Genetic Epilepsies

Genetic Epilepsy

Understanding genetics can be complicated. There are hyperlinks throughout this resource to try and help explain genetic words (click on a word highlighted in colour and this will link to a website explaining that word). You can also visit the links / resources tab for more resources to help explain genetics.

A “genetic” epilepsy is caused directly by a change in the sequence (spelling) of a gene associated with epilepsy and is relatively rare. A genetic cause means that there is a change in the instructions (or genes) that make us who we are. There are other causes of epilepsy, including head trauma and brain infections.

Genetic testing is useful in some types of epilepsy, such as the more severe genetic epilepsies that involve other symptoms (for example, developmental delay, intellectual disability, autism, behavioural issues, sleep disturbance, poor head growth (microcephaly) and/or visual problems) and that require multiple medications. These more severe epilepsies are often caused by a change in a single gene that is important in brain functioning. Your GP or specialist will decide if genetic testing might be worth considering for your child.

Occasionally where there is a clear family history of epilepsy, genetic testing may also be helpful where an inherited form of epilepsy is suspected.

For other types of epilepsy (e.g. childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy), there are likely a number of genetic changes that combine to increase the person’s chance/risk of having epilepsy. This is called polygenic (the combination of multiple genes) or multifactorial (the combination of multiple genes and the environment) inheritance. In addition, these epilepsies are often well controlled with medications. The chance of finding one single meaningful change in one gene in these forms of epilepsy is low, and therefore genetic testing is often not offered to these individuals or families with these types of epilepsy at this current time.

Having a “genetic” epilepsy does not always mean it is “inherited”. Sometimes, the genetic changes are new events that have not been inherited. Further information on genetic inheritance can be found in the “Genetic Inheritance” tab above.

 

Genetic Inheritance

The instructions that make us who we are (called genes) are carried in pairs. Genes are made up of thousands of molecules of DNA. DNA is made up of four proteins that are in a specific sequence within each gene. These genes are bunched together onto structures called chromosomes. We inherit one copy of each gene (and therefore each chromosome) from each of our parents. Additional information on DNA, chromosomes and genes can be found here.

A genetic epilepsy can occur in multiple generations in a family or be unique to one person, and may cause different symptoms in different members of the same family. There are five main ways genetic epilepsies can occur in families (there are other rare exceptions which will not be explored here but can be explained by your genetics team):

1.       A new genetic change in the affected person

  • Inheritance: This type of change is genetic, but it is not inherited from the parents, who do not have epilepsy.
  • This is called a ‘de novo’ (or new) event, resulting from a change in only one of the copies of our genes. The other copy is still working, but some particular genes require two working copies in order to provide instructions for general good health. This pattern of inheritance is called Autosomal Dominant inheritance. More details about this form of inheritance can be found here.
  • Implications for family planning:
    • Parents of a child with a de novo change have a low, but not zero, chance of having another affected child. This is because the genetic change may be present in a pocket of eggs or sperm (‘gonadal mosaicism’). This possibility can be discussed in more detail with your genetics specialist.
    • There is a 1 in 2 (50%) chance that an affected person will pass the condition on to their future children.

 

2.       An inherited genetic change from an affected parent

  • Inheritance: This change has been inherited from a parent who also has the same condition.
  • This is called ‘Autosomal Dominant inheritance’, resulting from a change in only one of the copies of our genes. The other copy is still working, but this particular gene requires two working copies in order to provide instructions for general good health. More details about this form of inheritance can be found here.
  • Implications for family planning: There is a 50% chance that an affected individual will pass the condition on to their future children.

 

3.       A combination of genetic changes from each parent

  • Inheritance: These changes are inherited from the affected individuals’ parents, although the parents themselves will be unaffected.
  • This is called Autosomal Recessive inheritance. As each parent has two copies of every gene, in their eggs or sperm, they only pass on one copy. One copy from each parent combines to create their child. Should the parents both carry a change in the same gene, the child is at risk of inheriting both changed copies and having the genetic condition. There is often no family history of the condition. More details about this form of inheritance can be found here.
  • Implications for family planning: Parents of children with recessive conditions will have a 1 in 4 (25%) chance of having another baby with the same condition. Affected individuals will be unlikely to pass the condition on to their own children, but should have their partner screened prior to family planning (to avoid the low risk of a partner being a carrier).

