Genetics

Clinical geneticists are medical doctors that specialise in genetics and genetic diseases. Genetic counsellors are health professionals that are trained in both counselling and medical genetics. Genetic counselling is a process that can help the whole family understand how TSC is inherited and to make decisions about management and reproduction.

• At present it is impossible to predict who will remain only mildly affected and who will be more severely affected by TSC. Even members of the same family can be affected differently.
• There are two genes that are known to be associated with TSC. These are called TSC1 and TSC2. People with TSC – regardless of the severity of their symptoms – all have a variation in one of their TSC genes that makes it faulty.
• The pattern of inheritance of the faulty gene causing TSC is described as autosomal dominant inheritance.
• When a parent has a faulty TSC gene copy they have a 1 in 2 (50%) chance in each pregnancy of having a child with TSC.
• In about 30% of the cases, TSC is inherited from an affected parent. In the remaining 70% of cases, the person with TSC is the first in the family with the condition. This is likely to have occurred due to a change in one copy of a TSC gene during the formation of the egg or sperm, during conception or shortly after conception (a spontaneous mutation that occurred for unknown reasons).
• The diagnosis of TSC is based on clinical features and genetic testing is usually not required. However, genetic testing for changes in the TSC genes can be helpful in some situations, such as testing a baby in pregnancy for TSC where one of the parents is affected. It is highly recommended that testing be discussed in the context of genetic counselling.

Genes, chromosomes and genetic conditions

In all the cells of our body, our genes are found on chromosomes (long strings of genes). Most of our chromosomes (and therefore our genes) come in pairs – one of each copy from each parent. The only exception is the sex chromosomes, which determine whether we are male or female. We have many thousands of genes that provide information for our body to grow, develop and remain healthy. The gene sends messages to the cell to make important chemical products such as proteins.

Everyone has variations in the information in their genes, which is why we are all unique. Variations can either be harmless or at times, can cause a gene to be faulty. Variations that make a gene faulty are called mutations. The information contained in the faulty gene, and its product, is impaired (see Genetics Fact Sheet 4 & Fact Sheet 5).

Faulty genes do not work as they should in the body and are unable to provide the correct information to our cells. A fault in either of two different genes – one called TSC1 and one called TSC2 – can cause TSC. These genes make proteins that make sure cells only grow as fast as they need to. TSC1 has the instructions for creating a protein called hamartin and TSC2 has the instructions for a protein called tuberin. If these proteins are not being produced correctly, some cells grow in an uncontrolled way forming the tumours seen in people with TSC.

When we know that a person has TSC, we can look for the responsible gene change in the TSC1 and TSC2 genes. We find that a TSC2 gene change is found in about one quarter and a TSC1 gene change is found in about two-thirds of people with TSC. Current genetic testing technologies do not find a gene change responsible for TSC in all people with a diagnosis of TSC. For more information, see “What does it mean if my DNA test did not find a mutation?”

A faulty TSC gene can either be passed down (inherited) from a parent or may occur as a new faulty gene just before or after conception. Once a faulty gene is present in an individual’s egg or sperm cells, it can be passed on to future generations. This is referred to as genetic inheritance.

Two factors influence the pattern of inheritance of a faulty TSC gene.

1. The TSC genes are located on one of the numbered chromosomes (autosomes), not the sex chromosomes.
2. The effect of the faulty TSC gene is ‘dominant’ over the information in the working copy of the gene (see Genetics Fact Sheet 1, Fact Sheet 4 & Fact Sheet 5).

The pattern of inheritance in families of the faulty gene causing TSC is therefore described as autosomal dominant inheritance (see Genetics Fact Sheet 8).

In about 30% of the cases, TSC is inherited from an affected parent. When one of the parents has TSC due to the faulty TSC gene, there are four possible combinations of the genetic information that can be passed on to their children. This means that, in each pregnancy:

• There are 2 chances in 4 (1 chance in 2, or 50%) that their child will inherit the faulty TSC gene and will therefore be affected by TSC.
• There are 2 chances in 4 (1 chance in 2, or 50%) that their child will inherit the working TSC gene from the affected parent. In this case, the child will not develop TSC and cannot pass on the faulty TSC gene copy to any of their children.

