Tuberous sclerosis: 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 couselling is a process that can help the whole family understand how TSC is inhetited 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.
What causes Tuberous Sclerosis Complex (TSC)?
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. If these proteins are not being produced correctly, some cells grow in an uncontrolled way forming the tumours seen in people with TSC.
What is the pattern of inheritance in TSC families?
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.
- The TSC genes are located on one of the numbered chromosomes (autosomes), not the sex chromosomes.
- 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 9).
When a parent has TSC
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.
Figure 1: Autosomal dominant inheritance when one parent has a faulty copy of one TSC gene. The faulty TSC gene copy is represented by ‘D’; the working copy by ‘d’
When neither parent has TSC but they have a child with the condition
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 earlier.
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 2%. 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. 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.
Can a person have a test for a faulty TSC gene?
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.
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 17C & 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 (see Genetics Fact Sheet 3).
Prepared by: A/Prof Kristine Barlow-Stewart & Ron Fleischer, The Centre for Genetics Education; Clare Stuart, The Australasian Tuberous Sclerosis Society. This page has been adapted from the Genetics Fact Sheet that has been co-authored by The Australasian Tuberous Sclerosis Society and The Centre for Genetics Education.
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. GeneReviewsâ„¢ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. (Accessed April 2012)