 

4.       A genetic condition which only affects boys

  • Inheritance: The condition may occur for the first time in an affected boy, or may be inherited from a carrier girl. There may be a family history of affected boys or no family history at all.
  • This is called X-linked recessive inheritance. The genes, which provide instructions to make a boy or a girl, are located on the X and Y chromosomes. Girls have two X chromosomes and boys have an X and Y. If there is a change in a gene located on the X chromosome, girls can carry one change and one working copy and be well and healthy (called a ‘carrier’). Boys have only one X chromosome and therefore if they have a change in their X chromosome they will have the genetic condition. More details about this form of inheritance can be found here.
  • Implications for family planning: Girls who are carriers have a 1 in 4 (25%) chance of having an affected boy. Boys who have the condition cannot have an affected son (as they will pass their Y chromosome to their sons). Boys who have the condition will pass their changed X chromosome to their daughters, making all their daughters carriers.

 

5.      A genetic condition which only affects girls

  • Inheritance: The condition may occur for the first time in an affected girl (the most common), or may be inherited from a mildly affected mother or an unaffected father (rare). There may be a family history of affected girls or no family history at all.
  • This is called X-linked dominant inheritance. The genes which provide instructions to make a boy or a girl are located on the X and Y chromosomes. Girls have two X chromosomes and boys have an X and Y. If there is a change in a gene located on the X chromosome, some genes on the X chromosome are important in females and require two functioning copies in order to be well and healthy. If an affected girl has a change in one X chromosome, this causes the condition to occur.
  • These conditions can have a wide range of variability, meaning that some girls can carry the change and be unaffected, through to a girl who is severely affected.
  • Boys who carry the variant are usually unaffected or more mildly affected.
  • Implications for family planning:
    • Parents of a child with a de novo change (in this case on the X chromosome) have a low, but not zero, chance of having another affected child. This will be the majority of patients with X-linked dominant changes. This is because the genetic change may be present in a pocket of eggs or sperm (‘gonadal mosaicism’). This possibility can be discussed in more detail with your genetics specialist.
    • A father who carries a variant on the X chromosome (but is asymptomatic) will have a 50% chance of having an affected daughter, and a 50% chance of having an unaffected son.
    • A mother who carries a change in an X-linked dominant gene has a 25% chance of an affected daughter, a 25% chance of an unaffected daughter, a 25% chance of an unaffected (non-carrier) son, and a 25% chance of having a boy who is unaffected but has the change (this would have implications for the boys children).

 

Genetic Testing

A “genetic” epilepsy is caused directly by a change in the sequence (spelling) of a gene associated with epilepsy and is relatively rare. A genetic cause means that there is a change in the instructions (or genes) that make us who we are. There are other causes of epilepsy, including head trauma and brain infections.

Genetic testing is useful in some types of epilepsy, such as the more severe genetic epilepsies that involve other symptoms (for example, developmental delay, intellectual disability, autism, behavioural issues, sleep disturbance, poor head growth (microcephaly) and/or visual problems) and that require multiple medications. These more severe epilepsies are often caused by a change in a single gene that is critically important in brain functioning. Your GP or specialist will determine if genetic testing might be worth considering for your child.

In rare instances where there is a clear family history of epilepsy, genetic testing may also be helpful where an inherited form of epilepsy is suspected.  

There are many different types of genetic tests available. Your treating doctor and/or a genetic specialist will offer the most appropriate genetic test for your child, based on their medical history and clinical presentation.

 

Genetic Testing typically involves the following:
  • A Genetic Counselling appointment (see: “what to expect at a genetic appointment” for more information)
  • Collection of specimen (urine/blood/saliva)
  • An appointment to obtain the results of testing

Before deciding if you would like to proceed with genetic testing, it may be helpful to consider some of the reasons for and against it.

