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GENETIC TESTING FOR TSC

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Molecular genetic testing is commercially available for many inherited diseases and tuberous sclerosis complex (TSC) can now be added to the list.  There are three primary uses for this genetic testing: (1) confirmation of diagnosis made on clinical grounds; (2) carrier testing for other at-risk family members; and (3) prenatal diagnosis.

Because TSC is different in how it affects each individual, sometimes a clear diagnosis cannot be made on clinical findings alone. For individuals that fall into this category, genetic testing may be considered so that a definite diagnosis can be made. Having the right diagnosis is important so that appropriate medical follow-up and screening can be conducted. In cases where it is difficult for an individual to go through imaging studies required for the clinical diagnosis, genetic testing may offer an easier solution.

Currently, there is one diagnostic laboratory that offers clinical genetic testing for TSC, Athena Diagnostics, that began offering genetic testing for TSC in October 2002.  There are other laboratories studying the TSC genes, but on a research basis. Athena Diagnostics’ clinical genetic test identifies approximately 80% of the mutations in samples that are submitted for testing from individuals who have a definite diagnosis of TSC based on accepted diagnostic criteria. In the other 20% of the cases, the mutation is a type of mutation not detectable by the methodology used by Athena.  This can happen when:

• The mutation in one of the TSC genes is a large gene deletion or insertion.  
• There is mosaicism for the mutation.  
• There is a mutation that we do not yet understand (i.e. potentially a mutation in a gene that we do not yet know causes TSC or a mutation in an area of the TSC1 or TSC2 gene that we do not understand as disease-causing).

For more information on the genetic diagnostic test for TSC, please visit Athena Diagnostics’ website at www.athenadiagnostics.com or call 1-866-AthenaDx (1-866-284-3623), ext. 2.

If my child or I already have a clinical diagnosis of TSC, why would I have a genetic test?

Genetic testing serves a number of purposes.  It allows the persons/parents to know which gene (TSC1 or TSC2) was mutated, or changed, to cause TSC.  While at this time we cannot tell someone what symptoms they may or may not develop based on their gene mutation, we do think that persons with TSC1 mutations have some milder symptoms than those individuals who have a mutation in the TSC2 gene.  Perhaps having this information may, in the future, enable doctors to predict symptoms of TSC that will and will not appear in an individual and will enable them to determine which tests (i.e. MRIs, ultrasounds, CT scans) are and are not necessary on an individual basis.

If a person with TSC has a known mutation, his or her family members, if they choose, can be quickly and easily tested to see if they have the TSC gene.  This is helpful in the case of testing newborns, for whom MRI and CT scans are difficult if not impossible, to perform. Some people decide to have genetic testing so their siblings or other family members, if they choose, can be tested to determine if they have TSC.  Some people use the knowledge from genetic testing to make life decisions (such as having
children) with a clear understanding of whether or not TSC can be passed on through their family, and if so, the amount of risk involved.  In some families, prenatal diagnosis or a variation on such testing, known as pre-implantation genetic diagnosis (PGD), is utilized to predict the TSC status during a pregnancy or even prior to conception.

What does it mean if I learn that I have a mutation in a TSC gene?

If a mutation or change is identified in your TSC1 or TSC2 gene, then you definitely have TSC. In most cases, this will not be a surprise, as most persons undergoing testing already had a diagnosis or suspected diagnosis.  If you have a mutation and show no symptoms of TSC, a specialist familiar with symptoms of TSC should refer you for genetic counseling regarding the result and possible further evaluation.

What does it mean if no mutation is found?

If a mutation is not found, it can mean a number of things, depending on who is being tested.  If a mutation is not found in a person with a definite clinical diagnosis of TSC, then that person is thought to have a mutation in either their TSC1 or TSC2 gene that is not readily identifiable by DNA test procedures currently utilized.  Future research is being conducted to develop methods to detect such mutations.  A negative result does not change the clinical diagnosis.

