Gene test interpretation: TSC1 and TSC2 (tuberous sclerosis complex genes)

INTRODUCTION — TSC1 and TSC2 are disease genes for tuberous sclerosis complex (TSC), a neurocutaneous disorder in which hamartomas and other benign tumors form in many organs including brain, skin, and kidneys. Neurological manifestations including autism, intellectual disability, and epilepsy are also common. (See 'Overview of tuberous sclerosis complex' below.)

This monograph summarizes the interpretation of genetic testing of TSC1 and TSC2. Evaluation and management of TSC are discussed separately [1]. (See 'Resources' below.)

How to read the report — Considerations are summarized in the table (table 1). These include the importance of viewing the actual report, checking qualifications of the testing laboratory, determining which gene(s) and which variants were tested, and reviewing the testing method. Considerations specific to TSC1 and TSC2 are noted below. (See 'TSC1 and TSC2 genes' below.)

Testing for clinical care should be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (or other nationally certified laboratory). If the results would impact clinical decision-making and the original testing was not from a CLIA-certified laboratory, it should be repeated. This applies both to positive results and to negative results in an individual considered to be at risk.

Terms that may be used in the report are summarized in the table (table 2). An extensive glossary is also available. (See "Genetics: Glossary of terms".)

TSC1 and TSC2 genes — TSC1 and TSC2 are the main disease genes responsible for TSC. They act as tumor suppressors. Individuals with TSC are heterozygous for a pathogenic variant on one allele of the affected gene, and a second hit (somatic loss of the normal allele) results in complete loss of protein function and eventually tumor development.

The mechanism of hamartoma formation is thought to involve deregulated entry into the cell cycle caused by increased activity of the mTOR protein kinase. This occurs due to increased activity of the mTORC1 complex, which controls protein synthesis, the G1-S cell cycle transition, and cell proliferation in response to nutrient availability and redox changes.

●TSC2 encodes tuberin, a GTPase-activating protein that regulates the mTORC1 complex.

●TSC1 encodes hamartin, a protein chaperone that stabilizes tuberin and prevents its degradation.

Increased activity of mTOR leads to deregulated entry into the cell cycle. Inhibition of mTOR with mTOR inhibitors such as rapamycin can treat many of the manifestations of TSC.

Approximately one-third of TSC cases are inherited and two-thirds (approximately 70 percent) arise de novo (see 'Inheritance' below). Inherited cases are divided equally between TSC1 and TSC2 variants; for de novo cases, four-fifths are due to TSC2 variants. Thus, overall, approximately 30 percent of individuals with TSC have a pathogenic variant in TSC1 and 70 percent have a pathogenic variant in TSC2. TSC2 variants are generally thought to be associated with more severe disease, but this is not always the case.

Implications for TSC1 and TSC2 genetic testing include the following:

●Diagnosis in an individual not previously suspected of having TSC.

●Confirmation of suspected TSC in a person meeting one major or two minor criteria (especially helpful prenatally [fetus with rhabdomyoma] and in infants and young children too young to fulfill criteria).

●Increased ease of evaluating parents and siblings using testing for a known familial variant.

●Preconception counseling and planning, which may include preimplantation genetic testing (PGT) or chorionic villus sampling or amniocentesis during pregnancy.

●Possibility of diagnosing combined TSC and polycystic kidney disease (PKD). The TSC2 gene is physically adjacent to the PKD gene PKD1, and some individuals have a contiguous deletion including both genes. (See "Renal manifestations of tuberous sclerosis complex", section on 'TSC2/PKD1 contiguous gene syndrome'.)

●Possibility of obtaining prognostic information via genotype-phenotype correlations.

●Possibility of identifying somatic or gonadal mosaicism (germline gene variant in some tissues but not others). (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Mosaicism'.)

OVERVIEW OF TUBEROUS SCLEROSIS COMPLEX

Inheritance — Inheritance of TSC is autosomal dominant and can be inherited from a parent. However, two-thirds (approximately 70 percent) of individuals with TSC appear to have a de novo mutation. (See 'TSC1 and TSC2 genes' above.)