 

Some reasons people wish to have genetic testing:
  • To confirm/find a diagnosis
  • Guide for future family planning and pregnancies
  • Explanation of family history
  • Assess if there are health or reproductive implications for the wider family (conditions may have implications for not only an individual but also for others in the family, including siblings, parents, aunts, uncles)
  • Helping to come to terms with why the child has epilepsy
  • Access to financial and social supports
  • To assess if a diagnosis helps their doctor better treat or manage the child’s epilepsy

 

Some reasons people wish not to proceed with genetic testing:
  • A diagnosis of the genetic condition may reveal a more severe disease than initially predicted
  • The family are not planning further children
  • Concern about revealing non-maternity or non-paternity
  • Concerns about discrimination (e.g. life/mortgage /income protection insurance applications, NOT health insurance). More information on the implications of genetic testing on insurance in Australia can be found here.
  • Concerns about privacy

Speaking to a geneticist/genetic counsellor will help you decide whether genetic testing is the right decision for you and your family right now. It’s also important to consider how likely genetic testing will find an answer for your child right now. Even with the most advanced genetic testing, many families will not get a clear-cut answer as to why their child has epilepsy. The good news is that our understanding of genetics an is improving all the time. This means that if testing does not find an answer right now, there may l be the option of redoing the testing in the future, with a better chance of getting an answer. 

Even if a genetic test DOES find a diagnosis for a family right now, many genetic epilepsies are rare, and only recently described. That means you may not get much information about what a particular genetic diagnosis means for your child in the future.  Your doctor might not change any therapies, as little is still known about the right therapies or management of many genetic epilepsies. However a genetic diagnosis can be a starting point to getting more information in the future.  Your genetics team will discuss these points (the advantages and limitations of testing) before testing begins.  Some more information on the pros and cons of genetic testing can be found here: pros cons.

 

Types of tests
  • Chromosome Array
    • This test examines if there are small losses or gains of whole genes or parts of genes
    • Results for this test are usually available within 4-8 weeks
    • More information on this type of testing can be found here
  • Epilepsy Gene Panel
    • This test examines the DNA sequence of multiple/a targeted set of genes that are associated with epilepsy at one time
    • Results for this test are usually available within 3-4 months
    • More information on this type of testing can be found here
  • Whole Exome testing and Whole Genome testing
    • The DNA sequence within a gene is made up of exons (protein-making) parts and introns (non-protein making) parts. Most genetic conditions occur as a result of changes within the DNA sequence of the exons.
    • Whole exome sequencing examines the DNA sequence of all the exons of all our 20 000 genes at the same time  
    • Whole Genome Sequencing examines the DNA sequence of the introns AND exons of all our 20 000 genes at the same time
    • Results for exome sequencing are usually available within 4-6 months
    • Genome sequencing is not routinely available in Australia        
    • More information on this type of testing can be found here

 

Outcomes

Outcomes of testing will depend on the type of testing undertaken. Common tests include array, gene panel or exome sequencing.

Possible results may include (but not be limited to):

  • Pathogenic (Likely)
    • A definitive explanation for the epilepsy. The change in the gene will affect an individual and cause epilepsy
  • Variant of Uncertain Significance
    • The effect of the change on the gene is unclear. Additional information and evidence may be required in order to work out if this change will cause epilepsy or is a normal variation.
  • Benign
    • The change will not cause epilepsy and is not the cause of the condition. It is considered a normal variation.
  • Incidental/Additional finding
    • A change in a gene which causes a health issue which is unrelated to the reason for the test.
    • Example: finding a change in a gene associated with heart disease, when the reason for testing was epilepsy

All possible outcomes of testing should be discussed with your ordering clinician prior to undertaking testing as part of an informed consent process. An infographic explaining these possibilities can be found here

 

Limitations of testing include (but are not limited to):
  • Remaining uncertainty with a diagnosis
    • Genetic epilepsies are often rare. Lack of long term studies on large numbers of patients with the same underlying genetic condition mean that clinicians are often unable to provide accurate prognostic (seeing into the future) information
    • As new genes are discovered, the first cohort described often have similar (and often more severe) medical complications
    • Over time, with more individuals being tested, a clearer picture of the full spectrum of the condition will be seen, but this can take several years.
  • Remaining uncertainty without a diagnosis
    • Information about genetic causes of health conditions changes over time
    • This means that a negative result (no cause found) one day does not rule out the possibility of a genetic condition in an individual
    • This is because there remains the possibility that new gene discovery, technology or understanding will clarify the reason when future reanalysis or more testing is available in the future.

Reanalysis

An individual who receives a negative result on an exome or genome will generally be advised to consider reanalysis (the laboratory reassessing the data for a diagnosis) as future discoveries may provide a diagnosis. The current suggested reanalysis timeframe is every 18 months.

 

Payment and Cost

There are multiple options for investigation of a genetic cause for epilepsy. Medicare covers some of these, others incur an out-of-pocket fee. Often this out-of-pocket fee will be covered by the hospital or health service if the patient is being seen through the public health service, although this will vary between services and states.

