1. NGS panel - Genetic testing for Dravet syndrome

Dravet syndrome

June 30, 2017

Clinical features

Dravet syndrome (DS) is a group of early infantile epileptic encephalopathies (EIEE) characterized by early onset, progressive encephalopathy, and severe seizures. DS is characterized by the onset of clonic or tonic-clonic seizures within the first year of life in infants with previously normal development. The seizures include myoclonic jerks, absence and focal seizures and they commonly result in status epilepticus. Unfortunately, most Dravet syndrome-associated seizures are resistant to common anti-epileptic drugs.

Dravet syndrome is clinically characterized by the following specific features:

  • Seizures beginning in the first year, commonly associated with fever (febrile convulsions)
  • Episodes of status epilepticus (prolonged seizures)
  • Seizures do not respond to standard anticonvulsant therapy
  • Myoclonic seizures occur around the age 18 months
  • Seizures could be triggered by vaccinations, hot baths, or warm temperatures.

The phenotypes included in Dravet syndrome are characterized by persistent seizure disorders and resistance to anti-epileptic therapy, and they include the following 1:

  • Febrile seizures are characterized by the following:

    • Onset from six months of age
    • Fever higher than 38°C
    • No other identifiable cause
    • Duration greater than 15 minutes
    • Occurrence of more than one seizure within 24 hours
    • Presence of any partial features during the seizure.

  • Febrile seizures plus (FS+) are characterized by the following:

    • Onset before age one year
    • Persistence beyond age six years
    • Unusual severity (including status epilepticus)
    • Occurrence of unprovoked seizures of any kind.

Dravet syndrome seizures could be of any type: generalized tonic-clonic, myoclonic, and hemiconvulsive. Early onset seizures are associated with high fever, while later in the course of the disease seizures are mostly myoclonic and they often coincide with the appearance of cognitive dysfunction, ataxia, and psychomotor regression. Status epilepticus is common in Dravet syndrome patients. The initial EEGs are often normal, but over time epileptiform activity appears. Patterns can include generalized spike and wave discharges, multiple spike and wave discharges, and multifocal spikes 1.

Mutations in several genes are related to Dravet syndrome: the sodium channel related genes SCN1A, SCN2A, and SCN9A; and the GABA receptor associated gene GABRG2 (Table). Mutations in the SCN1A gene are the major cause of Dravet syndrome, and these are detected in more than 90% of affected cases 1. According to genetic research data about 73-92% of all Dravet syndrome-associated genetic variants can be detected using sequencing of the SCN1A gene 2, 3 and an additional 8-27% 4, 5 can be identified using deletion/duplication analysis.


Overview of genes included in Dravet syndrome panel offered by CENTOGENE

Gene
(OMIM)
chr. locus Frequency of mutations Associated/allelic disorders
SCN1A
(182389)
2q24.3 73%-92% for sequencing-detected mutations 1, 2, 3
8%-27% for del/dupl 3, 4, 5
70-80% of all DS 3
Epilepsy, generalized, with febrile seizures plus, type 2 (604403); Epileptic encephalopathy, early infantile, 6 (607208); Febrile seizures, familial, 3A (604403); Migraine, familial hemiplegic, 3 (609634)
GABRG2
(137164)
5q34 1/140 patients 6 Epilepsy, generalized, with febrile seizures plus, type 3; Febrile seizures, familial, 8 (611277); Epilepsy, childhood absence, susceptibility to, 2 (607681)
SCN2A
(182390)
2q24.3 1:9 compared to SCN1A mutations 7 Epileptic encephalopathy, early infantile, 11 (613721); Seizures, benign familial infantile, 3 (607745)
SCN9A
(603415)
2q24.3 Rare 3 Epilepsy, generalized, with febrile seizures plus, type 7; Febrile seizures, familial, 3B (613863); Erythermalgia, primary (133020); HSAN2D, autosomal recessive; Insensitivity to pain, congenital (243000); Paroxysmal extreme pain disorder (167400); Small fiber neuropathy (133020); {Dravet syndrome, modifier of} (607208)

Therapy for Dravet syndrome includes anticonvulsants that have been shown to be very useful for chronic seizure management. They include benzodiazepines, topirimate, and valproic acid. Several other drugs and treatments can also be used for the treatment and prevention of seizures. Recently a new drug, Perampanelin1 (non-competitive antagonist of AMPA receptors), has shown good effects in a pediatric population with refractory epilepsies. In order to determine the best possible therapy for the affected individual, physicians must know the precise diagnosis, and the most precise diagnoses are obtained using genetic testing.

CENTOGENE offers a Dravet syndrome NGS panel that includes the following genes: SCN1A, GABRG2, SCN2A, SCN9A. We also offer several NGS panels associated with Dravet syndrome-related epilepsies such as: the Epileptic encephalopathy panel. Each gene in these panels can also be ordered individually as a single gene test.


Differential diagnosis

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

  • Pyridoxine-dependent seizures and B6-related epilepsies
  • Folinic acid-responsive seizures
  • Inborn errors of metabolism, including mitochondrial dysfunction
  • Biotinidase deficiency
  • Glucose transporter type 1 deficiency
  • Hepatic porphyrias.

Testing strategy

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

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

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

Step 2: If no mutation is identified after analysis of the Dravet syndrome panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.


Referral reasons

The following individuals are candidates for Dravet syndrome panel testing:

  • Individuals (infants) with a family history of Dravet syndrome and presentation of the most common symptoms, including seizures commonly associated with fever, or later in life associated with myoclonus
  • Individuals (infants) without a positive family history, but with symptoms resembling Dravet syndrome
  • Individuals (infants) with a negative but suspected family history of Dravet syndrome, in order to perform proper genetic counseling.

Test utility

Sequencing, deletion/duplication of the panel genes should be performed in all individuals suspected of having Dravet syndrome and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype 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 Dravet syndrome and related disorders, identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.


More information on CENTOGENE´s Dravet syndrome panel can be found in our genetic test catalogue.