Penetrance is complete (all individuals with a pathogenic variant in TSC1 or TSC2 will manifest features of TSC), but expressivity is highly variable; the specific manifestations, including disease severity and affected organs, can differ widely, even in individuals from the same family with the same pathogenic variant. These concepts and mechanisms are explained separately. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Penetrance and expressivity'.)

The incidence of TSC at birth is approximately 1 in 6000 to 1 in 10,000; prevalence declines with age due to early mortality in severely affected individuals [2].

Clinical features — Different organ manifestations predominate at different stages of life, which has implications for the timing of surveillance and interventions:

●Heart – The most common presenting feature in infancy is intracardiac rhabdomyoma (60 percent) [3]. This may be diagnosed prenatally by fetal ultrasound, which may diagnose 35 percent of cases prenatally. Cardiac rhabdomyomas tend to regress over time.

●Neurologic – Seizures are the presenting sign in up to 15 percent of infants [3]. Seizure activity may present as infantile spasms, focal seizures, or generalized seizures. Seizure prevalence is as high as 90 percent. (See "Tuberous sclerosis complex: Clinical features".)

Over 90 percent of infants will have structural brain changes including cortical tubers and subependymal nodules (SEN). These lesions are most likely to develop during active brain remodeling. SEN will grow to become subependymal giant cell astrocytomas (SEGAs; also called subependymal giant cell tumors [SGCTs]) in approximately 25 percent of individuals. SEGAs are rarely present in infancy [3].

Other neurologic manifestations include developmental delay, learning difficulty, autism, and behavioral problems.

●Kidney – Tumors in the kidney (hamartomas, angiomyolipomas [also benign]) tend to grow with age. They can compress normal tissues and/or bleed extensively, which can cause kidney failure. Kidney cysts may also be noted, and some individuals with variants in TSC2 can have polycystic kidney disease (PKD). (See 'TSC1 and TSC2 genes' above and "Renal manifestations of tuberous sclerosis complex".)

●Skin – Skin lesions include ash leaf spots or hypomelanotic macules (which can be seen anywhere on the body, including in the hair), angiofibromas (typically on the face), fibrous plaques (typically on the forehead), shagreen patches (typically on the lower back), and ungual fibromas (in the nail bed). Hypomelanotic macules are the presenting feature in approximately 40 percent of patients and may require a Wood's lamp for identification [3]. Other dermatologic findings may develop or progress over time. (See "The genodermatoses: An overview", section on 'Tuberous sclerosis complex'.)

Some individuals are diagnosed later in adulthood with minimal clinical findings, often after the birth of an affected child to two seemingly unaffected parents.

Evaluation — Diagnostic criteria (table 3) were updated in a 2021 consensus conference [4].

Individuals with possible TSC based on suggestive clinical findings and/or an affected first-degree relative should be evaluated as early as possible. Early diagnosis may facilitate interventions to reduce complications, especially for young children who are at the greatest risk for seizures. Those with an affected first-degree relative require an evaluation even if clinical manifestations are not obvious. An approach to testing first-degree relatives is summarized in the algorithm (algorithm 1).

●Known familial variant – If a familial pathogenic or likely pathogenic variant is known, testing can be restricted to that variant.

•Family members who test positive for the variant have TSC and should be evaluated as soon as possible (table 4). Infants under five or six months may be able to undergo brain magnetic resonance imaging (MRI) without general anesthesia; older children may require anesthesia for MRI.

•Family members who test negative for the variant can be reassured that they do not have TSC, provided testing was accurate (see 'How to read the report' above). This allows the individual to avoid the costs and burdens of extensive evaluations.

●Familial variant unknown – If a familial variant is not known, genetic testing and clinical evaluations (table 4) can be performed. Either may confirm the diagnosis if positive; if both are negative, the diagnosis is excluded.

Genetic testing can be used to confirm the diagnosis and to assist in testing and counseling of first-degree relatives.

●Pathogenic variant – Individuals with a pathogenic or likely pathogenic variant in TSC1 or TSC2 meet criteria for TSC, provided testing was performed correctly, and they should be evaluated and monitored according to accepted clinical guidelines. This applies regardless of the reason for testing (expected or unexpected finding). (See 'Management' below.)

●VUS – Individuals with a variant of uncertain significance (VUS) in TSC1 or TSC2 should be managed based on their clinical history.

