetic information might be used to tailor medication management in ways that will improve efficacy, reduce adverse effects, or increase the efficiency of medication trials.
Section Summary. The evidence on genetic testing for the common epilepsies is characterized by a large number of studies that evaluate associations of many different genetic variants with the various categories of epilepsy. The evidence on clinical validity is not consistent in showing an association of any specific genetic mutation with any specific type of epilepsy. Where associations have been reported, they are not of strong magnitude, and in most cases, have not been replicated independently or through the available meta-analyses. Because of the lack of established clinical validity, the clinical utility of genetic testing for the common epilepsies is also lacking.
Summary
Genetic testing for epilepsy covers a wide range of clinical syndromes and possible genetic defects. For rare epilepsy syndromes, which may be caused by single-gene mutations, there is only a small body of research, which is insufficient to determine the clinical validity and clinical utility of genetic testing. There may be a potential role in differentiating these syndromes from the common epilepsies and from each other, and in improving the efficiency of the diagnostic work-up. There also may be a potential role for genetic testing in identifying syndromes that are resistant to particular medications, and thereby directing treatment. However, at the present time, the evidence is limited and the specific way in which genetic testing leads to improved outcomes is ill-defined.
For the common epilepsies, which are thought to have a complex, multifactorial basis, the role of specific genetic mutations remains uncertain. Despite a large body of literature of associations between genetic variants and common epilepsies, the clinical validity of genetic testing is poorly understood. Published literature is characterized by weak and inconsistent associations, which have not been replicated independently or by meta-analyses. This literature does not permit conclusions on the clinical validity of genetic testing. Because of the lack of conclusions on clinical validity, conclusions on clinical utility are also lacking.
For epilepsy pharmacogenomics, there are numerous studies that evaluate the associations of genetic variants with medication response. This body of evidence also 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.
Regulatory Status
No U.S. Food and Drug Administration (FDA)-cleared genotyping tests were identified. The available commercial genetic tests for epilepsy are offered as laboratory-developed tests. Clinical laboratories may
2015 Update
A literature search conducted through October 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Clinical Input Received From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
In response to requests, input was received from 2 academic medical centers and 3 specialty societies, for a total of 6 reviewers while this policy was under review for 2015. The review was limited to input related to the use of genetic testing for infantile and early-childhood onset epileptic encephalopathies. There was consensus that genetic testing for early onset epileptic encephalopathies is medically necessary. Particular areas of clinical utility noted by reviewers included making specific treatment decisions in SCN1A-related epilepsies and avoiding other diagnostic tests and for reproductive planning for multiple types of early-onset epilepsies.
At the present time, evidence related to specific ways that genetic testing leads to improved outcomes is limited. Clinical input indicated strong support for the use of genetic testing in the evaluation of infantile- and early childhood- onset epilepsy syndromes associated with encephalopathy. The clinical utility of genetic testing occurs primarily when there is a positive test for a known pathogenic mutation. The presence of a pathogenic mutation may lead to targeted medication management, avoidance of other diagnostic tests, and/or informed reproductive planning.
Practice Guidelines and Position Statements
In 2010, the European Federation of Neurological Societies (EFNS) issued guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias.40 The guidelines made the following recommendations pertaining to epilepsy:
2017 Update
A literature search conducted using the MEDLINE database through October 2017 did not reveal any new information that would prompt a change in the coverage statement.
Early-Onset Epilepsy And Epileptic Encephalopathies
Moller et al (2016) reported the testing yield with an epilepsy gene panel including 46 genes in a cohort of 216 consecutive patients referred for genetic testing with epileptic encephalopathies phenotypes or familial epilepsy (Moller, 2016). The patients ranged in age from 2 weeks to 74 years; the majority (52%) had epileptic encephalopathies. The criterion for including a gene in the panel was that it had been reported more than once in patients with monogenic epilepsies as of January 2014. Overall, a presumed disease-causing variant was found in 49 (23%) patients and a variant of uncertain significance (VUS) was found in 3%. The yield was highest in patients with epileptic encephalopathies (32%) and neonatal-onset epilepsies (57%). Variants were found in 19 genes, including SCN1A, STXBP1, CDKL5, SCN2A, SCN8A, GABRA1, KCNA2, and STX1B.
