Genetic Testing

Why Genetic Testing?

Why consider genetic testing?

Genetic testing can find an underlying genetic diagnosis for up to 60% of individuals with severe early-onset childhood epilepsy in whom environmental and symptomatic (e.g. structural, infective, immune) causes have been excluded.  Genetic testing can also be considered in some familial types of epilepsy (see below).

Genetic testing can be helpful for:
  • Treatment decisions – a genetic diagnosis may help the neurologist select appropriate medication, diet or surgery

  • Clinical trial entry – certain genetic epilepsies (will) have access to clinical trials

  • Limit further unnecessary testing – such as neuroimaging or muscle biopsies

  • Accurate genetic counselling – about the chance of recurrence and options for testing before or around a future pregnancy

  • Patient and family support provide an explanation for the epilepsy and help connect with other families with the same diagnosis


A specific webpage discussing the potential benefits of genetic testing for epilepsy can be found here:  ILAE position statement Genetic Testing in the Epilepsies.


Diagnostic Yield

Genetic testing has the highest diagnostic yield for patients with:
  • Neonatal onset seizures

  • Developmental delay or intellectual disability in addition to the epilepsy

  • Difficult to treat seizures (requiring multiple anti-epileptic therapies)

  • Epilepsy associated with progressive neurological disease or with the involvement of other organ systems


Diagnostic yield is currently low for:
  • Patients with West syndrome (infantile spasms) that is non-syndromic or when the spasms are preceded by normal development.

  • Patients with late childhood/adolescent-onset epilepsy with normal development.


Chromosomal Microarray

Chromosomal microarray (CMA) is also known as comparative genomic hybridisation (CGH) array,  or single nucleotide polymorphism (SNP) array. This test finds deletions or duplications of chromosomal material.


CMA is a first-line test for developmental delay/intellectual disability/autism, with or without epilepsy. This test cannot screen for all genetic causes. It does not screen for Fragile X syndrome which has a separate Medicare item.


CMA has a diagnostic yield of 10-15% for intellectual disability/autism. It has a similar yield in developmental and epileptic encephalopathies. The yield is lower if cognition is normal.

Sample requirements:

Important to check with individual genetic laboratories. Most labs require 5-10ml EDTA but some can provide saliva collection kits. 

Result turnaround:

Typically, 4-6 weeks.


Rebate is available for this test if the affected patient has developmental delay/intellectual disability and/or autistic spectrum disorder and/or two or more congenital abnormalities. To ensure Medicare rebate is provided, and to aid result interpretation, clinical information should be included in request forms.

Pre-test counselling: 

Genetic testing options are complex and informed consent is mandatory. We recommend that ordering clinicians use the consent form recommended for their state (the NSW Health genetic consent form can be accessed here).  An information sheet should be provided to all families and these important points covered:

  • This test screens for additional or missing sections of chromosomal material
  • It is NOT a screen for all possible genetic conditions
  • There are four possible test outcomes:
    1.  it may provide a definitive explanation for the child’s epilepsy
    2.  it may be non-informative
    3. it may detect a variant in a gene where we are not sure if it causes the epilepsy or not
    4. it may include an incidental finding (that is a genetic variant which causes a condition other than epilepsy)

*It is important to note that an incidental finding may occur in addition to any of the options above or in isolation (i.e. you may get an incidental finding alone OR you may get a diagnosis and an incidental finding)

  • It can also provide information on misattributed parentage (non-paternity or non-maternity) or may suggest a closer parental relationship than is known or suspected, for example parents who are first cousins.


Fragile X PCR

This test checks for expansion in the Fragile X gene (FMR1) and is a screen for Fragile X syndrome, which is an important condition to screen for if there is comorbid intellectual disability or autism.


Fragile X PCR is a first-tier test for both boys and girls with unexplained intellectual disability and/or autism. Fragile X syndrome is NOT screened for by chromosomal microarray (CMA) and needs to be separately requested.


Fragile X syndrome is the most common known cause of inherited intellectual disability, affecting around 1 in 4000 males and about 1 in 6,000 females. Testing is not recommended for children with epilepsy who do not have developmental delay or intellectual disability.

Sample requirements:

Important to check with individual genetic laboratories. Most labs require 5-10ml EDTA but some can provide saliva collection kits. 

