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Genetic Testing

Even though TSC (Tuberous Sclerosis Complex) is a genetic condition, genetic testing is not needed to diagnose the condition. Most people with TSC will have enough physical signs of the condition for a specialist to diagnose them with confidence – view the diagnostic criteria for TSC.

Testing the TSC1 and TSC2 genes will find a mutation in up to 90% of affected individuals. This is possibly because the current genetic testing techniques are not yet sensitive enough to pick up all the variations that can cause TSC. Recent research has led to the agreement that most, possibly all, of these individuals are mosaic at such a low level that standard genetic testing cannot pick up the mutation. More detailed testing is becoming increasingly available to detect such mutations in these individuals.

Genetic testing can however be helpful in some situations such as:
• When an individual is suspected to have TSC but does not have enough signs of the disease to meet the full diagnostic criteria and for a specialist to make a confident diagnosis, a genetic test may be useful to confirm or rule out TSC.
• Genetic testing may also be useful to be able to test for TSC in family members. This includes when a child in a family is diagnosed with TSC and the parents wish to have more children in the future. Siblings of an individual with TSC may also find genetic testing for TSC helpful in establishing whether or not they have TSC and in planning their families.
• Testing a baby in pregnancy (prenatal testing) or an embryo in an IVF setting (pre-implantation genetic testing) for TSC where one of the parents is affected by TSC.

Genetic testing may also be helpful in the future as new treatments for TSC may be specific to either the TSC1 or TSC2 gene.

Genetics and TSC

What Causes TSC and Surveillance Needs
Passing Down or Inheriting TSC
Genetic Testing

Having a genetic test

A small amount of blood is drawn (usually one or two tubes), and the blood is shipped to the laboratory performing the genetic testing by the laboratory performing the blood draw. Occasionally, genetic testing may be done in a sample other than blood.

Find out how to access genetic services in your area.

It is highly recommended that any genetic testing for TSC is done in the context of genetic counselling. Genetic counselling provides education, information and support.

Possible findings of genetic testing

TSC1 or TSC2 mutation

TSC1 is a gene on chromosome 9 and TSC2 is a gene on chromosome 16. Genetic testing for TSC looks for a mutation on one of these two genes. If one is found, you may be told that you have TSC due to either TSC1 or TSC2.

There has been a lot of research that looks at how the gene mutation may correlate with which signs and symptoms of TSC an individual has. These studies have shown that this is a complex relationship and knowing the gene mutation will not predict the number or severity of TSC symptoms in an individual.

These studies have shown differences when a group of people with a TSC1 mutation are compared to people with a TSC2 mutation. The group with a TSC2 mutation will, on average, be more severely affected by TSC. This includes a higher proportion with profound intellectual disability. However, both groups will contain some people who are mildly affected by TSC and some people who are more severely affected by TSC. This means we cannot predict the severity of TSC symptoms based on knowing whether an individual has a TSC1 or TSC2 mutation.

Research continues to better understand whether different mutations correlate with how an individual responds to treatment. It is possible that knowing an individual’s gene mutation may influence treatment choices in the future.

If your DNA test did not find a mutation

If a mutation is not found, it can mean different things depending on who is being tested.

If a mutation is not found in a person with a definitive clinical diagnosis of TSC, the negative result does not change the diagnosis.

This is because TSC can be diagnosed either by looking for the signs and symptoms of the disease or by finding a gene change in TSC1 or TSC2 that is known to cause TSC.

In up to 10% of cases when gene testing is done for a person with TSC, no disease-causing gene change is found. This likely means that that person has a mutation in either their TSC1 or TSC2 gene that is not readily identifiable by current tests. Usually, it is a mosaic change, and further genetic testing may be available to look for such a mutation. Please talk to your geneticist or genetic counsellor to see if such testing may be available and suitable for you. However, because the mutation has not been found:

  • it is not possible to test other family members’ blood to see if they have TSC. Instead, family members will need to be tested by looking for the clinical signs of TSC in their body
  • it is not possible to use pre-implantation genetic testing (PGT) or prenatal genetic testing.