Trump et al (2016) also reported the yield of a gene panel including 46 genes in 400 patients with early-onset seizure disorders and/or severe developmental delay who were referred for gene panel testing in the United Kingdom (Trump, 2016) Patients with major structural brain malformations or clinically significant copy number defects on microarray were not included. Authors reported that genes were included in the panel if they had been “established” as causes of early-onset seizures and/or severe developmental delay in patients without frequent major structural brain anomalies. Approximately half of the included genes overlapped with genes on the panel from Moller et al. Genes were added to the panel over time so that the original panel used in the first 48 patients included 29 genes, a second panel used in 94 patients included 39 genes, and the final panel used in the remaining 258 patients included 46 genes. Variants were found in 21 genes, most commonly SCN2A, CDKL5, KCNQ2, SCN8A, FOXG1, MECP2, SCNA1, STXBP1, KCNT1, PCDH19, and TCF4.
Prediction of Sudden Unexplained Death in Epilepsy
Coll et al (2016) evaluated the use of a custom resequencing panel including genes related to sudden death, epilepsy, and SUDEP in a cohort of 14 patients with focal or generalized epilepsy and a personal or family history of SUDEP, including 2 postmortem cases (Coll, 2016). In 4 cases, rare variants were detected with complete segregation in the SCN1A, FBN1, HCN1, SCN4A, and EFHC1 genes, and in 1 case a rare variant in KCNQ1 with an incomplete pattern of inheritance was detected. New potential candidate genes for SUDEP were detected: FBN1, HCN1, SCN4A, EFHC1, CACNA1A, SCN11A, and SCN10A. Bagnall et al (2016) performed an exome-based analysis of rare variants related to cardiac arrhythmia, respiratory control, and epilepsy to search for genetic risk factors in 61 SUDEP cases compared to 2936 controls (Bagnall, 2016). Mean epilepsy onset of the SUDEP cases was 10 years and mean age at death was 28 years. De novo variants, previously reported pathogenic variants, or candidate pathogenic variants were identified in 28 (46%) of 61 SUDEP cases. Four (7%) SUDEP cases had variants in common genes responsible for long QT syndrome and a further 9 (15%) cases had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen (25%) cases had variants or candidate pathogenic variants in epilepsy genes; 6 cases had a variant in DEPDC5. DEPDC5 (p=0.00015) and KCNH2 (p=0.0037) were highly associated with SUDEP. However, using a rare variant collapsing analysis, no gene reached criteria for genome-wide significance.
2018 Update
A literature search was conducted through October 2018. There was no new information identified that would prompt a change in the coverage statement.
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Esterhuizen et al analyzed data from 22 South African infants with provisional diagnoses of Dravet syndrome (DS) who underwent targeted resequencing of DS-associated genes (Esterhuizen, 2018). Disease-causing variants (SCN1A = 9, PCDH19 = 1) were identified in 10 children (45.5%), and results suggested that a clinical DS risk score of >6 and seizure onset before age 6 months were highly predictive of SCN1Aassociated DS. For 10 of the 12 variant-negative children, clinical reassessment resulted in a revised diagnosis. No limitations to the analysis were reported.
Peng et al published an analysis of 273 pediatric patients with drug-resistant epilepsy who underwent genetic testing using whole exome sequencing (WES; n=74), epilepsy-related gene panel testing (n=141), or clinical WES gene panel testing (n=58) (Peng, 2018). Ninety-three likely disease-causing mutations in 33 genes were identified in 86 individuals (31.5%). The most frequently mutated genes were SCN1A (24.4%), TSC2 (8.1%), SCN8A (5.8%), CDKL5 (5.8%), KCNMA1 (4.6%), TSC1 (4.6%), KCNQ2 (3.5%), MECP2 (3.5%), PCDH19 (3.5%), and STXBP1(3.5%). Of the 34 individuals who accepted corrective therapy according to their mutant genes, 52.9% became seizure-free and 38.2% achieved seizure reduction. No limitations to the analysis were reported.
Hesse et al published a retrospective analysis of 305 patients (age range <1–69 years old with 88% <18 years old) referred for genetic testing with a targeted epilepsy panel between 2014 and 2016 (Hesse, 2018).34 Positive yield was 15.1%, with pathogenic, likely pathogenic, predicted deleterious mutations identified in 46 individuals. Twenty-nine distinct genes were present, and known pathogenic variants were identified in 7 genes (BRAF, DPYD, GABRG2, PAX6, SCN1A, SLC2A1, and SLC46A1). No limitations to the analysis were reported.
Lindy et al published an industry sponsored analysis of 8565 consecutive individuals with epilepsy and/or neurodevelopmental disorders who underwent genetic testing with multigene panels (Lindy, 2018). Positive results were reported in 1315 patients (15.4%), and, of 22 genes with high positive yield, SCN1A (24.8%) and KCNQ2 (13.2%) accounted for the greatest number of positive findings. Results found 14 distinct genes with recurrent pathogenic or likely pathogenic (P/LP) variants (most commonly in MECP2, KCNQ2, SCN1A, SCN2A, STXBP1, and PRRT2). Greater than 30% of positive cases had parental testing performed; all variants found in CDKL5, STXBP1, SCN8A, GABRA1, and FOXG1 were de novo, however, 85.7% of variants in PRRT2 were inherited. No P/LP variants were found in ATP6AP2, CACNB4, CHRNA2, DNAJC5, EFHC1, MAGI2, and SRPX2. No limitations to the analysis were reported.
