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Genetic testing for tuberous sclerosis complex (TSC) has been routinely available for some time now and has already helped many families receive their or their child’s diagnosis of TSC. However, genetic testing cannot always give you a “yes or no” answer about a TSC diagnosis. The following explains some of the limitations of genetic testing, and the most common reason for an “inconclusive” or uncertain test result.

Genetic testing for TSC, at this time, is able to detect mutations in the TSC1 or TSC2 genes in 75-90% of individuals who have a definite diagnosis of TSC based on clinical criteria. Detection rates vary based on different studies that have been performed. Unfortunately, at this time, we cannot find a causative gene mutation for between 10 and 25% of TSC patients who have a definite clinical diagnosis of TSC. For some of these patients, the testing is inconclusive.

Q: What does this mean for you or your child?

If your or your child’s TSC genetic test indicates that a TSC mutation was found, then you have the answer that the gene test was looking for! But, what if you are in the inconclusive or negative result group? The implications of an inconclusive or negative result mean different things, depending on whether you or your child has a definite clinical diagnosis of TSC.

If you/your child has a definite diagnosis of TSC: An inconclusive or negative genetic test result does not change that diagnosis; you or your child still has TSC. The diagnosis made by your doctor based on symptoms and features of TSC will not be changed by your genetic test result. If the test is inconclusive, there may be more testing options available to you. See the section below entitled “The test was inconclusive, now what?”

If you/your child does not have a definite diagnosis of TSC: Sometimes an individual has some features of TSC but does not have enough of them to make a definite diagnosis of TSC. If genetic testing identifies a TSC mutation, then the diagnosis is definite, giving you some more information about your or your child’s health. But what if the test result is inconclusive or negative? If it is inconclusive, one more step can usually be taken to clarify the test results (see “The test was inconclusive, now what?”). If the test result was negative, there may still be a chance that you or your child has TSC.

You should discuss this chance with the doctor and ensure that further clinical testing and care is offered in accordance with published guidelines for TSC diagnosis and evaluation.

Remember, even if the genetic test is negative, you or your child may still have TSC!

Q: The test was inconclusive, now what?

Inconclusive genetic test results may indicate one of the following possibilities:

  1. The laboratory was unable to examine every section of both TSC genes.
  2. The laboratory found a change in one of the TSC genes, but cannot predict whether that change is causing symptoms of TSC.

If possibility #1 is the reason for your inconclusive result, you should speak with the physician or genetic counselor that sent your genetic test and arrange to have another blood sample sent to the testing laboratory, if needed.

The more complicated possibility is #2; this is likely a common occurrence that can be difficult to explain and understand. The most likely explanation for this inconclusive result is the detection of a very small change in a TSC gene that has not been seen before in other families. Before we explain these small changes, we need to review the TSC genes, gene mutations and genetic testing.

TSC genes, gene mutations and genetic testing: The purpose of doing a genetic test for TSC is to look at the two genes that can have changes, or mutations, in them that cause TSC. One gene is called TSC1; the other is called TSC2. What a genetic test does, essentially, is look for a “spelling error” in one of these genes that causes it to be “read” incorrectly by the body. It is important that the genes are read and understood the right way for the body and its organs to grow and function normally. If a TSC gene (one or the other) has a mutation, or “spelling error” in it, it is not read correctly and causes TSC.

If the genetic test reads the two TSC genes and finds one of these “spelling errors,” often we know that the error is a mutation and that it causes TSC. For example, if a sentence in a book should read “Grey is my favorite color” but instead reads “Gryi sm yf avoritec olor,” then we know that the deletion, or removal of the E in the first word, leads to a sentence that is misread altogether. A gene mutation (a deletion mutation in particular) works the same way.

Q: What are the very small changes?

Sometimes, the TSC gene has a “spelling error” that may or may not affect the gene (it’s not always possible for us to tell). Using the example above, if the sentence is supposed to have read “Grey is my favorite color” and instead reads “Gray is my favorite color,” the sentence still makes sense even though one of the letters in the sentence changed (the E changed to an A). In genes, a change like this one can either represent a polymorphism or a mutation. If the change happens, but the gene is still read the right way, then we know that the change is a polymorphism, or a benign, normal change in the gene that does not cause a disease. If the change happens and it does affect the way the gene is read, then we call the change a mutation, and we determine that it is the cause for the disease.

With TSC, genetic testing often finds one of these “polymorphism versus mutation” changes described above. Because researchers still don’t know enough about how the TSC genes are “read” by the body, they can’t always tell whether the change is benign or causes TSC. In such cases, they have to resort to further testing (usually of the parents of the person with TSC) in an attempt to determine which type of gene change it is!

Q: Is it a polymorphism or a mutation?

The most straightforward way to tell whether a small gene change is a polymorphism or a mutation is to test the parents of the person with TSC. Please note that this option only works when the parents themselves have no signs or symptoms of TSC. If the parents have TSC too, then further testing options may be available and involve special testing on a number of your family members, both with and without TSC. Such testing is too complicated to describe here and should be discussed with your physician or genetic counselor.

