This test analyzes the TSC1 and TSC2 genes. Pathogenic variants in these genes are associated with tuberous sclerosis complex (TSC). Characteristics of TSC include benign tumors in the brain, kidneys, lungs, heart, and skin, as well as seizures, intellectual disability, and increased risk of brain and kidney cancer.
Many of the features of TSC are nonspecific, can occur as isolated findings, and can present as features of other conditions. Genetic testing may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.
TSC1 and TSC2 can also be ordered as part of a broader panel to test for different types of hereditary cancer conditions. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. Any of these broader panels can be ordered for no additional charge.
Tuberous sclerosis complex (TSC) is a highly variable condition whose features include numerous benign tumors of the skin, brain, kidneys, lungs, heart, and other organs. TSC can also cause mild-to-severe neurodevelopmental and behavioral impairments, often manifesting as autism spectrum disorder.
Most affected individuals develop non-malignant brain tumors that have malignant potential, specifically cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas; these are easily identified by neuroimaging. These lesions are often associated with seizures; TSC is a known cause of infantile spasm/hypsarrhythmia syndrome.
Renal tumors develop in most cases. While typically non-malignant, these tumors can lead to life-threatening renal disease. Such lesions include benign angiomyolipoma, epithelial cysts, and oncocytoma. Though uncommon, renal cancers associated with TSC include malignant angiomyolipoma and renal cell carcinoma.
Benign cardiac and pulmonary tumors are also features of TSC. Adult-onset lymphangiomyomatosis develop primarily in women. Cardiac rhabdomyomas, if present, are often seen on prenatal ultrasound and are largest in the neonatal period. These tumors regress and ultimately disappear; fortunately, surgical intervention is unnecessary in most cases.
Virtually everyone with TSC has one or more of the characteristic skin findings, which include hypopigmented (hypomelanotic) macules, shagreen patches, facial angiofibromas, fibrous facial plaques, and ungual fibromas.
Essentially all individuals with a disease-causing pathogenic variant in TSC1 or TSC2 will express the condition and manifest symptoms, often beginning in childhood. TSC is highly variable, though, and the signs and symptoms can vary significantly among affected individuals, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may benefit most patients who are found to have a pathogenic variant.
|Cancer type||Lifetime risk|
|Brain (subependymal giant cell astrocytomas)||6%-14%|
|Kidney (malignant angiomyolipoma, renal cell carcinoma)||2%-5%|
Pathogenic variants in TSC1 and TSC2 are identified in approximately 85% of individuals who meet the clinical diagnostic criteria for TSC.
Approximately one third of cases are inherited from an affected parent in an autosomal dominant pattern. The remainder are sporadic and occur as the result of a spontaneous de novo mutation.
The prevalence of TSC is approximately 1 in 6,000 individuals.
Analysis of the TSC1 and TSC2 genes may be considered in individuals with features including:
Clinical diagnostic criteria for tuberous sclerosis have also been proposed:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|