Result turnaround:

Typically 2- 4 weeks.


Clinical information should be included on the test request form to ensure rebate. Rebate is available for this test under the following clinical situations:

  • The patient exhibits intellectual disabilities, ataxia, neurodegeneration, or premature ovarian failure consistent with a FMR1 mutation; OR

  • The patient has a relative with the FMR1 mutation.

Pre-test counselling

Genetic testing options are complex and informed consent is mandatory. As a minimum verbal consent should be documented in the medical notes.  An information sheet should be provided to all families and these important points covered:

  • The test screens for Fragile X Syndrome (FXS), the most common cause of inherited intellectual disability.

  • People with FXS can have developmental delay, learning difficulties, anxiety, autism and epilepsy.

  • The features of FXS vary from mild to severe with males more likely to be severely affected than females because the gene is found on the X-chromosome.

  • Screening can also reveal carrier status (intermediate or premutation expansion) which can have implications for the health of the child and other members of the family, as well as genetic counselling implications.



First-line Metabolic testing

First-line Metabolic Testing involves an extended urine metabolic screen which includes an Amino Acid quantitation, Creatine metabolites, selected Purines and Pyrimidines, Piperidine-6-carboxylate, GAG (Glycoasaminoglycan) screen and Organic Acids.  The test is available in NSW through the NSW Biochemical Genetics Department at the Children’s Hospital at Westmead. For other states contact your local Biochemical genetics team.


This testing can screen for metabolic causes of severe early onset epilepsy, including conditions with targeted treatments such as specialist diet.


Although overall yield is less than 5%, seizures are a frequent symptom in metabolic disease, having been reported in more than 200 different inborn errors of metabolism (IEMs), and the screen may quickly reveal conditions with targeted therapies.

Sample requirement:

Random urine, 10 mL (minimum 2 mL), which the collection centre needs to deliver immediately on ice or freeze within 2 hours of collection and transport on dry ice with no added preservative to the NSW Biochemical Genetics Department at the Children’s Hospital at Westmead.

Result turnaround:

Typically, 2-3 days.


Partial rebate is available for this testing (metabolic profile, amino acid – please refer to the Medicare website). Clinical information should be included on test form to aid interpretation and for Medicare rebate.

  • Urine Metabolic Screen information.
  • Other specialist metabolic tests may be organised by a neurologist, for example screening for congenital disorders of glycosylation, B12 and folate deficiency, peroxisomal disorders and disorders of neurotransmission. 


Exome | Panel

Gene panel, exome sequencing and whole genome sequencing technologies (also known as next generation or massively parallel sequencing) test different parts of an individuals’ genetic code (their ‘genome’). These tests require accurate genetic counselling and a full assessment of the clinical presentation.  Currently they are typically requested by a neurologist in consultation with a clinical genetics team. Funding and availability of these tests varies across the country and is evolving rapidly.

  • Panel tests: test a set of genes known to cause epilepsy, or certain types of epilepsies such as developmental and epileptic encephalopathies. Gene panels vary widely in the genes that are included and will identify variants in the more common epilepsy genes but may not include rarer or only recently described epilepsy genes.
  • Exome sequencing: can test most coding genes. Often exome sequencing is limited to genes currently known to cause a medical condition and may be referred to as a ‘Clinical Exome’ or ‘Mendeliome’.
  • Whole genome sequencing (WGS): tests the majority of DNA, including coding genes and the DNA between genes. WGS has the potential to detect complex structural genetic rearrangements that may not be detected by chromosomal microarray, and variants in the mitochondrial DNA.

Yield is highest for developmental and epileptic encephalopathies (DEE) and neonatal onset seizures. Yield will vary depending on included genes and precise analysis techniques, and it is important to contact individual diagnostic laboratories for further information. Yield can also be increased by a ‘trio’ approach whereby DNA from the affected child and both unaffected parents is analysed at the same time. If the test is non-diagnostic, individual laboratories may offer a reanalysis service after 1- 2 years, which can improve diagnostic yield by up to 20%.

  • Gene panels: result in a diagnosis for 20-30% of children with DEE.
  • Exome / whole genome sequencing: result in a diagnosis for 30-50% of children with DEE.