Miao et al published an analysis of 141 Chinese patients under 14 years of age with epilepsy who underwent genotype and phenotype analysis using an epilepsy-associated gene panel between 2015 and 2017 (Miao, 2018). Certain diagnoses were obtained in 39 probands (27.7%); these causative variants were related to 21 genes. The most frequently mutated gene was SCN1A (5.6%), but others included KCNQ2, KCNT1, PCDH19, STXBP1, SCN2A, TSC2, and PRRT2. The treatments for 18 patients (12.8%) were altered based on their genetic diagnosis and on genotype-phenotype analysis. No limitations to the analysis were reported.
Butler et al published a retrospective analysis of epilepsy patients screened using a 110-gene panel between 2013 and 2016; 339 unselected individuals (age range 2.5 months to 74 years, with more than 50% <5 years old) were included (Butler, 2017). Pathogenic and likely pathogenic variants were identified in 62 patients (18%), and another 21 individuals (6%) had potentially causative variants. SCN1A (n=15) and KCNQ2 (n=10) were the frequently identified potentially causative variants. However, other genes in which variants were identified in multiple individuals included CDKL5, SCN2A, SCN8A, SCN1B, STXBP1, TPP1, PCDH19, CACNA1A, GABRA1, GRIN2A, SLC2A1, and TSC2. The study was limited by the lack of clinical information available for approximately 20% of participants.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2020. No new literature was identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Another single-center retrospective study by Hoelz et al. described the effect of next-generation sequencing on clinical decision-making among children with epilepsy (Hoelz, 2020). Testing was performed a mean of 3.6 years after symptom onset. Most of the patients had epileptic encephalopathy (40%) followed by focal epilepsy (33%) and generalized seizures (18%). Sixteen patients (18%) who underwent testing had a pathogenic or likely pathogenic gene identified. Subsequently, 10 of these 16 patients (63%) had changes in their clinical management, including medications (n=7), diagnostic testing (n=8), or avoiding future surgical procedures (n=2).
Alsubaie et al. evaluated the diagnostic yield of whole exome sequencing among 420 patients at a single center in Saudi Arabia (Alsubaie, 2020). Epilepsy was the reason for testing in 15.4% (n=65) patients. Whole exome sequencing confirmed the diagnosis of epilepsy in 14 patients (positive yield of 21.5%) with variants in the following genes: ARID1B, UGDH, KCNQ2, PAH, PARS2, ARHGEF9, CNA2, CASK, SLC23A3, TBCD, QARS, CBL, GABRB2, and SUOX. Genetic test results were inconclusive in 15 of the 65 patients with epilepsy (23%). Thirty patients with negative whole exome sequencing results underwent comparative genomic hybridization, which identified 4 additional variants (positive yield of 13.3%).
Johannsen et al. published a cohort study of 200 adult patients (range 18 to 80 years) with epilepsy who were referred for genetic testing between 2013 and 2018 in Denmark (Johannsen, 2020). Most of the patients (91%) also had intellectual disability. Various gene panels (range 45 to 580 genes) were used. A genetic cause of epilepsy was identified in 23% of patients (n=46). Pathogenic variants were found in 22 genes (SCN1A, KCNT1, STXBP1, CDKL5, CHD2, PURA, ATP6V1A, DCX, GABRB3, GABRG2, GRIN2A, HNRNPU, IQSEC2, KCNA2, KIAA2022, MECP2, MEF2C, MTOR, IPF2PBL, PCDH19, SCN8A, SLC2A1, SYNGAP1, and IRF2BPL). Among the 46 patients who received a diagnosis, variants in the SCN1A gene were most prevalent (36%). A change in management occurred in 11 patients after diagnosis, which led to improved seizure control and/or cognitive function.
Minardi et al. published a single-center analysis of 71 adult patients (age range: 21 to 65 years) with developmental and epileptic encephalopathies of unknown etiology who underwent whole exome sequencing (Minardi, 2020). Almost all patients (90.1%) had prior negative genetic tests. The analysis identified 24 variants that were considered pathogenic or likely pathogenic. The variants were: DYNC1, ZBTB20, CACNA1, DYRK1A, ANKRD11, GABRG2, KCNB1, KCNH5, SCN1A, GABRB2, YWHAG, STXBP1, PRODH, LAMB1, PNKP, APC2, RARS2, KIAA2022, and SMC1A. No clinical characteristics were significantly different between patients with pathogenic variants and patients with variants of unknown clinical significance; however, sample sizes were small. In half of the diagnosed cases (n=9), clinical management changed after diagnosis, including medication selection, additional testing, and reproduction-related decisions.
