TSC1

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  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Associated disorders

The TSC1 gene is associated with autosomal dominant tuberous sclerosis complex (TSC) (MedGen UID: 344288).

Pathogenic variants in the TSC1 gene are associated with ~24% of clinical cases of tuberous sclerosis complex.

The TSC1 gene encodes a protein called hamartin. Within cells, hamartin interacts with a protein called tuberin, which is produced from the TSC2 gene. Nutrient-sensing is central to essential cellular functions like growth, division, and survival. Hamartin inhibits nutrient-sensing pathways, and could result in unrestrained or unorganized cell growth when not properly regulated

  1. Northrup, H, et al. Tuberous Sclerosis Complex. 1999 Jul 13. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1220/ PMID: 20301399
  2. Au, KS, et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet. Med. 2007; 9(2):88-100. doi: 10.1097GIM.0b013e31803068c7. PMID: 17304050
  3. Northrup, H, et al. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr. Neurol. 2013; 49(4):243-54. doi: 10.1016/j.pediatrneurol.2013.08.001. PMID: 24053982
  4. Crino, PB. mTOR signaling in epilepsy: insights from malformations of cortical development. Cold Spring Harb Perspect Med. 2015; 5(4):None. PMID: 25833943
  5. Zhang Y, et al. Coordinated regulation of protein synthesis and degradation by mTORC1. Nature. 2014 Sep 18;513(7518):440-3. PMID: 25043031
  6. Jones AC, et al. Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet. 1999 May;64(5):1305-15. PMID: 10205261
  7. Dabora SL, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet. 2001 Jan;68(1):64-80. PMID: 11112665
  8. Sancak O, et al. Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype--phenotype correlations and comparison of diagnostic DNA techniques in Tuberous Sclerosis Complex. Eur J Hum Genet. 2005 Jun;13(6):731-41. PMID: 15798777

TSC1 Tuberous Sclerosis
MedGen UID: 344288

Clinical condition
Tuberous sclerosis complex (TSC) is a highly variable, multisystemic neurocutaneous condition. Features include numerous, benign hamartomatous tumors of the skin, brain, kidneys, lungs, heart, and other organs as well as epilepsy, mild-to-severe neurodevelopmental, and behavioral impairments (PMID: 26564073).

Brain: Most affected individuals develop benign brain tumors that have malignant potential; specifically, cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs) (PMID: 27447981, 26564073). Over 90% of affected individuals have cortical tubers of varying size and number (PMID: 27797139). These lesions are hamartomas composed of disorganized neuronal and glial cells (PMID: 26564073). Subependymal nodules are TSC-related benign brain tumors that develop in the subependymal region of the ventricles (PMID: 26564073). SEGAs often develop from calcified subependymal nodules and are observed in 5-15% of affected individuals (PMID: 26564073, 9568761). While most develop in childhood, SEGAs may also present neonatally (PMID: 26564073). They may be unilateral or bilateral, and typically extend into the lateral ventricles potentially causing secondary obstructive hydrocephalus (PMID: 26564073).

The primary neurologic features of TSC are epilepsy, intellectual disability, and autism spectrum disorder (PMID: 26564073, 12622312, 16043792). The severity of neurologic symptoms has been suggested to correlate with the number and size of the cortical lesions (PMID: 26564073, 27797139). Approximately 80-90% of affected individuals have epilepsy (PMID: 27797139, 26564073). Those with multiple, large cortical tubers appear to have earlier onset and more severe seizures (PMID: 27797139). Infantile spasms are particularly common during the first year of life while generalized tonic-clonic and complex partial seizures are mostly seen in older individuals (PMID: 26564073).

At least half of those with TSC have intellectual disability, ranging from mild to severe (PMID: 26564073). Intellectual disability appears to strongly correlate with severe, uncontrolled seizures (PMID: 26564073, 16043792, 12622312). In addition, affected individuals with multiple, large cerebral lesions seem to have a greater risk of both uncontrolled seizures and intellectual disability (PMID: 26564073, 27797139, 16043792).

