Tuberous Sclerosis Complex

Preferred DNA test to confirm clinical diagnosis of TSC

  • Use to confirm diagnosis of TSC in a fetus with suspected cardiac rhabdomyoma on ultrasound
  • Use to confirm diagnosis in a fetus at risk for TSC based on a positive family history
  • This is the recommended test for a known familial sequence variant previously identified in a family member.
  • A copy of the family member’s test result documenting the known familial variant is required.

Tuberous sclerosis complex (TSC) is a multisystem, genetic disorder causing numerous benign tumors as well as intellectual and developmental disabilities. Tumors can occur in the skin, brain, kidneys, and other organs, and can lead to significant health complications. TSC may be life threatening. Nearly all affected individuals have skin findings that develop early in life and can include pigmentary changes, thickened skin, growths in the nails, and facial angiofibromas. Intellectual changes are common and can present in a variety of ways, including autism spectrum disorder, behavioral changes, and intellectual disability. Seizures occur in >80% of affected individuals. TSC may be suspected prenatally due to the presence of a fetal cardiac rhabdomyoma, the most common cardiac tumor seen on ultrasound.

Disease Overview

Diagnostic Criteria

  • A diagnosis of TSC should be suspected in individuals with either one major feature or two or more minor features.
  • A definitive diagnosis is established by any of the following:
    • The presence of two major features
    • One major feature with two or more minor features
    • Identification of a pathogenic variant in either TSC1 or TSC2  by molecular genetic testing
Major Features Minor Features

Angiofibromas or a fibrous cephalic plaque

Cardiac rhabdomyoma

Cortical dysplasias

Hypomelanotic macules

LAM

Multiple retinal nodular hamartomas

Renal angiomyolipoma

Shagreen patch

Subependymal giant cell astrocytoma

Subependymal nodules

Ungual fibromas

“Confetti” skin lesions

Dental enamel pits

Intraoral fibromas

Multiple renal cysts

Nonrenal hamartomas

Retinal achromic patch

LAM, lymphangioleiomyomatosis

Prevalence

1 in 6,000 individuals 

Etiology

Pathogenic variants in either the TSC1 or TSC2 gene

Inheritance

  • Autosomal dominant
  • ~66% are de novo  

Genotype-Phenotype Correlation

TSC2 pathogenic variants produce a more severe phenotype and are more likely to be sporadic (de novo) than TSC1 variants. Individuals with TSC2 variants are at a greater risk for renal malignancy, intellectual disability, autism spectrum disorder, and infantile spasm. However, there is variable expressivity and clinical overlap between TSC1 and TSC2 variants.

Test Description

Clinical Sensitivity

95% 

  • TSC1: ~26%
  • TSC2: ~69%
  • Unknown: ~5%

Limitations

  • A negative result does not exclude a diagnosis of TSC.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the targeted genes
    • Regulatory region variants and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Noncoding transcripts
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massive parallel sequencing
    • Single exon deletions/duplications or deletions/duplications less than 1 kb by array
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive or homologous regions
    • Low-level somatic variants
    • Single exon deletions/duplications will not be called for the following exons:
      • TSC2 (NM_000548) 17, 29, 41

Analytical Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

99.9

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

99.9

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

References