More than 85% of patients diagnosed with Dravet syndrome have an SCN1A mutation [1]. The SCN1A gene codes for the production of sodium ion channels, which are pore-like proteins embedded in the cell membrane that allow sodium ions into and out of the cell, propagating electrical signals. Some patients have other mutations including SCN2A and PCDH19.

Mutation Graph 2 600x338 1

  • 90% of SCN1A mutations are de novo, meaning they are not found in the patient’s parents
  • 4-10% of SCN1A mutations are inherited from the parent. In this case, there is a 50% chance of passing the mutation on to future children
  • There are over 6,000 places for a mutation to occur on the SCN1A gene. Therefore, most patients’ mutations have not been reported in other people
  • Any type of SCN1A mutation can be seen in Dravet syndrome, and mutation type does not predict the severity of the disease
  • SCN1A mutations are also associated with migraines, febrile seizures (FS), generalized epilepsy with febrile seizures plus (GEFS+)

After a positive genetic test result, consultation with a genetic counselor is recommended. While a mutation is not necessary for diagnosis, it can support a clinical diagnosis and it is helpful to understand what DNA, genes, and mutations are. Each person has two copies of the SCN1A gene: one from each parent. Many mutations found in Dravet syndrome render one copy dysfunctional, leaving only one functional copy. This results in a condition called haploinsufficiency, which means that one functioning copy is not sufficient to prevent symptoms. Approximately 90% of Dravet mutations are de novo, meaning they are not inherited from a parent, but rather are new mutations in the child [1,4].

My infant has received genetic test results indicating an SCN1A mutation. What does this mean?

In years past, a mutation in the SCN1A gene has confirmed a diagnosis of Dravet syndrome in patients that were already showing the typical disease progression. When access to genetic testing was more limited, most diagnoses occurred after associated health issues had already started to develop. In more recent years, with greater access to genetic testing, patients are now receiving confirmation of the mutation at very young ages before the typical progression of the disease becomes apparent, leading to confusion in patient families on what to expect for their child’s prognosis.

There is a spectrum of disorders associated with SCN1A mutations, ranging from mild to severe, including Familial Hemiplegic Migraines, Generalized Epilepsy with Febrile Seizures Plus (GEFS+), and Dravet syndrome. Genetic testing can help to guide diagnosis, but it must be considered in the context of clinical symptoms. For example, two patients might carry the exact same mutation and still have different diagnoses, such as Dravet syndrome and GEFS+. Additionally, even within the diagnosis of Dravet syndrome, there can be a lot of variability in when and to what extent symptoms present. Published studies of the patient population can report common trends, but there are outliers and a lot of variability.

When will I know if my child has Dravet syndrome or a different SCN1A disorder?

With earlier genetic diagnoses, we will gain a better understanding of the full spectrum of SCN1A disorders in the coming years. Until then, once seizures occur and a mutation in SCN1A is identified, it is essential to follow a treatment protocol based on the international treatment consensus for Dravet syndrome*. This ensures that contraindicated medications are avoided and that patients receive the highest quality of care. Earlier intervention with the most appropriate treatment plans may also improve the overall picture of long-term outcomes for patients with Dravet syndrome. *In a small proportion of cases, mutations in SCN1A may be Gain-of-Function, rather than the Loss-of-Function mutations that lead to Dravet syndrome. Patients with Gain-of-Function mutations in SCN1A may respond to a different treatment protocol. Some of the key clinical signs that may suggest looking to see if there is a Gain-of-Function mutation including seizures onset before 3 months of age, non-seizure movement disorders, and/or joint contractures.

Some clinicians may decide early on to give an infant the diagnosis of Dravet syndrome based on the seizure types and other symptoms in conjunction with an identified mutation in SCN1A, while other clinicians may wait to see if other developmental areas are impacted before giving an official diagnosis. Regardless of the eventual final diagnosis and long-term outcomes for patients, early intervention and appropriate medication choices based on the expert-consensus recommendations give patients the best chance for positive outcomes regardless of where they land on the spectrum of SCN1A-related disorders.

One of the biological parents of my child has also tested positive with an SCN1A mutation. Does this mean that this parent also has Dravet syndrome?