If a mutation is not found in a person whose diagnosis of TSC is uncertain, then the physician can consider other testing and/or diagnoses 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.  But, because approximately 1% of apparently sporadic cases of TSC are due to germ line mosaicism in one of the clinically unaffected parents, the parents should know that they 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.  The sibling would either have TSC or not have TSC; there is no "in between" like there is with parents of affected children.

What exactly is germ line mosaicism?

Germ line means those cells that can pass DNA from one generation to the next – in other words the eggs (oocytes) from a woman and the sperm from a man.  Germ line mosaicism means that the individual’s TSC genes are not all alike in either the oocytes or sperm.  What this could mean for an individual with TSC is that in only some of their oocytes or in some of their sperm is there a mutation in one of the TSC genes.  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.

What if my mutation cannot be identified?

If you have a clear clinical diagnosis of TSC and the DNA test does not identify a mutation, and then it is likely that your mutation is one of the hard to find mutations or is a new mutation not yet known to cause TSC (about 20% of all known mutations).

What is the price of the test and will my insurance cover it?

Athena Diagnostics is using the DNA sequencing technology to evaluate mutations in the TSC1 and TSC2 genes. Sequencing is considered to be the gold standard in evaluating genetic muta tions and offers the highest sensitivity (ability to identify a mutated gene) and specificity (ability to identify a normal gene). The TSC genetic test is expensive because they have to evaluate the entire length of both the TSC1 and TSC2 genes, and they are very large genes.

Payment for testing can also depend on the lab that does the blood draw and sends the sample to Athena; you can call Athena Client Services directly at 866 Athena Dx ext. 2 to ask for their help in finding a lab near you. In addition, Athena will be happy to work with individuals on a case-by-case basis to help them receive pre-authorizations, maximize reimbursement and help in cases of economic hardship. Athena does not bill Medicaid, but offers a discount of 50% to all individuals with Medicaid coverage.

What are the steps involved in having the test done?

Steps for the health care provider:  First your physician, geneticist or genetic counselor would write a prescription ordering the TSC genetic test. Ideally, they would also fill out Athena Diagnostics form requesting the test (this form can be found at www.athenadiagnostics.com or can be given to the ordering physician by requesting an Athena sales representative to stop by the office).  Athena provides postage-paid shipping kits to health care providers. These can be requested by calling Athena’s client services at 866 ATHENA DX ext. 2.

Steps for the individual being tested:  A small amount of blood is drawn (usually one or two tubes), and the blood is shipped to Athena Diagnostics by the laboratory performing the blood draw. 
 
 
When will I receive results?

Normally, results are available in 6-8 weeks.  As with most genetic tests, the person being tested and/or their parents/legal guardians should receive genetic counseling regarding the ramifications of the test and should give written consent to testing prior to submitting their blood samples.  Such counseling and consent documentation can be coordinated by your doctor's office.

How will I get my results back?

Normally, genetic test results are given to the physician or genetic counselor who ordered the test, who then gives them to the family.  Because genetic tests are complicated, and the interpretation of their results can be difficult (see above), testing should be undertaken only after receiving thorough genetic counseling regarding the process.  A genetic counselor can aid you throughout testing, from ensuring that you understand the benefits, risks and limitations of the testing, to coordinating the submission of blood samples to Athena, to accurately interpreting the test results for you and your family.  Many physicians do not understand the limitations to and complicated nature of genetic testing and may, inadvertently, misinterpret test results. If you receive results from someone other than a genetic counselor or physician trained in genetics, feel free to refer yourself to a genetic counselor.  Genetic counselors can be located by contacting the National Society of Genetic Counselors, 610-872-7608, http://www.nsgc.org or the TS Alliance at 800-225-6872.

By Aimee Tucker Williams, M.S., Certified Genetic Counselor, and Hope Northrup, M.D., Medical Geneticist
  
**Tuberous Sclerosis Alliance Information Sheets are intended to provide basic information about TSC. They are not intended to, nor do they, constitute medical or other advice. Readers are warned not to take any action with regard to medical treatment without first consulting a physician. The TS Alliance does not promote or recommend any treatment, therapy, institution or health care plan.

Made possible through an educational grant from the Schnurmacher Foundations.  June 2006