1. NGS panel - Genetic testing for childhood absence epilepsy

Childhood absence epilepsy

July 28, 2017

Clinical features

Childhood absence epilepsy (CAE) is a form of hereditary pediatric epilepsy, characterized by very frequent absence seizures. This formusually soccurs in children between the ages of 4 and 10 years and in most cases has a good prognosis. CAE accounts for 10-17% 1, 4 of all cases of epilepsy diagnosed in school-aged children 1 and its incidence has been estimated at 1-8 per 100,000 2, 3. Females are usually more affected than males, representing 60-76% of patients 4.

Childhood absence epilepsy is characterized by frequent absence seizures with abrupt onset and offset. Photosensitivity is reported in 18% of CAE patients. In rare cases CAE is also associated with increased rates of adverse behavioral, psychiatric, language, and subtle cognitive changes, including attention deficit hyperactivity disorder (ADHD), anxiety, and depression.

The main clinical characteristics of absence childhood epilepsy include the following 5:

  • Onset in children of school age (peak manifestation 6–7 years)
  • Very frequent (multiple per day) absences
  • EEG with bilateral, synchronous, symmetrical spike-waves, usually at 3 Hz
  • Development of generalized tonic-clonic seizures occurring during adolescence.

Absence seizures are brief, most commonly lasting 5-10 seconds with an abrupt start and end. They occur frequently, 10-100 times a day 5. Seizures occur spontaneously but may be precipitated by multiple factors, including emotional, intellectual, or metabolic. The main feature of absence seizures is loss of responsiveness with cessation of ongoing activity.

Depending on the associated symptoms, following types of absence seizures can be identified 5:

  • Simple absence, manifesting only as impaired consciousness (10%)
  • Absence with mild clonic components, usually involving the eyelids (50%)
  • Absence with atonic components, resulting in gradual lowering of the head or arms (20%)
  • Absence with tonic components (rotating the eyes upwards)
  • Absence with automatisms that are either perseverative (i.e., the patient persists in what he is doing) or de novo, such as lip smacking or swallowing (60%)
  • Absence with autonomic components (e.g., pupillary dilatation, flushing, tachycardia).

Childhood absence epilepsy is genetically determined, and mutations in several genes have been reported so far (Table):

  • The CACNA1H gene encodes voltage-entdependent calcium channel expressed in neurons. Mutations in CACNA1H have been reported in childhood absence epilepsy (16/49), idiopathic generalized epilepsy (10/49), hyperaldosteronism (2/49), and other conditions, mostly characterized with seizures (HGMD® Professional 2017.1). Missense mutations in CACNA1H have recently been associated with amyotrophic lateral sclerosis 6.
  • The GABRA1 gene encodes GABA receptor protein, thus participating in neuronal membrane activity. Therehave been 35 mutations reported in this gene so far (HGMD® Professional 2017.1), reported as disease-causing for epileptic encephalopathy (10/35), Dravet syndrome (3/35), early infantile epileptic encephalopathy (2/35), childhood absence epilepsy (1/35), and other epilepsy-related phenotypes. Small deletion c.975delC was reported in a family affected with childhood absence epilepsy 7.
  • GABRB3 also encodes the GABA receptor protein, and 50 different variants have been reported in this gene so far, in association with autism spectrum disorders (18/50), epileptic encephalopathy (15/50), childhood absence epilepsy (1/50) and other epilepsy-related conditions (HGMD® Professional 2017.1).
  • The GABRG2 gene encodes additional GABA receptor protein, and so far the mutations in this gene have been associated primarily with generalized epilepsy with febrile seizures (7/26). Mutations in GABRG2 have also been associated with Rolandic epilepsy (2/26), childhood absence epilepsy (2/26), generalized epilepsy (2/26), and others.
  • Missense mutation c.1367C>T, p.T456MJRK reported in the JRK gene was associated with childhood absence epilepsy that evolved to juvenile myoclonic epilepsy 8.
  • The SLC2A1 gene encodes glucose transporter 1 expressed in brain, placenta, and erythrocytes. Mutations in this gene have been associated with GLUT 1 deficiency syndrome (203/253), absence epilepsy (10/253), idiopathic generalized epilepsy (9/253), intellectual disability (4/2539 and other conditions. Heterozygous SLC2A1 pathogenic variants (p.Arg212Cys and p.Arg126Cys) have been reported as disease-causing in patients affected with dystonia 9 9.

An overview of genes associated with childhood absence epilepsy

Gene (OMIM) Locus Associated syndromes
CACNA1H
607904
16p13.3 Childhood absence epilepsy 6 (611942); Hyperaldosteronism, familial, type IV (617027)
GABRA1
137160
5q34 Epileptic encephalopathy early infantile 19 (615744);
Childhood absence epilepsy 4 (611136)
GABRB3
137192
15q12 Childhood absence epilepsy 5 (612269);
Epileptic encephalopathy early infantile 43 (617113)
GABRG2
137164
5q34 Childhood absence epilepsy 2 (607681);
Epilepsy, generalized, with febrile seizures plus, type 3 (611277);
Febrile seizures, familial, 8 (611277)
JRK
603210
8q24 Idiopathic generalized epilepsy (600669)
SLC2A1
138140
1p34.2 Idiopathic generalized epilepsy (614847);
GLUT1 deficiency syndrome 1, infantile onset, severe (606777);
GLUT1 deficiency syndrome 2, childhood onset (612126);
Stomatin-deficient cryohydrocytosis with neurologic defects (608885);
Dystonia 9 (601042)

Treatment of CAE involves the use of antiepileptic drugs such as ethosuximide, valproate, and lamotrigine. However, lack of response is common. An alternative choice for patients with CAE and photosensitivity could be the drugs levetiracetam or topiramate.

CENTOGENEsoffers full gene sequencing and deletion/duplication analysis for the Childhood absence epilepsy panel (genes: CACNA1H, GABRA1, GABRB3, GABRG2, JRK, SLC2A1). Wealso offer single gene tests for each gene included in the panel.


Differential diagnosis

The differential diagnosis of childhood absence epilepsy-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • 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).

Testing strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for childhood absence epilepsy using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Childhood absence epilepsy panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Childhood absence epilepsy panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.


Referral reasons

The following individuals are candidates for childhood absence epilepsy gene testing:

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

Test utility

Sequencing, deletion/duplication of childhood absence epilepsy related genes should be performed in all individuals suspected of having this particular phenotype. In parallel, other genes reported to be related with childhood absence epilepsy should 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 counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of childhood absence 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.


More information on CENTOGENE´s Childhood absence epilepsy panel can be found in our genetic test catalogue.