How is TSC Diagnosed?

In 2021, the International Tuberous Sclerosis Complex Consensus Group reviewed prevalence and specificity of TSC-associated clinical manifestations and updated the TSC diagnostic criteria published in 2013. Clinical features of TSC and genetic testing provide two ways of obtaining a diagnosis of TSC.

The clinical and genetic diagnostic criteria of 2021 are summarized below:

More About the Genetics of TSC

Genes are the biochemical instructions found inside the cell, not unlike the programs found inside computers.  Human beings have 22 pairs of chromosomes, as well as a pair of sex chromosomes. Females have two X chromosomes and males have an X and a Y chromosome. Our genes come in pairs, with one copy inherited from the mother and the other from the father. All people have variations in their genes – some of which cause diseases and others increase risk for developing some diseases, and some variations cause no problems at all. Some of these variations have been passed down from one parent, and some variations are unique to individual human beings.

TSC is caused by a change or variation (called a pathogenic variant when it causes disease) in either the TSC1 gene on chromosome 9 or the TSC2 gene on chromosome 16. TSC is an autosomal dominant genetic disorder. This means an individual with TSC has a pathogenic variant in one copy of either of the TSC genes that then causes the disease. Many genetic disorders such as TSC can be sporadic, meaning the disorder has not previously occurred in that family. Such sporadic occurrences are the result of a new genetic mutation and account for approximately two-thirds of all cases of TSC. The remaining one-third of cases are the result of a TSC gene containing a pathogenic variant being passed along (inherited) from either the mother or the father to their child.

Individuals with TSC have a 50% chance of passing their condition on to each of their children. If parents are unaffected, the chance of a sibling of someone diagnosed with TSC also having TSC is approximately 1% to 2%. The ability to differentiate between an inherited and sporadic occurrence of TSC sometimes relies on a thorough evaluation of the family members of the individual with TSC. This may involve evaluation of the parents, as well as some or all siblings.

There are no known cases of an individual having a pathogenic variant in both genes, and TSC does not skip a generation. It is possible for a member of the family to have such a mild case of TSC as to seem unaffected. At this point, the severity or risk of specific TSC features cannot be predicted by knowing an individual’s genetic mutation.

Significant progress in understanding the function(s) of the TSC genes has led to clinical trials testing medications for their ability to stop tumor growth and to impact the neurologic features of TSC, including seizures and cognition. The TSC genes work together as a complex in a specific signaling pathway in cells that regulate cell growth. Ongoing basic and clinical research are moving rapidly forward, hopefully to the day when the symptoms of TSC can be prevented.

Genetic Testing of TSC

Genetic testing allows individuals with TSC, family members and healthcare providers to know exactly what pathogenic variant in either the TSC1 or TSC2 gene caused TSC. This information may be helpful for a number of reasons. In some cases, the identification of a TSC1 or TSC2 pathogenic variant will facilitate a definite genetic diagnosis of TSC in an individual who has not yet developed enough symptoms for a clinical diagnosis. In approximately 15% of individuals with TSC, no pathogenic variant is identified in either TSC1 or TSC2. While a negative DNA test result cannot rule out a diagnosis of TSC, a positive result confirms the diagnosis.  In other cases, an individual may have a definite diagnosis of TSC, and family members may wish to know their own genetic status without undergoing extensive clinical evaluations. Upon identifying the TSC mutation in the individual with a definite diagnosis of TSC, any other family member can be easily tested to determine whether he or she is also affected. In addition, the identification of a pathogenic variant makes reproductive decision making possible.

Read more about reproductive decision making, prenatal diagnosis and preimplantation genetic diagnosis.

Despite advancing knowledge about TSC variants, it is not possible to predict the severity of symptoms in a person with a new diagnosis of TSC. A person can have TSC and have very few or mild symptoms, while a family member with TSC can have more severe or extensive symptoms. It is thought, however, that most people who have a TSC pathogenic variant will have some signs or symptoms if examined carefully by a physician familiar with the diagnosis of TSC. The distinction between sporadic TSC and familial (or inherited) TSC is important, as it affects the risk that other persons in the family are affected. Therefore, immediate family members of a person newly diagnosed with TSC should be thoroughly examined.

Another factor that complicates the genetics of TSC is germline mosaicism. Germline mosaicism occurs when an individual has cells in his or her germline (egg or sperm cells) that carry a pathogenic variant, cells in other parts of the body do not.  While quite rare, individuals with germline mosaicism may have one or more children with TSC but not have any clinical symptoms of TSC.

Given the complicated nature of TSC genetics, all families who have an affected relative with TSC should receive a referral to a genetic counselor or geneticist to discuss their unique genetic risk to either have TSC or to have a child with TSC.