Genetic Testing in TSC: Frequently Asked Questions

Genetic testing is not required in every individual with TSC. However it may be helpful in a number of situations.

When an individual is suspected to have TSC but does not have enough signs of the disease to meet the full diagnostic criteria, a genetic test may be useful to confirm or rule out TSC.

The 2012 revision of the diagnostic criteria for TSC included genetic testing criteria for the first time. This means tha it may be possible to diagnose TSC if a mutation is found on the TSC1 or TSC2 gene that is known to cause TSC in other individuals. Read more about diagnostic criteria for TSC.

Genetic testing may also be useful 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 planning their families.

When an individual with TSC wishes to plan for their own family, genetic testing may allow them to use prenatal testing to avoid passing on TSC to their children.

There is more information about these situations later in this article.

Tuberous Sclerosis is caused by a mutation on one of two genes. 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 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 the 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 is being done to understand whether different mutations correlate with how an individual responds to treatments. Knowing an individual’s gene mutation may influence treatment choices in the future.

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. It means that that person has a mutation in either their TSC1 or TSC2 gene that is not readily identifiable by current DNA tests, or they have a change in another gene not yet known to cause TSC. Future research is being conducted to develop methods to detect such mutations. However, because the mutation has not been found:

• it is not possible to test other famiiy 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 diagnosis (PGD) or pre-natal 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 germ line mosaicism in one of the clinically unaffected parents. These parents are still at a risk, albeit a small one, to have another child with TSC. Genetic testing cannot rule out germ line 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 germ line mosaics.

Germ line means those 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. Germ line mosaicism means that some sperm/ eggs have a mutated or changed copy of the TSC gene. In these cases, the parent with germ line mosaicism does not have any symptoms of TSC, but can pass the mutated TSC gene on to some of their children.

A person diagnosed with TSC has a 50% chance of passing on their TSC gene mutation to any child they have. A child that inherits their gene mutation may be more or less severely affected by TSC than their parent.

A geneticist or a genetic counsellor can be very helpful in helping an individual and their family understand their options and make decisions about having children and prenatal testing.

If a person with TSC wishes to avoid passing on their TSC gene change to their children, there are several options available. The main options are:

1. Preimplantation genetic diagnosis (PGD) is a specialised type of treatment offered by IVF (in vitro fertilisation) services. It involves testing for certain genetic conditions in an embryo prior to transferring it to the uterus to establish a pregnancy. Only embryos without the specific genetic condition that was tested for will be transferred.
2. Genetic diagnosis through pre-natal genetic testing. The two tests most commonly used are Chorionic Villus Sampling (CVS) and Amniocentesis. Each test has its advantages, disadvantages and limitations which must be discussed when deciding if a test is to be done and if so, which test is preferred.

NIPT is a test that uses a sample of the mother’s blood during pregnancy to determine if the developing baby has certain chromosome conditions that can affect health and development.

During pregnancy, some of the DNA from the baby (fetal DNA) crosses in to the mother’s bloodstream. This DNA carries the baby’s genetic information. It is this fetal DNA that is tested and analysed during NIPT.

Currently in Australia NIPT is available through some specialists to test for chromosome conditions in high risk situations. It may be available in the future as another option for prenatal genetic diagnosis of TSC.

Only a person with TSC is at risk of passing on TSC to their children. So it is important for you to know whether you carry a TSC mutation and therefore have TSC yourself. This may be the case even if you show no or few signs of TSC. If the mutation of your TSC affected sibling has been found then your blood can be tested to see if you carry the same mutation.

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.

Genetic testing for TSC is best done in the context of genetic counselling. Genetic counselling provides education, information and support.

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 criteria 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. Genetic testing that is looking for a TSC mutation for the first time in a family can cost up to $5,000. This test involves sequencing the TSC1 and TSC2 genes and looking for mutations that may be causing TSC in that person. Genetic testing that is looking for a TSC mutation in a family member when the mutation of a person with TSC has already been found can cost up to $1000.

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

Prepared by: Clare Stuart, The Australasian Tuberous Sclerosis Society.

Reviewed by: Ms Jacqui Robinson, Genetic Counsellor, Sydney Children’s Hospital

Family review provided by: Linda Cameron, Tony Chigioni, Sally Dewhurst

References:

1. Genetic Testing for TSC, Tuberous Sclerosis Alliance, viewed 16th February 2014, https://tsalliance.org/pages.aspx?content=588
2. Prenatal Testing Overview, Centre for Genetics Education, viewed 16th February 2014, https://www.genetics.edu.au/Publications-and-Resources/Genetics-Fact-Sheets/prenatal-testing-overview
3. Au, Kit S., Northrup, H., Genotype-Phenotype Studies in TSC and Molecular Diagnostics, in Tuberous Sclerosis Complex: Genes, Clinical Features and Therapeutics, D.J. Kwaitowski, V.H. Whittemore, and E.A. Thiele, Editors. 2010.