Q: If neither parent has any signs of TSC, what does testing them tell you?

Geneticists know that polymorphisms “run” in families, passed down from parent to child, and that they generally do not cause any health problems for the people who have them.

In fact, we all carry polymorphisms in many of our genes and don’t even know it because they don’t cause any health-related problems for us! It stands to reason that if a person has a TSC gene polymorphism (versus a mutation), then he/she must have inherited it from one of his/her parents. We also know that if a parent, who does not have TSC, passes a polymorphism on to their child, it cannot cause TSC in their child (because it doesn’t cause TSC in the parent). We can use that fact to determine if a change detected by genetic testing is a polymorphism or mutation.

Consider the following scenarios:

1. A child with TSC has an inconclusive genetic test result. Neither parent has any signs of TSC, but ONE OF THEM has the same change in their gene that the child does.

Because that parent has the gene change found by genetic testing, but does not have TSC, we know for a fact that that change does not cause TSC and is therefore a polymorphism, found in both the parent and their child. This child likely has another, unidentifiable gene change that caused the TSC symptoms.

And, conversely:

2. A child with TSC has an inconclusive genetic test result. Neither parent has any signs of TSC and neither of them has the same change in their gene that their child does. We now know two very important facts: a) the child did not inherit their gene change from either parent, so it happened as a new change in the child; and b) that child also has features of TSC. It stands to reason that if both of these things (the change and TSC) happened in the child at the same time, then gene change probably caused TSC.

As you can see from the scenarios above, testing the unaffected parents of a person with TSC can often change an inconclusive genetic test result to either a negative (no mutation found) or a positive (mutation found) test result.

Frequently Asked Questions

Q: My child, who has TSC, was determined to have an inconclusive genetic test result because they found a gene change of uncertain significance. I was tested and found to have the same change. I have never had any signs of TSC, and had a thorough evaluation after my child was diagnosed. Does this mean that I am going to develop TSC?

A: No, you most likely carry a polymorphism in your TSC gene. This polymorphism is probably a benign or normal change in your TSC gene and is not expected to cause TSC symptoms. In fact, you would have never known you had it if you hadn’t undergone testing to help interpret your child’s genetic test result. If your child only has that polymorphism in his/her TSC gene and did not have any other gene changes, then he/she may have another unidentifiable gene change that is causing his/her symptoms of TSC. It is very important that you discuss this question with your doctor, however, to ensure that you have had all testing need to rule out any chance that you have features of TSC and just don’t know it.

Q: I have many features of TSC and was given a definite diagnosis of TSC by my doctor. I later decided to have genetic testing for my TSC mutation, but a mutation was not found! Does this mean that my doctor gave me the wrong diagnosis? Do I really have TSC?

A: If you have signs/symptoms of TSC and have been evaluated and diagnosed with TSC by a physician familiar with this condition, then your genetic test result does not change that diagnosis. In this case, you still have TSC, but are one of the 10-25% of individuals who have a gene mutation that is unidentifiable.

Q: My child has seizures and three white spots (hypopigmented macules). Her doctor ordered TSC genetic testing and it came back negative (no TSC changes identified). What does this mean?

A: Unfortunately, the genetic test did not give you any more information that you had before testing. She may not have TSC and just happens to have two features of this condition by chance alone, or she may have TSC, and possibly has a milder case of the condition.

Because approximately 10-25% of people with TSC will have a negative genetic test result, a negative result in a person with an uncertain diagnosis does not rule TSC out completely.

Q: What do I do in this case?

A: Your best option is to discuss further testing possibilities with your child’s doctor. The doctor may want to perform further physical examinations or testing such as ultrasonography, MRI or CT scans (if not already done). If you have questions about TSC that your doctor cannot answer, you can refer him/her to the TS Alliance for written information and guidance about TSC evaluations and diagnoses. Sometimes it is helpful to receive a second opinion from another physician, particularly if that physician has worked with many TSC families in the past. Sometimes, the best option is to wait until your child gets a little older and have them evaluated for TSC again. This option should also be discussed with your daughter’s physician.

Q: Where can I get more information about the diagnosis and management of TSC?

A: Contact the TS Alliance at (800) 225-6872. We offer literature for use by anyone with TSC and their physicians explaining TSC, its diagnosis, genetic testing and care and treatment options. If you are interested in genetic testing for TSC, speak with your or your child’s physician to request a referral to a geneticist or search for a genetic counselor in your area via the search tool at the National Society of Genetic Counselors website located at

Written by Aimee Tucker Williams, M.S., Certified Genetic Counselor, and Hope Northrup, M.D., Medical Geneticist

Updated by Laura Farach, M.D., Medical Geneticist and Hope Northrup, M.D. Medical Geneticist (August 2013)

**This information from the Tuberous Sclerosis Alliance is intended to provide basic information about tuberous sclerosis complex (TSC). It is not intended to, nor does it, constitute medical or other advice. Readers are warned not to take any action with regard to medical treatment without first consulting a health care provider.  The TS Alliance does not promote or recommend any treatment, therapy, institution or health care plan.

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