The diagnosis of Dravet syndrome is based on clinical symptoms. Genetic testing can help to direct or confirm the diagnosis, but a mutation in SCN1A alone is not sufficient to automatically give someone the official diagnosis of Dravet syndrome. As mentioned above, there can be a range of disorders that result from mutations in SCN1A. Keep reading below for more explanation about how the same mutation could result in different outcomes in two individuals.

The International League Against Epilepsy helps to set the criteria for diagnosis of Dravet syndrome. You can read more on this page, but in brief, a diagnosis of Dravet syndrome involves: 

  • Recurrent, often prolonged seizures (often associated with fever but also unprovoked; focal or generalized)
    Onset of seizures between 1-20 months (although diagnosis should be looked at more carefully if on the very early or late range of those ages)
  • Typical development of infant at onset with a normal EEG outside of seizures (developmental impacts begin in early childhood and slowing of the EEG is common over time)
  • Medication-resistant seizures that may evolve over time
  • Intellectual disability that becomes apparent generally by school age (commonly moderate to severe; although there are rare reports of individuals who are less impacted in this area). The majority of patients with Dravet syndrome will need supportive care throughout their lifetime.
  • Additional symptoms commonly associated with Dravet syndrome include speech delays or impairments, behavior disorders, gait and movements disruptions (such as crouched gait developing during adolescence)

How is it possible for both my child and I to have an SCN1A mutation, yet I don’t have Dravet syndrome?

In a small portion of the patients with Dravet syndrome, mutations in SCN1A have been inherited from a parent who carries the mutation. On the surface this can be confusing, why did the mutation cause Dravet syndrome in the child but did not cause the parent to have the symptoms and diagnosis of Dravet syndrome? 

There are actually several factors that can impact how someone’s genotype (the actual ‘code’ of their DNA) impacts their phenotype (the physical symptoms that present from their DNA ‘code’). It is not unique to Dravet syndrome, or the SCN1A gene, to have variability in the presentation of symptoms from the same or similar mutations. Factors that can impact the phenotype resulting from a mutation include: 

  • Other parts of the person’s genetic code; for example, another small gene change that may compensate for a significant mutation in another gene. Studies of animal models and families with inherited SCN1A mutations have shown that there can be ‘modifier genes’ or additional mutations that are compensatory which impact the severity of the phenotype from an SCN1A mutation.
  • Environmental factors or exposures. In the context of Dravet, this could include things like being on contraindicated medications for long periods of time. In animal models, early-life stressors have been shown to worsen long-term outcomes.

So a mutation in SCN1A alone is not enough to always say “Dravet.” Which is why phenotype (or clinical symptoms) have to be taken into account with genotype (the mutation in SCN1A) to determine an accurate diagnosis, since there are scenarios where individuals carry a mutation that could be causative but do not develop symptoms (or as severe of symptoms).

What is DNA?

DNA is the set of instructions contained within each of our body’s cells. The instructions tell the cell how to build the proteins it needs to function. A strand of DNA is a long chain of 4 different nucleotides (abbreviated A, T, C, and G) strung together in a particular order, billions of nucleotides long. Because there is so much DNA in our cells, it is organized into 23 pairs of chromosomes, much like two sets of encyclopedias would be organized into 23 volumes each. When a sperm and an egg, each containing 23 chromosomes, combine, the result is 46 total chromosomes, organized into 23 matching pairs.

5 DNA Structure e1625681111829

What is a gene?

The 23 pairs of chromosomes are further divided into smaller segments called genes. A gene is much like a chapter in an encyclopedia and contains the instructions for producing a specific protein. Each gene is a small segment of DNA and is thus also a long chain of 4 different nucleotides strung together in a particular order. Because our cells have one copy of each gene from each parent, every cell has two copies of each gene unless the gene is carried on the sex-determining X or Y chromosome. SCN1A is not on the X or Y chromosome.

Genes are read in groups of 3 nucleotides called codons. Each codon is translated into one of twenty amino acids, which are then strung together like beads on a necklace. The amino acids interact with each other based on their chemical properties similar to how magnetic beads attract and repel each other when folded up in one’s hand. As the amino acids interact, the long chain folds on itself to form a very specific 3-D shape.

