Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is one of the most common neurocutaneous disorders, affecting approximately 50,000 children and adults in the US.1 Children with TSC typically present with either seizures/infantile spasms or developmental delay with features of an autism spectrum disorder. 

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Tuberous sclerosis complex (TSC) is one of the most common neurocutaneous disorders, affecting approximately 50,000 children and adults in the US.1 Children with TSC typically present with either seizures/infantile spasms or developmental delay with features of an autism spectrum disorder. 

TSC primarily affects the skin and nervous system. Additional complications can arise in the lungs, kidneys, heart, and eyes. Genetic testing can confirm a diagnosis of TSC and allow for appropriate anticipatory guidance and surveillance. Genetic testing can also be used to identify affected relatives and then monitor for early detection of symptoms, which leads to earlier treatment and better overall outcomes.2

Disease Name 
Tuberous sclerosis complex (TSC)
Disease Information 

TSC is an autosomal dominant multi-system condition. About two thirds of affected individuals have a de novo mutation,1 though screening of parents for sub-clinical features of TSC is recommended when a child is diagnosed. Diagnosis can be based on either genetic testing results or clinical criteria. Genetic diagnostic criteria include the identification of a pathogenic TSC mutation in DNA from normal tissue. A negative DNA test for TSC does not exclude the diagnosis and does not impact the use of the clinical diagnostic criteria.3

Clinical diagnostic criteria for TSC3 exist and are based on the presence of both major and minor features of the disorder. A definitive diagnosis of TSC requires two major features, or one major and two or more minor features. A possible diagnosis of TSC is established for anyone with one major feature, or two or more minor features.

Major Features Minor Features
Hypomelanotic macules (ash leaf spots): ≥3 at least 5mm in diameter "Confetti” skin lesions
Angiofibromas (≥3) or fibrous cephalic plaque Dental enamel pits (>3)
Ungual fibromas (≥2) Intraoral fibromas (≥2)
Shagreen patch Retinal achromatic patch
Multiple retinal hamartomas Multiple renal cysts
Cortical dysplasias Nonrenal hamartomas
Subependymal nodules
Subependymal giant cell astrocytoma
Cardiac rhabdomyoma
Lymphangioleiomyomatosis (LAM)
Angiomyolipomas (≥2)

 

TSC exhibits variability in clinical findings both among and within families. Any organ system can be involved, and males tend to have more significant disease than females.4,5 The skin is affected in almost all people with TSC, though none of the skin lesions result in serious medical problems. About 80% of children with TSC have an identifiable renal lesion by age 10.6

More than 80% of people with TSC have seizures and at least half have developmental delay or intellectual disability. Autism spectrum disorders are common, affecting approximately 40-60% of people with TSC.7,8 ADHD and aggression are also common.1  

Central nervous system tumors are the leading cause of morbidity and mortality. Renal disease is the second leading cause of early death, and individuals with TSC have a 2-5% lifetime risk of renal cancer.9 Some individuals have features of both TSC and autosomal dominant polycystic kidney disease (ADPKD), caused by a contiguous gene deletion of both TSC2 and PKD1.10

TSC is caused by mutations in either TSC1 or TSC2. The phenotypes caused by mutations in these two genes cannot be distinguished clinically, making genetic testing necessary to determine which gene is causing the disease. TSC is thought to be 100% penetrant, meaning that all individuals with a pathogenic mutation will develop some features of the condition. There is evidence that TSC2 mutations typically produce a more severe phenotype than TSC1 mutations.4,5,11,12

Testing Benefits & Indication 

Genetic testing is useful for diagnostic confirmation in symptomatic individuals and for testing of at-risk asymptomatic family members (including prenatal diagnosis). Molecular confirmation of a diagnosis may help avoid unnecessary testing and procedures, and allow for appropriate anticipatory guidance and medical surveillance.

Analysis of TSC1 and TSC2 is recommended for any of the following:

  • Any individual with suspected TSC, who does not meet clinical criteria
  • Any child presenting with infantile spasms (medical management of infantile spasms is different for children with TSC than those without)
  • Any individual with a family history of TSC 
  • Any individual with a clinical diagnosis of TSC interested in pursuing preimplantation genetic diagnosis or prenatal testing for TSC
Test Description 

TSC1 coding exons 1-21 and TSC2 coding exons 1-41 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for all coding exons. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.13  Gross deletion/duplication analysis of TSC1 and TSC2 using read-depth from NGS data is also performed. Any copy number changes detected by NGS are confirmed by targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification (MLPA).

Mutation Detection Rate 

Gene sequence and deletion/duplication analysis of both TSC1 and TSC2 can detect ~85% of individuals with TSC5 (clinical sensitivity). Of all individuals with a mutation, ~31% are found in TSC1 and ~69% are found in TSC2.5 Ambry's TSC1 and TSC2 analysis can detect >99.9% of described mutations, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above in the Quick Links section at the top of this page.

Turnaround Time 
TEST CODE TECHNIQUE TURNAROUND TIME
5904 TSC1/TSC2 Gene Sequence and Deletion/Duplication Analysis           2-3 Weeks

 

Specialty 
Genes 
TSC1
TSC2
References 
  1. Baker P, et al. Autism and tuberous sclerosis complex: prevalence and clinical features. J Autism Dev Disord. 1998;28:279–285.
  2. Bombardieri R, et al. Early control of seizures improves long-term outcome in children with tuberous sclerosis complex. Eur J Paediatr Neurol2010;14:146–149.
  3. Northrup H, et al. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International tuberous sclerosis complex consensus group. Pediatr Neurol. 2013;49(4):243-254.
  4. 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;13:731–741.
  5. 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;9:88–100.
  6. Ewalt DH, et al. Renal lesion growth in children with tuberous sclerosis complex. J Urol. 1998;160:141–145.
  7. Numis AL, et al. Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex. Neurology. 2011;76:981–987.
  8. Ehninger D, et al. Rapamycin for treating tuberous sclerosis and autism spectrum disorders. Trends Mol Med. 2011;17:78–87.
  9. Borkowska J, et al. Tuberous sclerosis complex: tumors and tumorigenesis. International Journal of Dermatology. 2011;50(1):13-20.
  10. Martignoni G, et al. Renal disease in adults with TSC2/PKD1 contiguous gene syndrome. Am J Surg Pathol. 2002;26:198–205.
  11. 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;68:64–80.
  12. Lewis JC, et al. Genotype and psychological phenotype in tuberous sclerosis. J Med Genet. 2004;41:203–207.
  13. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.