1. Hereditary (Partial) Epilepsy Panel

Hereditary (Partial) Epilepsy Panel

November 28, 2018

Disease summary:

The hereditary (partial) epilepsy panel is a comprehensive gene panel of the key genes linked to heritable partial (focal) epilepsy. Partial epilepsy (also referred to as focal epilepsy) specifically refers to epilepsy that causes complex or simple seizures localized to one area of the brain only.1,2,3 Focal seizures most commonly arise from the temporal lobe.

Partial epilepsy is a factor of many hereditary epilepsy syndromes in both children and adults, examples include generalized idiopathic epilepsy, childhood absence epilepsy, juvenile absence epilepsy and juvenile myoclonic epilepsy. Focal epilepsy also occurs within early infantile epileptic encephalopathy, a group of severe epileptic diseases with an early onset where persistent seizures contribute to progressive cognitive or neurological decline from an early age, often with a risk of early morbidity.

  • Autosomal dominant

  • 1-8 / 100,000 Childhood absence epilepsy4,5
  • 6-10/100,000 Temporal lobe epilepsy6
  • 2-3/10,000 (West syndrome, a form of early infantile epileptic encephalopathy)7
  • 1/40,000 Severe myoclonic epilepsy7

Major clinical symptoms7,8

  • Seizures often preceded and/or involving one or more of the following: 
    • Premonitory sensation, butterflies, tingling, nausea 
    • Stiffening, jerks, twitch, sudden shakes, sharp movements
    • Automatisms such as eyelid flutters, lip smacking, chewing motions, Finger rubbing, small movements of both hands
    • Low consciousness/awareness
    • Visual and auditory auras
    • Other sensory disturbances
    • Aphasia
  • Absence seizures
    • Seizures activation by hyperventilation or photic stimulation
    • Sudden stop in motion without falling 
    • Absent-minded stare
  • Sleep-related seizures
  • Febrile seizures
  • Photosensitivity
  • Cognitive, behavioral, and neurological deficits or decline (early infantile epileptic encephalopathy).

  • Clinical classification of epilepsy and focal origin of seizure type considering the results of investigations such as electroencephalography (EEG) and neuroimaging studies together with other studies exploring the underlying etiology of the epilepsy.1,3
  • The clinical definition of epilepsy was revised in 2017 to include any of the following conditions: 1) at least two unprovoked seizures occurring >24 hours apart; 2) one unprovoked seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; 3) diagnosis of an epilepsy syndrome.2
  • Monotherapy with antiepileptic medication dependent on the type and classification of epilepsy. Examples include benzodiazepines, ethosuximide, valproate, lamotrigine, levetiracetam, zonisamide and topiramate.1,2
  • Rufinamide is effective in decreasing the seizure frequency in the epileptic encephalopathy with either tonic or atonic seizures. It can be also effective as adjunctive therapy in children and adolescents with drug-resistant partial seizures. See here for more details.
  • Lack of response with one or more treatment can occur; surgery referral is an option when epilepsy is refractory to antiepileptic medication.
  • Other, generalised forms of epilepsy
  • Non-epileptic seizures
  • Partial epilepsy is in a factor in many different epilepsy syndromes, groups and sub-types; differential diagnosis will vary depending on the major presenting symptoms. 

Childhood absence epilepsy

  • Epilepsy with myoclonic absences 
  • Jeavons syndrome
  • Juvenile absence epilepsy 
  • Perioral myoclonia with absences 
  • Juvenile myoclonic epilepsy 
  • Encephalopathy due to GLUT1 deficiency 
  • Absence seizures associated with chromosomal anomalies (ring chromosome 20, 15q13.3 microdeletion syndrome). 