Individuals with TSC often manifest a variety of neuropsychiatric symptoms, collectively known as tuberous sclerosis-associated neuropsychiatric disorders (TAND) (PMID: 26706013, 27267556). These include psychosocial, behavioral, psychiatric, and learning difficulties manifesting with aggression, sleep disturbance, attention deficit disorder, and frank psychosis (PMID: 26564073). In addition, autism spectrum disorders (ASD) are observed in approximately 25% of individuals with TSC, and in half of those with both TSC and intellectual disability (PMID: 26564073). The severity of ASD ranges from mild to severe.

Kidneys: TSC-related renal lesions include epithelial cysts, oncocytomas, and angiomyolipomas and develop in approximately 70-80% of affected individuals (PMID: 27447981, 26564073). Angiomyolipomas are benign renal lesions that may be unilateral of bilateral (PMID: 27447981, 26564073). Their prevalence and size increase with age (PMID: 26564073). While small angiomyolipomas are typically asymptomatic, large tumors may cause life-threatening renal disease with signs and symptoms including hematuria, flank or abdominal pain, retroperitoneal hemorrhage, renal failure, and arterial hypertension (PMID: 27447981, 26564073). While uncommon, renal cancers associated with TSC include malignant angiomyolipoma and renal cell carcinoma. The risk of renal malignancy in individuals with TSC is approximately 2-5% (PMID: 21182496).

Eyes: Unilateral or bilateral retinal hamartomas or retinal astrocytic hamartomas are observed in approximately 50% of individuals with TSC (PMID: 2747981). Retinal hamartomas generally remain stable and rarely affect vision; however, some can develop subretinal fluid and rarely cause retinal detachment (PMID: 27447981, 26564073). Hypopigmented hamartomas of the iris and ciliary epithelium have also been described as well as eyelid angiofibromas; however these are much less common compared to retinal findings (PMID: 2747981, 26564073). Obstructive hydrocephalus secondary to subependymal giant cell astrocytomas (SEGAs) can occur and may produce papilloedema (PMID: 2747981).

Lungs: Lymphangioleiomyomatosis (LAM) develops primarily in adult women with TSC (PMID: 26564073). While many with LAM are asymptomatic, some develop symptoms including dyspnea with exertion, cough, hemoptysis, and spontaneous pneumothorax, which can trigger acute pulmonary dysfunction (PMID: 26564073). Estrogen and cigarette smoking have been suggested to exacerbate LAM (PMID: 26564073). Approximately 80% of women with TSC have evidence of cystic lung disease by 40 years of age (PMID: 27267556).

Heart: Two-thirds of newborns with TSC are diagnosed with one or more benign cardiac rhabdomyomas (PMID: 26564073). If present, these are often identified on prenatal ultrasound and are largest in the neonatal period. Over time, they typically regress and spontaneously resolve (PMID: 26564073). Most do not cause any symptoms; however, in some cases, cardiac rhabdomyomas can cause cerebral thromboembolism (PMID: 26564073).

Skin: The hallmark skin findings in TSC include hypomelanotic macules (also known as “ash leaf” spots), facial angiofibromas, cephalic plaque, shagreen patches, and periungual fibromas. While these skin findings are hamartomas and may increase in number over time, they do not appear to have malignant potential (PMID: 26564073). Hypomelanotic macules are observed in over 90% of affected individuals and are the single most consistent physical finding among affected individuals (PMID: 26564073). These lesions are often present in early infancy; however, they may be difficult to identify without an examination using ultraviolet light (PMID: 26564073). Clusters of smaller hypomelanotic macules are also observed and are sometimes called “confetti macules” (PMID: 26564073).