●Negative result – Individuals for whom a pathogenic variant is not identified (including those with a benign or likely benign variant) are managed based on their clinical history. If a pathogenic or likely pathogenic familial variant is known and the individual tests negative for that variant, they can be reassured that they are unaffected. If clinical features of TSC are present, the individual should be managed based on the clinical diagnosis; inability to document a disease variant does not affect their management. Consultation with a genetics expert may help determine if further testing could clarify the diagnosis or assist with evaluations of relatives. (See 'Resources' below.)

Management — Individuals with TSC should be managed by (or in consultation with) a multidisciplinary team with expertise in TSC.

The table lists the age to initiate evaluations and surveillance monitoring intervals (table 4) [5].

The following illustrates the scope of management implications:

●Education

•Anticipatory education about infantile spasms and seizures, including how to recognize them and what to do if they occur. (See "Infantile epileptic spasms syndrome: Clinical features and diagnosis".)

•Genetic counseling; testing and counseling of first-degree relatives. (See 'Inheritance' above.)

•Support resources. (See 'Resources' below.)

●Surveillance (intervals listed in the table (table 4))

•Examinations

-Checklist for TSC-associated neuropsychiatric disorder (TAND)

-Blood pressure

-Ophthalmologic, dental, and skin examinations

•Imaging

-Brain MRI (non-contrast)

-Ultra low-dose computed tomography (CT) of the lungs in all females 18 years and older and in symptomatic males

-Abdominal MRI

Due to the number of repeat scans and unknown long-term effects, contrast agents are avoided unless there is a growing lesion or clinical suspicion for a SEGA. If contrast is used, group 1 agents should be avoided [4].

•Other testing

-Pulmonary function tests

-Echocardiogram and electrocardiogram

-Electroencephalogram (EEG)

-Assessment of kidney function (determination of glomerular filtration rate [GFR])

●Interventions

•Tumors – mTOR inhibition with everolimus is used for tumors causing functional impairment, SEGAs >1 cm or causing hydrocephalus, growing kidney tumors, and cardiac tumors causing heart failure. Therapy can cause tumors to regress; typically, it is continued indefinitely. Surgery may be appropriate in selected cases.

•Seizures – Vigabatrin is used for infantile spasms, with possible prophylactic use in selected individuals. Seizures are treated with an appropriately chosen antiseizure medication. Interventions for medically refractory epilepsy may include epilepsy surgery, dietary therapy (such as ketogenic diet), vagus nerve stimulation, everolimus, and/or cannabidiol. Clinical trials are evaluating interventions for seizure prophylaxis (vigabatrin, everolimus); specialist input can address the latest recommendations.

•Cognitive/behavioral – Early interventions and services are provided as needed. Seizure prevention is emphasized.

•Skin – Interventions include sun protection, laser therapy or dermabrasion for cosmesis, possibly topical mTOR inhibitor therapy.

•Cardiac tumors – These can spontaneously regress and may not require surgical intervention unless they cause symptoms.

Specialty centers will be aware of clinical trials that could be appropriate.

RESOURCES

●Information in UpToDate

•Pathogenesis – (See "Tuberous sclerosis complex: Genetics and pathogenesis".)

•Diagnosis – (See "Tuberous sclerosis complex: Clinical features" and "Tuberous sclerosis complex: Evaluation and diagnosis".)

•Treatment – (See "Tuberous sclerosis complex: Management and prognosis".)

•Kidney – (See "Renal manifestations of tuberous sclerosis complex".)

•Skin – (See "The genodermatoses: An overview", section on 'Tuberous sclerosis complex'.)

•Lung – (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)

●TSC resources

•TSC Alliance (United States) – tscalliance.org

•Tuberous Sclerosis Association (United Kingdom) – tuberous-sclerosis.org

•Other societies – (See "Society guideline links: Tuberous sclerosis".)

•National Institutes of Health (NIH) – Fact sheet for patients

•List of TSC clinics (United States) - tscalliance.org/individuals-families/tsc-clinics/

•List of TSC organizations around the world – tscinternational.org/find-a-tsc-organization/

●Locating a genetics professional

•Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)

•Genetic counselors – National Society of Genetic Counselors (NSGC)