Codons 768x346 1

In the case of SCN1A, this 3-D shape is an ion channel that functions as a gated channel in the cell membrane, letting sodium ions into and out of the cell. The inward and outward flow of ions like sodium allows electrical signals to be generated along neurons. These electrical signals are how the cells in our brain, neurons, communicate with each other and the rest of the body.

SCN1A 2 800x465 1

What is a mutation?

A mutation is a change in the expected sequence of nucleotides (the order of the ‘A’,’T’,’G’,and ‘C’ units) within a gene. This change in the original sequence of DNA may then alter the sequence of amino acids that are translated from the DNA code to build the protein. A mutation may cause the chain of the protein to end too early, fold incorrectly, or otherwise change the ability of the sodium ion channel to function properly. Dysfunctional sodium ion channels can result in improper electrical activity and seizures.

Although SCN1A has 160,000 nucleotides, the body edits this sequence of 160,000 down to about 6,000 in the final SCN1A RNA transcript that serves as the instructions for making the sodium ion channel [2]. Still, with over 6,000 nucleotide positions, it is no wonder that most mutations reported in the literature have not yet been seen in another patient.

Remember that every cell actually contains two copies of SCN1A; one from each parent. Usually, only one copy is mutated, a condition termed heterozygosity [3]. Approximately 4% of the mutations seen in Dravet syndrome are inherited directly from parents, with the parent often experiencing fewer and less severe symptoms than the child in a phenomenon known as reduced penetrance [1]. This could be because of other impacts of their personal genetic make-up, or something called mosaicism (discussed more below).

There are three main types of mutations: missense, nonsense, and insertions/deletions.

Missense:

A missense mutation is a simple substitution of one nucleotide for another at a single location in a gene. This slight change in the sequence of nucleotides may or may not result in one changed amino acid in the long chain.

If a missense mutation occurs near a pore-forming region of the sodium ion channel, it is likely to significantly alter the ion channel’s function and cause a more severe case of SCN1A-related epilepsy such as Dravet syndrome [5]. If a missense mutation occurs at a less critical location on the gene, it may produce milder clinical symptoms or no symptoms at all. Approximately 47% of the mutations seen in Dravet patients are missense mutations [1].

A missense mutation reported by a testing company may look like this:

  • Variant 1: Transversion G>T
  • Nucleotide Position: 4073
  • Codon Position: 1358
  • Amino Acid Change: Tryptophan>Leusine
  • Variant of Unknown Significance (heterozygous)

This says that the mutation was a substitution of T for G at the 4073rd nucleotide position (of 6000 in the final gene that is read) [6]. Remember that nucleotides are read in groups of 3, called codons, so 4073 divided by 3 gives you the amino acid or codon position of 1358. The amino acid Leucine was substituted for the amino acid Tryptophan. The lab is unable to determine the significance because missense mutations can be associated with both mild and severe clinical presentations. The patient has only one copy of this mutation and is thus heterozygous. This real-life mutation is indeed in a pore region of the sodium ion channel, and this patient does have Dravet syndrome.

Nonsense:

Nonsense mutations are similar to missense mutations in that one nucleotide is substituted for another. However, in the case of a nonsense mutation, that substitution causes the codon to be read as a “STOP” signal. The cell stops reading the gene prematurely, and the protein is significantly shortened, or truncated. Nonsense mutations are often associated with more severe SCN1A-related epilepsies such as Dravet syndrome [5]. Approximately 20-40% of mutations in Dravet syndrome are nonsense (truncation) mutations [1,10]. A nonsense mutation may be reported like this:

“The mutation c.3985C>T (heterozygous) resulting in a termination or stop codon at Arg 1329 was detected in exon 20 of the patient sample and is associated with Dravet syndrome.”