Early infantile epileptic encephalopathy 

  • Complex partial seizures
  • Generalized tonic-clonic seizures
  • Autism
  • Acquired epileptic aphasia
  • Absence seizures
  • Temporal lobe epilepsy

To confirm/establish the diagnosis, CENTOGENE offers the following tests:

  • Epilepsy (partial) hereditary NGS Panel includes sequencing of the genes CACNA1H, CACNB4, CHRNA2, CHRNA4, CHRNB2, CLCN2, CPA6, DEPDC5, EFHC1, GABRA1, GABRB3, GABRD, GABRG2, JRK, KCNMA1, KCNQ2, KCNQ3, KCNT1, LGI1, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SLC2A1, SRPX2 
  • Epilepsy (partial) hereditary NGS Panel + CNV which includes sequencing and additionally detection of large deletions and duplications from the NGS data for the above genes

The following individuals are candidates for partial epilepsy gene testing:

  • Individuals with a family history of partial epilepsy and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling partial epilepsy.
  • Individuals with a negative but suspected family history, in order to perform proper genetic counselling (prenatal analyses are recommended in families with affected individuals). 

Sequencing, deletion/duplication of partial epilepsy-related genes should be performed in all individuals suspected of having this condition. In parallel, other genes reported to be related with other forms of epilepsy could also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes. 

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counselling and may direct medical management. Genetic counselling can provide a patient and/or family with the natural history of focal epilepsy, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources. 

Table 1. Overview of the genes in CENTOGENE's Epilepsy (partial) hereditary panel:

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
CACNA1H 607904 childhood absence epilepsy type 6 AD 41
CACNB4 601949 Epilepsy, Idiopathic Generalized, Susceptibility To, 9; Episodic ataxia, type 5 AD 10
CHRNA2 118502 Epilepsy, Nocturnal Frontal Lobe, 4 AD 13
CHRNA4 118504 Tobacco Addiction, Susceptibility To; Epilepsy, nocturnal frontal lobe, 1 AD 14
CHRNB2 118507 Epilepsy, nocturnal frontal lobe, 3 4
CLCN2 600570 Epilepsy, Idiopathic Generalized, Susceptibility To, 11; Leukoencephalopathy with ataxia AD, AR 14
CPA6 609562 Epilepsy, familial temporal lobe, 5; Febrile seizures, familial, 11 AD, AR 7
DEPDC5 614191 Epilepsy, familial focal, with variable foci AD 21
EFHC1 608815 Epilepsy, myoclonic juvenile AD 8
GABRA1 137160 Epilepsy, Juvenile Myoclonic, Susceptibility To, 5; early infantile epileptic encephalopathy, 19 AD 9
GABRB3 137192 Epilepsy, Childhood Absence, Susceptibility To, 5 AD 14
GABRD 137163 Epilepsy, idiopathic generalized, 10 AD 12
GABRG2 137164 Epilepsy, Childhood Absence, Susceptibility To, 2 AD 15
JRK 603210 22
KCNMA1 600150 Generalized epilepsy and paroxysmal dyskinesia AD, AR 26
KCNQ2 602235 benign familial neonatal epilepsy; early-onset epileptic encephalopathy 7 AD 62
KCNQ3 602232 Seizures, Benign Familial Neonatal, 2 AD 8
KCNT1 608167 early infantile epileptic encephalopathy 14; nocturnal frontal lobe epilepsy 5 AD 75
LGI1 604619 Epilepsy, familial temporal lobe, 1 AD 8
SCN1A 182389 generalized epilepsy with febrile seizures plus 2; early infantile epileptic encephalopathy 6; familial hemiplegic migraine-3 AD 132
SCN1B 600235 generalized epilepsy with febrile seizures plus-1; Brugada syndrome 5; Epileptic encephalopathy, early infantile, 52 AD, AR 8
SCN2A 182390 benign familial neonatal-infantile seizures type 3; early infantile epileptic encephalopathy 11 AD 61
SCN8A 600702 Cognitive impairment with or without cerebellar ataxia; early infantile epileptic encephalopathy 13; Seizures, benign familial infantile, 5 AD 41
SCN9A 603415 primary erythermalgia; Paroxysmal extreme pain disorder; INDIFFERENCE TO PAIN, CONGENITAL; early infantile epileptic encephalopathy 6; generalized epilepsy with febrile seizures plus 7 AD, AR 77
SLC2A1 138140 Dystonia-9; GLUT1 deficiency syndrome; dystonia 18; Epilepsy, idiopathic generalized, suscpetibility to, 12 AD, AR 38
SRPX2 300642 Rolandic Epilepsy, Mental Retardation, And Speech Dyspraxia, X-Linked 5

Abbreviations: AD autosomal dominant; AR autosomal recessive