Sample requirements:

Important to check with individual genetic laboratories. Most labs require 5-10ml EDTA but some can provide saliva collection kits. 

Result turnaround:

typically, 2- 4 weeks.


Medicare funding for exome or genome sequencing commenced 1st May 2020. Currently, Medicare funding is limited to testing in the following clinical circumstances:


  1. The affected individual is 10 years old or younger and is strongly suspected of having a monogenic (single gene) condition, based on the presence of:

              - Global developmental delay or intellectual disability of at least moderate severity (as determined by a specialist paediatrician) 


              - Dysmorphic facial appearance and the presence of one or more major structural congenital anomalies.


  1. Is requested by a clinical geneticist or a specialist paediatrician in consultation with a clinical geneticist.  

It is recommended that the local clinical genetics team be contacted in order to discuss preferred local practice regarding genetics consultation.

There is currently scope under Medicare for exome/genome sequencing to be conducted once per lifetime, but that reanalysis of genomic data can be requested under Medicare for a maximum of two times per individual up to the age of 15 years. Reanalysis needs to be at least 18 months from the last genomic report.

There are provisions under the current Medicare funding for an exome to be performed for an individual alone (‘singleton’) analysis or in combination with both biological parents (‘trio’) analysis.

For further details, it is recommended that the clinician reviews the Medicare Benefit Scheme website and refers to item numbers 73358-73363.

Although it is anticipated many children with a suspected genetic epilepsy will be able to obtain genomic sequencing via Medicare funding, children not meeting these criteria should be discussed with the clinical genetics team on an individual basis. It is likely that Medicare criteria will be modified in the future as the evidence base for the benefit of genetic testing grows.

Pre-test counselling

Genetic testing options are complex and informed consent is mandatory. It is preferable that counselling is provided by a medical specialist or genetic counsellor. Diagnostic laboratories typically require a signed consent form to proceed with testing.  An information booklet should be provided to all families and these important points covered:

Potential outcomes of testing:

Potential outcomes are like those for chromosomal microarray. The test may:

  • Find a definitive cause of the condition.
  • Not find a cause that could explain the condition.
  • Find a result of ‘variant of unknown significance’ (VUS), which means that it cannot be understood today. Sometimes testing in other family members for the VUS may help to understand if it could be the cause of a condition. The understanding of VUS may change over time. Future testing may help clarify this
  • Detect an incidental finding. As this test looks at many genes at once, there is a small chance a variant may be found in a gene that is not related to the child’s epilepsy.  Such ‘incidental findings’ may be important to know for the child’s current or future health and/or the health of family members.

Other issues to be covered in a formal consent process include implications for insurance, sharing results with family members and data and sample sharing.


When to refer to Genetics

When to refer to Genetics services

You may wish to refer to genetics before or after genetic testing, in consultation with the managing neurologist. Some genetics services offer a phone consultation service.  A list of local genetics services is available here .

Pre-testing discussion points could include:
  • Questions regarding consent process/ appropriate forms
  • What test(s) to order.
  • Logistics of sample collection (refer to testing laboratory) and test ordering
Post-testing discussion points could include:
  • Test result: Variant of uncertain significance (VOUS): Referral to a genetics service may be initiated to help with interpretation of variants of uncertain significance, which may include the possibility of further segregation of the variant in the family or clinical research. Some laboratories/ genetics team also have the possibility of discussing the variant in a multidisciplinary team meeting.
  • Test result: (Likely) pathogenic finding variant.

A genetics consultation can help with provision of information regarding rare or very recently described genetic conditions, where there is a lack of easily available information.  This may not be needed for well-described conditions, such as SCN1A-related Dravet syndrome. A list of genetic epilepsy information sites is on the PENNSW family website page.

Genetic Counselling:  

For inheritance and recurrence risk, including discussion of reproductive screening/ testing if appropriate.

Test result: non diagnostic.

A referral to genetics team could consider if any further genetic testing would be helpful or possible, including any current options for genetic testing on a research basis. The genetics team can also discuss the possibility of future reanalysis of exome/ genome data if appropriate.

Test result: incidental finding.

A genetics team can discuss this result in consultation with the appropriate medical specialists.





Information last reviewed: 13/08/2020.



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