The diagnosis of Dravet syndrome is based on the child’s history of seizures and other symptoms that emerge as the seizures progress. Typically, when Dravet syndrome is diagnosed there is no history of significant brain injury, such as birth asphyxia or meningitis, to explain the epilepsy (Dravet and Guerrini, 2011).

Standard investigations such as Magnetic Resonance Imaging (MRI) and electroencephalography (EEG) appear normal at first.

Molecular Diagnosis – Prof. Le Guern (FRANCE)
Genetics of Dravet syndrome – Dr. Christelle Depienne (FRANCE)

In 2001 it became clear that Dravet syndrome is caused by a defect in the electrical function of brain cells (Claes et al. 2001).


In order to better understand the causes of Dravet syndrome, here are some basic information on
chromosomesThe microscopically visible carriers of the genetic material. They are composed of DNA (deoxyribonucleic acid), proteins and that looks like little rods when watched under a microscope.
genes The basic biological units of heredity. Segments of deoxyribonucleic acid (DNA) needed to contribute to a function.
DNA (DeoxyriboNucleic Acid) DeoxyriboNucleic Acid is a long molecule that encodes genetic information.
The human body is made up of a huge number of
[1]cellsThe cell is the basic structural, functional and biological unit of all known living organisms. Cells are the smallest unit of life that is classified as a living thing, and are often called the "building blocks of life".
. Each cell has a core structure (
nucleusThe part of a cell that controls its growth, DNA is stored in the nucleus of a cell.
) that contains
[2]chromosomesThe microscopically visible carriers of the genetic material. They are composed of DNA (deoxyribonucleic acid), proteins and that looks like little rods when watched under a microscope.

Chromosomes, genes and DNA

Human karyotype

In every cell, humans have 22 pairs of chromosomes and 1 pair of sexual chromosomes (males are XY and females are XX), as shown below on the karyotype (image of chromosomes under the microscope).

Each chromosome is made up of tightly coiled strands of [3]DNA (DeoxyriboNucleic Acid). [4]Genes are segments of [3]DNA that determine specific traits, such as eye or hair colour. Humans have more than 20,000 genes.

A gene mutation is an alteration in DNA, that may be inherited or acquired over a person’s lifetime, as cells age or are exposed to certain chemicals. These DNA changes can result in genetic disorders.

Genetic Causes


In 2001, a Belgian team showed that Dravet syndrome is in most cases due to a genetic mutation in the SCN1A gene (de Claes et al. 2001). About 85% of Dravet syndrome cases are associated with a mutation in the SCN1A gene (Rosander et al. 2015).

The SCN1A gene, located on chromosome 2, encodes the alpha 1 subunit of the voltage-dependant sodium channel, also called Nav1.1. channel. This channel, permeable to sodium ions, is directly involved in the electrical signals generated by brain cells.


Human karyotype and voltage dependant sodium channel schema

A mutation in this gene can modify the proper functioning of the sodium ion channel and/or reduce the number of these channels in brain cells.

Mutations found in patients with Dravet syndrome are of all types (truncating, missense). To date, more than 1,448 different mutations have been identified throughout this gene (Jiang et al. 2018). This leads to different forms of SCN1A-related disorders from a mild form (familial hemiplegic migraine) to a very severe form (Dravet syndrome) as shown on the figure below.

The spectrum of SCN1A disorders

In patients with Dravet syndrome, the identification of an SCN1A mutation along with the genetic testing of both parents is necessary to determine whether the mutation is inherited or not. To prevent passing on the mutation and the risk of having another child with Dravet syndrome, a prenatal diagnosis may be proposed during
Genetic counselling An educational counselling process for individuals and families who have a genetic disease or may be at risk for a disease to facilitate informed decision-making.
To prevent passing on the mutation and the risk of having another child with Dravet syndrome, a prenatal diagnosis may be proposed during the genetic counselling part.

a. Non-inherited (de novo) mutation in Dravet Syndrome

95% of SCN1A mutations (Harkin et al. 2007) appear to be “de novo (or new to the patient), meaning the mutation is not inherited from parents, but that the mutation occurs in the germ cell (egg or spermatozoid) of one of the parents. It occurs independently of the rank of birth in the family and affects children of both sexes.


Genetic testing of the parents is recommended to confirm that the mutation is de novo. The identification of the mutation is performed through molecular diagnosis as shown below:

When the mutation is de novo, the chance to have another child with Dravet syndrome is minimum. However, genetic counselling is recommended, with the aim of helping families understand the risk of recurrence of Dravet syndrome in their other children.

