Which genes cause Dravet Syndrome?

Over 90% of people with a diagnosis of Dravet Syndrome have a change (mutation or deletion) in the gene known as SCN1A. This is short for ‘sodium channel alpha 1 subunit’.

The SCN1A gene contains instructions, or genetic code, to create an important protein in the brain, known as a ‘sodium ion channel’. The movement of sodium ions in and out of nerve cells helps to control electrical messages in the brain. A change, or mutation, in the code of the SCN1A gene can lead to the faulty functioning of this protein.

Each person has two copies of the SCN1A gene – one from each parent. Many of the gene mutations found in Dravet Syndrome prevent one of these two copies from working as it should. That leaves only one functional copy of the SCN1A gene. This is why mutations that cause Dravet Syndrome are called ‘loss of function’ mutations.

If one of the SCN1A copies is not working properly, not enough sodium ion channel protein is made. The faulty protein can cause the brain messages to get mixed up.

Dravet Syndrome is classified as a Developmental and Epileptic Encephalopathy as the SCN1A mutation causes both the seizures and the neurodevelopmental aspects of the condition.

A spectrum of SCN1A conditions

But having a mutation in the SCN1A gene doesn’t necessarily lead to Dravet Syndrome:

• There is a spectrum of loss of function SCN1A conditions. Dravet Syndrome lies at the severe end of that spectrum. Other loss of function SCN1A mutations are associated with less severe forms of epilepsy, such as Genetic Epilepsy with Febrile Seizures+ (GEFS+).
• Gain of Function SCN1A mutations also cause developmental and epileptic encephalopathies with different characteristics to Dravet Syndrome.

SCN1A mutations can occur in many different parts of the gene so someone with Dravet Syndrome is unlikely to have exactly the same mutation as another person with the condition.

Genes other than SCN1A that can cause Dravet Syndrome

Around 10% of people with Dravet Syndrome either have no detected SCN1A change, or have mutation(s) in genes other than SCN1A. It may be that the SCN1A mutation does exist in these people, but scientists can’t identify it yet. Or there could be other factors other than the gene mutation at play.

For a small amount of people, a clinical diagnosis of Dravet Syndrome is linked to a change in genes other than SCN1A. In most cases, people who have a gene change that isn’t SCN1A have a different neurological condition. They will have different seizures and characteristics and comorbidities to those with SCN1A-related Dravet Syndrome and may respond differently to medications. But some people with these genetic variations can have very similar symptoms to Dravet Syndrome.

In the past, patients with mutations in genes like SCN2A, STXBP1, and PCDH19 may have received a diagnosis of Dravet syndrome, but these are now grouped as unique genetic syndromes.

SCN2A

Mutations of this gene have been found in people with a variety of syndromes including:

• benign familial neonatal infantile seizures (BFNIS)
• early infantile epileptic encephalopathy (EIEE)
• autism spectrum disorder.

Unlike people with SCN1A-related Dravet Syndrome, those with a SCN2A mutation may respond positively to sodium channel blockers as a treatment for seizures.

SCN8A

Unlike those with Dravet Syndrome, people who have this gene mutation:

• can have epileptic spasms. These are brief one to three second seizures where a child will extend or pull their arms and legs into the body
• are not likely to have fever-related seizures
• don’t have myoclonic seizures which may involve one part of the body or the whole body
• respond to sodium ion channel blockers to treat seizures.

SCN1B

This mutation has been found in several people with GEFS+ Dravet Syndrome. People who have a SCN1B mutation and Dravet Syndrome share very similar characteristics to those with the condition who have a change in the SCN1A gene. This includes developing Dravet Syndrome in early childhood, treatment-resistant seizures, intellectual disability and other comorbidities.

PCDH19

Although PCDH19 epilepsy is considered to be a distinct syndrome, it mimics Dravet Syndrome in several ways. Differences are:

• seizures usually start later, around 11 months, whereas the average is six months in Dravet Syndrome
• clusters of seizures are more common
• seizures can be treated with steroids
• photosensitivity, sensitivity to ultraviolet rays from the sun and other light sources, is less common.

GABRA1

As well as people with Dravet Syndrome, mutations of this gene have been found in several epilepsies, including:

• childhood absence epilepsy
• juvenile myoclonic epilepsy
• genetic generalized epilepsy.

GABRG2

Changes in GABRG2 have been found in a small number of people with GEFS+ or Dravet Syndrome.

STXBP1

Changes in this gene have been found in people with Ohtahara syndrome, West syndrome, and non-specific epilepsies. They have varying levels of intellectual disability and movement disorders.

HCN1

In some people, a change in this gene very closely resembles classic Dravet Syndrome.

CHD2

People with Dravet Syndrome who have CHD2 mutations experience their first seizures later than normal – between one to three years old. People with Jeavons syndrome, Lennox-Gastaut syndrome and other epilepsies, can have a change in this gene.

KCNA2

People who have Dravet Syndrome with this change have become seizure-free as adults. This doesn’t normally happen when someone has Dravet Syndrome.

Does the genetic change that causes Dravet Syndrome affect the support people get?

No, it shouldn’t. Dravet Syndrome is a clinical diagnosis. Everyone who has the condition should have access to appropriate therapies and support, regardless of what gene caused Dravet Syndrome to happen.

Here at Dravet Syndrome UK, we support all families living with Dravet Syndrome. Several members of our community have genetic mutations other than SCN1A.

Many thanks to our Medical Advisory Board member, Andreas Brunklaus, for his assistance in writing this content.