Comprehensive Epilepsy and Seizure Panel

This panel sequences genes associated with idiopathic and syndromic epilepsy in which seizures are a major clinical feature with consistent expressivity (>50% of cases) and/or where seizure onset is an early indication of disease. This panel also includes genes which have only been associated with epilepsy in a small number of cases, indicating that they are ultra-rare causes of disease or that the gene/disease association is not yet definitively established. 

Seizures are caused by abnormal activity in the brain resulting in changes in behavior, motor movements, feelings, or consciousness. Seizures may be triggered by an environmental insult such as head trauma, stroke, or febrile episode, or may be the result of a genetic disease. Seizures are classified based on their site of onset: focal, generalized, and unknown (Fisher et al. 2017. PubMed ID: 28276064).   

Epilepsy is defined as recurrent unprovoked seizures, and it is divided into subtypes based on the seizures involved: focal, generalized, combined generalized and focal, and unknown (Scheffer et al. 2017. PubMed ID: 28276062). Epilepsy occurs among individuals that are otherwise typically-functioning and as a comorbidity in complex neurological diseases. Epilepsy is heterogeneous—there is great variation in the age of onset, type of seizures, developmental outcome, EEG and image findings, response to medication, and associated comorbidities. An epilepsy syndrome refers to a cluster of features incorporating seizure types, together with EEG, and imaging findings (Scheffer et al. 2017. PubMed ID: 28276062).

The etiology of epilepsy is also classified by Scheffer et al. and includes structural, genetic, infectious, metabolic and immune, as well as unknown causes. Importantly, structural and metabolic etiologies may be caused by genetic variants. All etiologies with evidence for genetic causes are included in this panel.

One in 26 people will develop epilepsy in their lifetime (Epilepsy Foundation), and the estimated prevalence is 7 per 1,000 (Hirtz et al. 2007. PubMed ID: 17261678). Identifying the molecular basis of a patient’s epilepsy may provide valuable information to inform prognosis, recurrence risk, and treatment.  In particular, targeted therapy of genetic epilepsies is an area of rapid change and great promise (see table below). Some patients may benefit from drugs that target a specific pathway, gene product, or functional change to a specific protein (Musto et al. 2020. PubMed ID: 31889633; Reif et al. 2017. PubMed ID: 27781560).

Epilepsy is genetically heterogeneous. Over 300 genes are associated with disorders that include epilepsy as a major feature, and over 600 genes are associated with an increased risk for developing epilepsy.

Mild forms of epilepsy may be inherited as a familial trait; however, many epilepsy cases are sporadic, occurring in families with no prior history of seizure (Allen et al. 2013. PubMed ID: 23934111). Sporadic epilepsy may be inherited by X-linked or autosomal recessive transmission, but are more commonly caused by dominant, de novo variants in neuronally-expressed genes. De novo pathogenic missense variants are especially common among genetic epilepsies. For example, missense variants in ion channels (channelopathies) may modify gating kinetics, ion permeability, voltage sensitivity or ligand-binding imparting both gain- or loss-of-function effects (Kullmann. 2002. PubMed ID: 12023309). In addition, a large number of epilepsy-related genes are sensitive to null mutation, and chain-terminating variants that are well-documented to be pathogenic (Human Gene Mutation Database). Finally, rare cases of epilepsy have been attributed to copy number changes involving epilepsy-related genes (ARHGEF9, ARX, CDKL5, CHD2, DNM1, FOXG1, GABRA1, GABRB3, GABRG2, GRIN2A, MBD5, MECP2, MEF2C, PCDH19, PLCB1, PRRT2, SCN1A, SCN2A, SCN8A, SLC2A1, SLC9A6, SPTAN1, STX1B, STXBP1, TSC1 and TSC2). This test includes CNV analysis. 

This panel contains more than 300 genes associated with syndromic and non-syndromic epilepsy of diverse forms. Examples of well-characterized epilepsy syndromes are listed below and include developmental epileptic encephalopathies, epilepsy with intellectual disability, metabolic disorders, brain malformation disorders, mitochondrial disorders, brain tumors, etc. (Wilmshurst et al. 2015. PubMed ID: 26122601; Baldassari et al. 2016. PubMed ID: 27208208; Ricos et al. 2016. PubMed ID: 26505888; Møller et al. 2016. PubMed ID: 27781031; de Kovel et al. 2016. PubMed ID: 27652284; Hildebrand et al. 2016. PubMed ID: 27029629; von Spiczak et al. 2017. PubMed ID: 28667181; Hamdan et al. 2017. PubMed ID: 29100083).

Tuberous Sclerosis: TSC1 and TSC2

Infantile Spasm: ADSL, ARX, CDKL5, PNPO, MEF2C, SCN1A, SCN2A, STXBP1, TSC1, and TSC2

Focal epilepsy: CHRNA4, CHRNB2, CHRNA2, CNTNAP2, DEPDC5, KCNT1, GRIN2A, GRIN2B, LGI1, NPRL2, NPRL3, PCDH19, RELN, SCN1A, and TBC1D24

Dravet Syndrome: SCN1A, SCN1B, GABRG2, SCN2A, SCN9A, PCDH19, GABRA1, STXBP1 and CHD2

Generalized Epilepsy with Febrile Seizures Plus (GEFS+): SCN1A, SCN1B, SCN2A, SCN9A, GABRG2, and STX1B

Autosomal Dominant Nocturnal Frontal Lobe Epilepsy: CHRNA4, CHRNB2, CHRNA2, DEPDC5, and KCNT1

Benign Familial Neonatal or Infantile Seizures: KCNQ2, KCNQ3, and PRRT2

Early-onset Absence Epilepsy: SLC2A1

X-linked Infantile Spasms: ARX

Epilepsy and Mental Retardation Limited to Females: PCDH19

Ohtahara Syndrome: ARX, STXBP1, SCN2A, KCNQ2, KCNT1, SLC25A22, CDKL5, PNKP, and SPTAN1

Rett Syndrome: MECP2, CDKL5, and FOXG1

Angelman syndrome: UBE3A

Mowat-Wilson syndrome: ZEB2

Neuronal Ceroid Lipofuscinosis: TPP1, PPT1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSF, and KCTD7

Lafora Disease : EPM2A and NHLRC1

Selected Metabolic Disorders: FOLR1, GAMT, ALDH7A1, PNPO, and SLC19A3

Mitochondrial Disease: POLG, FARS2, and SLC25A22

Cortical dysplasia, complex, with other brain malformations: TUBA8, TUBB2A, TUBB2B, TUBB3, and TUBG1

Importantly, this panel includes over 26 genes that have been associated with precision therapy in gene-drug studies. 

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants. 

This panel includes genes causative for autosomal dominant, autosomal recessive and X-linked epilepsy and seizures. Extrapolating from previously published studies of next generation sequencing in large cohorts, a positive test result is expected in the proportions listed: 37% for early infantile epileptic encephalopathy (Della Mina et al. 2015. PubMed ID:24848745; Wang et al. 2014. PubMed ID:24818677; Ream and Mikati. 2014.PubMed ID:25108116), 25-35% for autosomal dominant nocturnal frontal lobe epilepsy, 12-37% for autosomal dominant focal epilepsy (Dibbens et al. 2013. PubMed ID:23542697; Picard et al. 2014. PubMed ID:24814846), 90% for Dravet syndrome (Carvill et al. 2014. PubMed ID:24623842).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.2% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).