It is difficult to provide accurate and up to date costs for out of pocket genetic tests when not ordered through the public health system. Costs are subject to change (usually becoming cheaper) and are laboratory dependent. We advise that individuals seek advice from their medical practitioner or local genetics service about current costs if the preference is to pay for a test privately.

Below is a list of tests and whether Medicare covers them. If Medicare does not cover them, options for fee coverage should be discussed with the ordering clinician.

  • Chromosomal Microarray (also known as Array, CGH, SNP array)
    • Medicare rebate (with referral requirements to be met)
  • Fragile X PCR
    • Medicare rebate (with referral requirements to be met)
  • Urine Metabolic Screen
    • Medicare rebate (with referral requirements to be met)
  • Gene Panel
    • No Medicare rebate
    • Often covered by local health service/genetics department, needs hospital consent (referral requirements to be met)( subject to change in 2020)
  • Exome Sequencing
    • Medicare rebate is now applicable for some children with epilepsy – currently for those under the age of 10 years, whose paediatrician has assessed them as having at least moderate global developmental delay or intellectual disability and/or congenital malformations.
    • If not covered by Medicare, costs may be covered by local health service/genetics department (needs hospital consent and referral requirements to be met)
  • Whole Genome Sequencing
    • Although the Medicare rebate is now applicable for some children with epilepsy, in reality, this currently more expensive test, is not likely to be completely covered by Medicare. Discuss this with your clinician.

What to expect at a genetic appointment

Your GP or specialist may offer you (and your child) a genetic appointment if they suspect an underlying genetic cause for your child’s condition.

Identifying a genetic cause may have implications for the health and management of your child and for their siblings or future children. A genetic appointment can help better understand the implications of a genetic diagnosis and provide detailed information to help you decide whether or not you wish to proceed with genetic testing for your child.

Who will you see?

Your child will be seen by a clinical geneticist and a genetic counsellor.

  • A clinical geneticist is usually a children’s doctor (paediatrician) with special training in genetic conditions that affect children and their impact on family members.
  • A genetic counsellor is an allied health professional with specific training and skills in counselling and genetics.
What’s involved?
  • The genetic counsellor may contact you by telephone before your appointment to discuss your family’s medical history and to gather a family tree.
  • At the appointment your family history will be discussed and your child’s history will be gathered.
  • A full examination with weight and height will be undertaken.
  • With permission, photographs may be taken and the doctor may wish to arrange other tests after discussion with you.
  • The appointment lasts about 1 hour and usually takes place in a public Outpatient Clinic.
Topics of discussion

The genetic counsellor will likely discuss with you some of the following:

  • the options for different types of testing
  • the limitations and timeframe
  • Which sample is most appropriate (e.g. blood, skin, saliva)
  • How long will the testing take (e.g. 1 week, 3 months, 6 months)
  • Organisation of sample collection
  • Possible outcomes of testing (e.g. a diagnosis, no answer, a complex result)
  • Consent
Receiving results

Once results are available, genetic counselling is provided to assist in the return of results to the family.

  • This may be in the form of a discussion with a member of a clinical genetics team (genetic counsellor or clinical geneticist) or a neurologist/other health professional.
  • The health professional can explain the results and assist with any other additional testing which may be required in the family to assist with understanding the results (sometimes testing in parents is required in order to be able to understand an individual’s results).
  • Results may provide information on the risks to the wider family, implications for family planning and future clinical information for the person affected with epilepsy.
Access to private services

There are private clinical geneticist and genetic counselling services in NSW and the rest of Australia. Services are evolving, but at the time of writing, some services include (but not limited to):

Other private genetic counselling services are available but provide specialist services such as prenatal (pregnancy)/reproductive or cancer testing only.

Links | Resources

This page contains some useful links and resources for families/individuals with genetic epilepsies. The information and links will continue to be updated as new information and resources become available.

Genetic Support groups (not a complete list)

 

Gene Specific information (not a complete list)

 

Support groups and organisations

 

General Information on genetics

 

Glossary of genetic terms: https://www.australiangenomics.org.au/resources/for-patients/genomics-glossary/#1543205241515-20146561-d080

 

Epilepsy genetic information

 

If you have additional links you would like us to include, please contact the team and we would be happy to discuss this.