Genetic testing steps

B. Inherited mutations in Dravet Syndrome


In some rare cases, children with Dravet syndrome have inherited the SCN1A mutation. One parent may carry the same mutation, without being affected, or while presenting milder SCN1A-related disorders (Depienne et al. 2006).

Parental mosaicism means that one of the parents has both cells with and without the mutation in the body. This phenomenon happens when the mutation arises during the parent’s own foetal development. These parents are said to be “mosaic”.

As shown by the illustration below, the possibility of detecting the mutation from a blood sample of the mosaic parent depends on the time at which the mutation occurred during the parent’s development (Depienne et al. 2006).

If the mutation appeared at a late stage of cell multiplication, the mutation will be present in a low number of the parent’s body cells, and therefore will not be detectable in blood cells (Depienne et al. 2006).

On the other hand, if the mutation appeared shortly after fertilization, all cells descending from the mutated cell will carry the mutation. Most of the parent’s cells will carry the mutation, increasing the chance of being detectable in blood cells. Parents with a high-level of mosaicism may also present a SCN1A-related disorder (Depienne et al. 2006).



Dravet Syndrome and Generalised Epilepsy with Febrile Seizures Plus (GEFS+) Families (missense mutations)

Different types of mutations exist within the SCN1A gene. Some are also found in other forms of epilepsy. These more benign forms are known as Genetic (formerly known as Generalised) Epilepsy with Febrile Seizures Plus (GEFS+) (Escoyg et al. 2010).

Children with Dravet syndrome who have a SCN1A mutation may come from families with a GEFS+ spectrum. In such cases, one of the parents carries the same SCN1A missense mutation as their child. This parent is usually less severely affected, and sometimes is not affected at all (Escoyg et al. 2010).

The mutation is transmitted to the children in autosomal dominant inheritance mode, meaning that all children have a 50% risk of receiving the mutation from the mutated parent (Escoyg et al. 2010).

Examples of GEFS+ families with inherited SCN1A mutation

The same mutation can lead to severe epilepsy in a child while other family members and parents may be unaffected or only mildly affected compared to the child with Dravet syndrome. The reason for this clinical variability remains unknown, but genetic or non-genetic factors other than the mutation itself may contribute to this difference (Escoyg et al. 2010).

A prenatal diagnosis can be carried out in GEFS+ families. However, since missense mutations found in GEFS+ families are usually associated with benign phenotypes, the request for prenatal diagnosis should undergo ethical approval (Escoyg et al. 2010).

2. Other Genes

About 15% of patients diagnosed with Dravet syndrome do not carry a SCN1A mutation. Research is ongoing worldwide in order to identify other genes and/or factors which may cause this type of epilepsy. Several other genes have been reported in patients with Dravet syndrome who test negative for SCN1A mutations (Steel ‎2017). However, the clinical presentation in most of these cases is atypical for Dravet syndrome (Wirrell et al. 2017).


Genes involved in Dravet Syndrome (adapted from Steel et al. 2017)


Genetic counselling

Genetic counselling is the process by which patients and relatives are advised of the nature and consequences of the disorder, the probability of developing or transmitting it, and the options available for family planning.

This counselling can be separated into two parts:

  • First, diagnosis:
  • Search for the causative mutation, its identification and genetic testing of the parents, therefore providing an estimation of the risk of recurrence.
  • Supportive aspects: psychological support.
  • Secondly, according to the type of mutation identified, a prenatal diagnosis and presymptomatic testing may be performed:
  • Prenatal diagnosis: the process by which a mutation identified in an affected individual of a family is tested in an at-risk foetus during pregnancy.

In some countries, this may require the advice of an ethical committee.

Prenatal testing is done on foetal cells sampled from chorionic villus (i.e. the foetus’s developing placenta) at ~12 weeks or from cells present in the amniotic fluid (the fluid surrounding the baby) after 15-16 weeks of pregnancy.

Genetic counselling


  • Presymptomatic testing: this is genetic analysis of an asymptomatic or unaffected individual who is at risk of a specific genetic disorder.

Not all genetic diseases manifest themselves immediately at birth or early in childhood. Although the gene mutation is present at birth, some diseases do not appear until adulthood. If a specific mutated gene responsible for a late-onset disease has been identified, a person from an affected family can be tested before symptoms appear.