Facial angiofibromas develop in approximately 75% of individuals with TSC (PMID: 26564073). In young children, these lesions appear as flat, erythematous macules. They later develop into small, raised, hardened structures due to underlying fibrous overgrowth (PMID: 26564073). Sun exposure appears to be a precipitating factor influencing the development of facial angiofibromas among affected individuals (PMID: 27267556) A fibrous cephalic plaque (often called a forehead plaque) may develop on the forehead (PMID: 26564073). Shagreen patches are also seen over the lower back in approximately half of individuals with TSC, usually during the first decade of life. Shagreen patches are large, raised lesions that have a texture similar to an orange peel (PMID: 26564073). Up to 80% of adults with TSC have one or more periungual fibromas (PMID: 26564073).

Mucosal findings: Dental enamel pits are present in most adults with TSC (PMID: 26564073). Fibromas of the gingiva, buccal mucosa, and labial mucosa may also be observed (PMID: 26564073).

There is also preliminary evidence suggesting an association between pathogenic variants in TSC1 and rhabdomyosarcoma, and this gene is therefore available as a “preliminary-evidence” gene on Invitae’s Sarcoma Panel (PMID: 11920808, 8466239). Preliminary-evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available and therefore clinicians may continue to order these preliminary-evidence genes.

Gene information
TSC1 is a tumor suppressor gene that encodes the hamartin protein which, together with tuberin, form the tuberous sclerosis complex, a key inhibitory component of the mTOR pathway. This pathway plays a role in the regulation of cell growth and metabolism (PMID: 26564073, 27797139, 27447981, National Library of Medicine. Genetics Home Reference. TSC1 gene. https://ghr.nlm.nih.gov/gene/TSC1. Accessed December 2016, NCBI. Gene. Gene ID: 7248 https://www.ncbi.nlm.nih.gov/gene/7248. Accessed December 2016).

In addition to TSC1, the TSC2 gene is also associated with TSC. Individuals with pathogenic variants in TSC2 are considered as a group to have an overall more severe clinical presentation, characterized by a greater number of tubers, earlier age at seizure onset, and higher prevalence of intellectual disability compared to TSC1 (PMID: 26706013). However, because TSC has a highly variable clinical presentation even among affected individuals within the same family, it is difficult to predict clinical severity based solely on the underlying genetic cause (PMID: 26706013).

Inheritance
TSC1 has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant. While approximately one third of cases are inherited from a parent, the majority occur spontaneously (an individual with a pathogenic variant has parents who do not have it; PMID: 20301399, 26564073).

Management
Due to the complexity of TSC, affected individuals are best served by seeking care through a multidisciplinary clinic with experience treating this condition. Early diagnosis allows immediate implementation of surveillance and management guidelines (PMID: 24053983, 26564073):

Brain:

  • Magnetic resonance imaging (MRI) of the brain every 1-3 years in asymptomatic TSC patients younger than age 25 years
    • More frequent MRI scans for those with large or growing SEGA, or with SEGA causing ventricular enlargement but yet are still asymptomatic
    • For those with SEGA, families should be educated regarding the potential of new symptoms
    • Adults with history of asymptomatic SEGA in childhood should continue to be imaged periodically
  • Baseline routine electroencephalogram (EEG)
    • Prolonged video EEG is appropriate when seizure occurrence is unclear or when unexplained sleep, behavioral changes, or other alteration in cognitive or neurological function is present
    • Frequency of follow-up EEGs should be determined by clinical need Prolonged video EEG is appropriate when seizure occurrence is unclear or when unexplained sleep, behavioral changes, or other alteration in cognitive or neurological function is present
    • Family education on how to recognize seizures
  • Baseline developmental or neurocognitive testing to identify TSC-associated neuropsychiatric disorder (TAND) and areas of concern with re-evaluation at least annually
    • Comprehensive formal evaluation for TAND at key developmental time points:
      • infancy (0–3 yr)
      • preschool (3–6 yr)
      • pre-middle school (6–9 yr)
      • adolescence (12–16 yr)
      • early adulthood (18–25 yr)
      • as needed thereafter
    • Consider the need for an individual educational program (IEP)
    • Prompt medical/clinical evaluation to evaluate sudden change in behavior

Kidneys:

  • At least annual screening for hypertension by obtaining an accurate blood pressure measurement
  • At least annual evaluation of renal function by obtaining a serum creatinine level to determine the glomerular filtration rate (GFR)
  • MRI of abdomen every 1-3 years to assess for presence of angiomyolipomas and renal cysts
  • Embolization followed by corticosteroids is first-line therapy for angiomyolipomas presenting with acute hemorrhage. Nephrectomy is to be avoided. For asymptomatic, growing angiomyolipomas measuring larger than 3 cm in diameter, treatment with an mTOR inhibitor is the recommended first-line therapy. Selective embolization or kidney-sparing resection are acceptable second-line therapy for asymptomatic angiomyolipomas

Eyes:

  • Annual complete ophthalmologic evaluation, including dilated funduscopy, to assess for retinal lesions and visual field defects (PMID: 27447981)

Lungs:

  • Baseline pulmonary function testing, 6-minute walk test, and high-resolution chest high-resolution chest CT (preferentially with a low-radiation protocol) in females age ≥18 years
    • Repeat pulmonary function testing every 5–10 yr if there is no evidence of lung cysts
    • Individuals with lung cysts should have annual pulmonary function testing (pulmonary function testing and 6-minute walk) and high-resolution chest CT interval reduced to every 2–3 years
    • Counseling for female patients in adolescence and into adulthood regarding avoidance of excessive estrogen exposure and cigarette smoking
  • Pulmonary function testing for symptomatic adult males

Heart:

  • Baseline echocardiogram in the pediatric age group (especially if age <3 years), if one has not been performed already
    • Echocardiogram every 1–3 years in asymptomatic individuals until regression of cardiac rhabdomyomas is documented
  • Electrocardiogram (ECG) every 3–5 years in asymptomatic patients of all ages to monitor for conduction defects
  • Asymptomatic cardiac rhabdomyoma need no treatment

Skin:

  • Detailed dermatologic inspection/exam annually
  • Surgical excision, laser, or possibly topical mTOR inhibitors to treat rapidly changing, disfiguring, or symptomatic TSC-associated skin lesions as appropriate

Oral care:

  • Detailed clinical dental inspection/exam at least every 6 months with panoramic radiographs by age 7 years
    • Surgical excision or curettage for symptomatic or deforming dental lesions, oral fibromas, and bony jaw lesions

mTOR inhibitors such as rapamycin have been shown to significantly reduce epilepsy severity and tumor volume in SEGAs, angiomyolipomas, facial angiofibromas, and lymphangioleiomyomatosis (PMID: 27797139). While this treatment appears effective, mTORs are associated with significant side effects including acne, amenorrhea, abnormal wound healing, and increased risk of infections among others (PMID: 27797139). In addition, tumors will regrow and epilepsy will return in most cases if therapy is discontinued (PMID: 27797139). Therefore, mTOR inhibitors require chronic treatment indefinitely (PMID: 27797139).

Conventional seizure treatments are insufficient in at least one third of affected individuals (PMID: 27267556, 27797139, 16043792). Treatment with mTOR inhibitors is challenging as epilepsy often begins in infancy, and the safety and efficacy of this therapy in infants is not yet established (PMID: 27797139). Therefore, TSC-related epilepsy treatment typically utilizes a variety of therapeutics including antiepileptic drugs, steroids, surgery (e.g., resection of cortical tubers and SEGAs), vagus nerve stimulation, and a ketogenic diet (PMID: 27797139). Vigabatrin appears to be highly effective for infantile spasms in children with TSC (PMID: 27267556). Ultimately, the treatment decision-making process should include a thorough discussion of the risks, complications, side effects, cost, length of treatment, and potential impact on TSC-associated comorbidities (PMID: 24053983).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors including personal medical history, family history as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.

It is advantageous to know if a pathogenic variant in TSC1 is present. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding TSC1 is constantly evolving and more clinically relevant data is likely to become available in the near future. Awareness of this cancer predisposition allows patients and their providers to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information, inform at-risk family members, and diligently follow condition-specific screening protocols.

Review date: February 2017

Assay and technical information

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
TSC1 NM_000368.4