In 2017, recommendations were published from a consensus panel of 14 physicians and 5 family members/caregivers of patients with Dravet syndrome (Wirrell, 2017). There was strong consensus among panel members that genetic testing should be completed in all patients with clinical suspicion for Dravet syndrome since this can lead to earlier diagnosis. Options for testing include SCN1A sequencing followed by testing for deletions and duplications if sequencing is negative, or epilepsy gene panel testing, with no consensus among panel members about which option is superior. There was strong consensus that epilepsy gene panel testing is preferred to SCN1A testing if the clinical presentation is less clear or if the patient has atypical features, and that karyotyping is not needed. The panel did not reach consensus about the utility of chromosomal microarray in patients with suspected Dravet syndrome (72.2% agreed, 22.2% disagreed, 5.6% did not know) and concluded that this test can be considered. Based on strong consensus, the panel recommended genetic testing in the following circumstances among children with normal development, seizures of unknown etiology, and no evidence of causal lesion in the brain: infants with at least 2 prolonged focal febrile seizures, or children aged 1 to 3 years with at least one prolonged febrile seizure before 18 months of age or myoclonic or atypical absence seizures that are refractory to at least one antiepileptic medication. Infants who experience a single prolonged focal or generalized convulsion do not require genetic testing (strong consensus), but this can be considered in children aged 1 to 3 years who experience multiple brief episodes of febrile seizure activity before 18 months of age or myoclonic or atypical absence seizures that do not respond to antiepileptic medication (moderate consensus). The panel had moderate consensus about the role of genetic testing (epilepsy gene panel) in teens and adults without congenital dysmorphism who have seizure activity resistant to antiepileptic medication and lack an early life history.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A number of studies have reported on the genetic testing yield in cohorts of pediatric patients with epilepsy, typically in association with other related symptoms. Below are some examples of genetic testing diagnostic yield in children with epileptic encephalopathy:
McKnight et al. conducted targeted gene panel testing (range, 89 to 189 genes) using next-generation sequencing in a cohort of 2008 adults with epilepsy (McKnight, 2021). Diagnosis occurred in 10.9% of patients, and 55.5% of these diagnoses led to changes in clinical management. Diagnostic yield was highest among individuals who first experienced seizure activity during infancy (29.6%) and among females with developmental delay or intellectual disability (19.6%). Patients with treatment-resistant epilepsy had a diagnostic yield of 13.5% and 57.4% of diagnoses led to changes in clinical management. The most common genes associated with a diagnosis were SCN1A and MECP2. The most common genes associated with changes in clinical management were SCN1A, DEPDC5, PRRT2, PCDH19, and TSC1. Nondiagnostic and negative genetic findings were common (70.1% and 19.0%, respectively).
Lin et al. conducted a prospective study of 96 children (age <2 years) with epilepsy and neurodevelopmental disability (Lin, 2021). A genetic cause of epilepsy was present in 28 children, while the remaining 68 children did not have an identified genetic cause. The incidence of drug-resistant epilepsy was 42.8% in patients with a genetic cause and 13.2% in patients without a genetic cause. Risk of drug-resistant epilepsy was significantly higher in the genetic group compared to the non-genetic group (adjusted OR, 6.50; 95% CI, 2.15 to 19.6; p=.03). Specific genes associated with drug-resistant epilepsy included TBC1D24, SCN1A, PIGA, PPP1CB, and SZT2.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
The study by Scheffer et al included 103 children and infants with developmental and epileptic encephalopathies. Singleton exome sequencing was done with the following results: 35% of patients with genetic etiology, 29% had pathogenic or likely pathogenic variants, 38% had variants of unknown significance, and 33% were negative on exome analysis. KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes (Scheffer, 2023). Thirteen of 36 patients with a known genetic cause for their condition had management implications. These included treatment for the underlying biochemical abnormality (1 patient with SLC2A1), choice of antiseizure medication (4 patients with KCNQ2, 3 with SCN1A, 2 with SCN8A, and 1 with SCN2A), choice of other medication (1 patient with ATP1A3), and screening for disease-related complications (1 patient with COL4A1).
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2022, the National Society of Genetic Counselors published a practice guideline on genetic testing and counseling for unexplained epilepsies (Smith, 2023).The Society made the following relevant recommendations:
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