This says that the nucleotide C was replaced with a T at position 3985, which resulted in the amino acid Arginine being replaced with a stop codon at position 1329. (3985 nucleotides, read in groups of 3, correspond to 1329 amino acids.) Only one of the two copies of SCN1A in the patient is mutated (heterozygous), as is usually the case. “Amber,” “Opal,” and “Ochre” may appear on the lab report and are some of the names for stop codons. The lab can be fairly confident this mutation is disease-producing because of the high correlation between truncation mutations and Dravet syndrome.

This same mutation may be reported by another lab like this:

Genetic Report 600x204 1

This report does not specify the nucleotide position, but it identifies the amino acid position as 1329, and the asterisk (*) next to the amino acid position indicates a stop codon. Again, the lab is confident this mutation will result in Dravet syndrome.

Insertions/Deletions:

Sometimes, one or more nucleotides are deleted from the gene. If one or two nucleotides are inserted or deleted, the reading frame of codons is shifted, and every amino acid is incorrect from that point in the chain on. This usually causes a dysfunctional sodium ion channel. In addition, the shift in reading frame will often cause one of the codons farther down the chain to be interpreted as a stop codon, prematurely terminating an already dysfunctional chain.

If a group of 3 nucleotides is inserted or deleted, only one codon is added or deleted, respectively, and the protein may still be functional depending on the location of that insertion or deletion.

Large segments of DNA may be inserted or deleted including the entire SCN1A gene and/or nearby genes. These mutations have varying phenotypes, and account for roughly 2-5% of Dravet mutations [1,5].

Mosaicism:

When the mutation occurs in the sperm, egg, or very soon after fertilization, all of the daughter cells derived from the growing embryo will contain the mutation. This is the case for most mutations found in Dravet syndrome [1].

However, if the mutation occurs later in the development of the embryo, only the cells descended from the mutated cell will carry the mutation. The cells descended from the non-mutated cells of the embryo will remain healthy. This results in an individual who is mosaic for the mutation. The later the mutation took place during development of the body, the lower the percentage of cells descended from the mutated cell, and the lower the “% mosaicism” or “mosaic load.” (This is a broad generalization: In reality, the degree of specialization of the cells at the time of mutation plays a significant role in where the mutated cells are concentrated in the patient’s body and what the ultimate mosaic load is.) One study reported that SCN1A mutations with 12-25% mosaic load were potentially pathogenic, with reduced penetrance, meaning not all who carried the mutation in mosaic form exhibited signs or symptoms [5].

SNP’s:

Mutations are actually a natural phenomenon that has been occurring in all organisms for thousands of years. Most changes in DNA sequence have little to no effect on the final protein products because they occur in regions that are edited out during gene processing, or their location in the final protein does not alter its function. In fact, many members of the healthy population have variants in their genes that are shared with a significant percentage of the population. Because these variants have no obvious clinical symptoms, they are called single nucleotide polymorphisms (SNP’s) and are not considered mutations. Your lab report may include these SNP’s, but their presence is not considered a positive SCN1A test.

Do healthy siblings or other family members need to be concerned about passing on Dravet syndrome?

In the majority of situations (90%), the mutations that cause Dravet syndrome are not inherited from parents, meaning there would not be any implication for unaffected siblings. However, in the situation where the genetic mutation has been inherited from a parent, siblings may want to speak with a genetic counselor and seek genetic testing. Often in families where genetic mutations causing Dravet syndrome are inherited, there is a family or parental history of seizures or other less severe form of epilepsy.

What does this mean for the patient?

Researchers and epileptologists are learning more about the role SCN1A mutations play in Dravet syndrome and related epilepsies every day. At this point, it is clear that SCN1A mutations of any kind can be responsible for Dravet syndrome. However, because some SCN1A mutations are present in individuals with mild symptoms, there are probably many modifying factors that determine the severity of symptoms that result from the mutation. SCN1A mutations are helpful in supporting a clinical diagnosis, but remember that roughly 20% of patients with Dravet syndrome have no detected mutation, and a mutation is not required for diagnosis.

Is it all bad news?

No! There is so much active research on SCN1A and related epilepsies that scientists are uncovering new knowledge and potential therapeutic pathways every day. The fact that an epilepsy syndrome like Dravet can be traced to a root cause, despite many unknown factors and modifiers, makes it an appealing target for research and gives patients hope for a cure.