What is tuberous sclerosis?
Tuberous sclerosis, or tuberous sclerosis complex (TSC) is a rare, multisystem genetic disease that causes benign tumors to grow in the brain and other vital organs. The genetic disorder has an autosomal dominant pattern of inheritance (see figure) and a variable penetrance. TSC is caused by mutations in two genes, TSC1 and TSC2, which encode for the proteins hamartin and tuberine respectively. TSC1 is located on chromosome 9 and TSC2 on chromosome 16. Both genes are tumor suppressor genes that regulate cell proliferation and differentiation.
TSC is characterized by kidney problems, brain tumors, heart tumors, tumors in the eye and a variety of skin problems. In addition to the benign tumors, other common symptoms include seizures, mental retardation and behavior problems.
Since it is a disease that is caused by gene mutations, genetic testing can help identify the probability of developing the disorder. In this article, a combined tuberous sclerosis complex DNA sequencing test will be discussed, as well as a deletion/insertion analysis.
Genetic testing for TSC
Since the identification of the TSC1 and TSC2 genes, thousands of individuals have had disease-causing mutations identified. Roughly three quarters of the tested individuals had mutations in the TSC2 gene, while the remaining quarter had mutations in TSC1.
Genetic testing of both genes is complicated by the large size of the two genes, the large number of disease-causing mutations and the high rate of somatic mosaicism (which means that some cells carry the mutations, but other cells may not).
- Sequence analysis
Mutations of the TSC1 gene are usually small deletions, insertions and nonsense mutations that can be detected by a complex DNA sequencing test for combined tuberous sclerosis. TSC2 mutations include significant numbers of large deletions and rearrangements that can not be detected by sequence analysis. Several studies that aimed to identify the disease-causing mutation through sequence analysis, were able to do so in 70-80% of the cases.
- Deletion/duplication analysis
The most sensitive method to identify large gene deletions is multiple ligation-dependent probe amplification (MLPA). MLPA is a variation of the polymerase chain reaction that permits multiple targets to be amplified with only a single primer pair. Using this method, scientists have been able to identify large or whole-gene mutations in over a quarter of the families in which no mutation had been identified by sequence analysis.
- After the symptoms are recognized, the patient’s physician orders a sequence analysis. A small amount of blood is drawn and sent to the diagnostic laboratory.
- A combined tuberous sclerosis complex DNA sequencing test is performed for the TSC1 and TSC2 gene.
- After 6 to 8 weeks the results are sent to the physician, who contacts the patient to discuss the results.
- If the sequence analysis did not yield any results, a deletion/duplication analysis is performed.
- For at-risk asymptomatic family members, presymptomatic genetic testing is recommended after the identification of a disease-causing mutation in the family.
- After a disease-causing mutation is identified, prenatal diagnosis or preimplantation genetic diagnosis is recommend for at-risk pregnancies.
Notes on the interpretation of the results
- A negative result can mean that there is no mutation in the researched gene. However, it can also signify that the sequence alteration could not be detected either because it is not within the capacity of the analysis, or because the alteration is in a region of the gene that is not covered by the test.
- When the test does not reveal a mutation, DNA testing of other tissues is recommended because of the possibility of somatic mosaicism.
International list of laboratories who perform one or several of the aforementioned tests
- GeneReviews: Tuberous Sclerosis Complex: https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=tuberous-sclerosis
- National Institute of Neurological Disorder and Stroke: Tuberous Sclerosis Fact Sheet: https://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm
- Tuberous Sclerosis Alliance: https://www.tsalliance.org/documents/Genetic%20Testing%20for%20TSC.pdf