While the picture shows the father as the parent with the faulty TSC gene copy, the same situation would arise if the mother had the faulty TSC gene copy. TSC usually affects men and women equally.

 

In approximately 70% of cases, the person with TSC is the first in the family with the condition. In these people, the condition resulted from a change that occurred in one copy of the TSC1 or TSC2 genes during formation of the egg or sperm, during conception or shortly after. These changes that make one of the TSC gene copies faulty are called ‘spontaneous mutations’. Spontaneous mutations are not caused by any action of the parents but arise by chance, as a new change.

Once a person has TSC s/he may potentially pass on the faulty gene copy to his/her children as described above.

If the TSC gene became faulty shortly after conception, not all of the baby’s cells may contain the gene variation; this individual is said to be ‘mosaic’ for the faulty TSC gene. They may experience milder symptoms because the faulty gene may not be present in all of the organs usually affected in TSC. The faulty gene might not be in all the egg or sperm cells of an individual with mosaic TSC. Their chance of passing on the faulty gene is therefore less than 50% (see Genetics Fact Sheet 13).

If a child of a parent who is mosaic for TSC inherits the faulty TSC gene copy, they may be more severely affected by TSC than their parent. This is because the child has the faulty gene in all the cells of their body, while their parent only has the faulty gene in some cells. That child also has a 50% risk of passing on the faulty gene copy to his or her children.

Because of the possibility that an unaffected parent of a child with TSC is mosaic for the faulty TSC gene, the chance of having another child affected by TSC is estimated between 1% and 3%. The chance that a spontaneous mutation in the TSC gene would happen again in further pregnancies is low.

TSC does not ‘skip generations’. However sometimes the features of the condition are so subtle that individuals do not realise they have TSC. This is the reason that the guidelines for people newly diagnosed with TSC are to review the newly diagnosed individual’s nearest three generations (siblings, parents, and either children or grandparents). An assessment by a skin specialist (dermatologist), eye doctor (ophthalmologist) and genetics doctor (clinical geneticist) may be useful in either confirming or ruling out that someone is affected with TSC.

Even though TSC 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

Genetic testing is available but is complex, time consuming and expensive. Testing the TSC1 and TSC2 genes will find a mutation in only about 80% of affected individuals. This is because there may be other genes that cause TSC that have not yet been identified. Alternatively, it is also possible that current genetic testing techniques are not yet sensitive enough to pick up all the variations that can cause TSC.

Genetic testing can however be helpful in some situations such as:

• Confirming a possible diagnosis of TSC where there aren’t enough clinical features for a specialist to make a confident diagnosis.
• Testing a baby in pregnancy (prenatal testing) or an embryo in IVF (pre-implantation genetic diagnosis) for TSC where one of the parents is affected (see Genetics Fact Sheet 17 & Fact Sheet 18)
• Testing parents, sisters or brothers of someone with TSC to establish whether or not they have 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.

It is highly recommended that testing be discussed in the context of genetic counselling.

Prepared by: A/Prof Kristine Barlow-Stewart & Ron Fleischer, The Centre for Genetics Education; Clare Stuart, Tuberous Sclerosis Australia. This page has been adapted from the Genetics Fact Sheet that has been co-authored by Tuberous Sclerosis Australia and The Centre for Genetics Education.

2017 revision by Genetic Counselling student Todor Arsov.

References:

1. Kwiatkowski D.J., Whittemore V.H. & Thiele E.A. (2010) Tuberous Sclerosis Complex: Genes, Clinical Features, and Therapeutics. Weinheim: Wiley-Blackwell
2. Northrup H, Koenig MK, Au KS. Tuberous Sclerosis Complex. 1999 Jul 13 [Updated 2011 Nov 23]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. (Accessed April 2012)

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

In 10-30% 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. It is also possible that 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 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 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.

Whenever parents of a child with TSC are tested for a 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 a germ line mosaic for the mutation. Germ line mosaicism is the reasons 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 between 1-3%. This is one of the reasons it is important to seek genetic counselling when a child is diagnosed with TSC.

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.

Last updated: 14 December 2021

Prepared by: Clare Stuart, Tuberous Sclerosis Australia. 2017 revision by Genetic Counselling student Todor Arsov. Updated by: Kim Kerin-Ayres, Tuberous Sclerosis Australia

Original page 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
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.