If a mutation is not found in a person whose diagnosis of TSC is uncertain, then the doctor can consider other testing to better understand whether or not the person has TSC.

If a mutation is not found in an asymptomatic parent of an affected child, then that parent does not have TSC. Approximately 1% of apparently sporadic cases of TSC are due to gonadal mosaicism (see the definition below) in one of the clinically unaffected parents. These parents are still at risk, albeit a small one, of giving birth to another child with TSC. Genetic testing cannot rule out gonadal mosaicism.

If a mutation is not found in an asymptomatic sibling of an affected child, then they do not have TSC, nor are they at increased risk for being gonadal mosaics.

Gonadal mosaicism

The gonads are the organs that produce the cells that can pass DNA from one generation to the next – in other words the eggs from a woman and the sperm from a man. Gonadal mosaicism means that some sperm/ eggs have a mutated or changed copy of one of the TSC genes. In these cases, the parent with gonadal mosaicism does not have any symptoms of TSC, but can pass the mutated TSC gene on to some of their children.

Whenever parents of a child with TSC are tested for a known TSC gene change there are two possibilities. Most likely, their child’s TSC is a result of a new (spontaneous) mutation. Less likely is that one of the parents is mosaic for the mutation. Mosaicism is the reason that some parents who do not have TSC have more than one child with TSC. For parents who have one child with TSC who do not have TSC themselves, each additional child they conceive has a risk of having TSC of between 1-3%. This is one of the reasons it is important to seek genetic counselling when a child is diagnosed with TSC.

The cost of genetic testing

The cost to a patient of genetic testing for TSC varies. Genetic services are provided by each state, and each service has different criteria for determining if the cost of the test will be covered by the service or by the patient. Usually this is based on clinical need, so it is important to discuss with your geneticist or genetic counsellor the reasons for the genetic testing.

If the genetic service is not able to cover the costs of the test the costs can be quite high, particularly for testing looking for a TSC mutation for the first time in a family (diagnostic testing). This test involves sequencing the TSC1 and TSC2 genes and looking for mutations that may be causing TSC in that person. Genetic testing in a family member looking for a known family TSC mutation costs less than the initial diagnostic testing.

The costs of genetic testing are likely to reduce over time as testing technology improves.

Last updated: 13 October 2022

Reviewed by: Dr Clara Chung, Clinical Geneticist, Sydney Children’s Hospital, Dr Fiona McKenzie, Clinical Geneticist, Genetic Services of WA, Dr David Mowat, Clinical Geneticist, Sydney Children’s Hospital

1. Peron A, Au KS, Northrup H. Genetics, genomics, and genotype-phenotype correlations of TSC: Insights for clinical practice. Am J Med Genet C Semin Med Genet 2018; 178: 281–290.

2. Northrup H, Koenig MK, Pearson DA, et al. Tuberous Sclerosis Complex. 1999 Jul 13 [Updated 2021 Dec 9]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1220/

3. Giannikou K, Lasseter KD, Grevelink JM, Tyburczy ME, Dies KA et al. Low-level mosaicism in tuberous sclerosis complex: prevalence, clinical features, and risk of disease transmission. Genet Med 2019; 21: 2639–2643.

4. TSC Alliance, How is TSC diagnosed?, viewed 20th September 2022, https://www.tscalliance.org/about-tsc/how-is-tsc-diagnosed/

5. Centre for Genetics Education, Preimplantation genetic diagnosis, viewed 20th September 2022, https://www.genetics.edu.au/SitePages/Preimplantation-genetic-diagnosis.aspx

6. Centre for Genetics Education, Diagnostic tests during pregnancy, viewed 20th September 2022, https://www.genetics.edu.au/SitePages/Diagnostic-tests-during-pregnancy.aspx

Parts of this information have been adapted with permission from copyrighted content developed by the TSC Alliance (tscalliance.org)

There is a large amount of helpful information on the website of the Centre for Genetics Education