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Tuberous Sclerosis Complex Panel, Sequencing and Deletion/Duplication

3002100

Tuberous Sclerosis Complex Panel, Sequencing and Deletion/Duplication 3002100

Method

Massively Parallel Sequencing

Preferred DNA test to confirm clinical diagnosis of TSC

3002096

Tuberous Sclerosis Complex Panel, Sequencing and Deletion/Duplication, Fetal 3002096

Method

Massively Parallel Sequencing

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

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

Tuberous sclerosis complex (TSC) is a multisystem, genetic disorder causing numerous benign tumors as well as cognitive 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, which can include pigmentary changes, thickened skin, growths in the nails, and facial angiofibromas. Changes in cognitive ability are common and can present in a variety of ways, including autism spectrum disorder, behavioral change, and cognitive disability. Seizures occur in more than 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

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 Lymphangioleiomyomatosis (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
Sources: Northrup, 2021; Northrup, 2013

Major Features

Minor Features

Angiofibromas or a fibrous cephalic plaque

Cardiac rhabdomyoma

Cortical dysplasias

Hypomelanotic macules

Lymphangioleiomyomatosis (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

Sources: Northrup, 2021; Northrup, 2013

Genetics

Genes Tested

TSC1 and TSC2

Prevalence

1 in 6,000 individuals

Etiology

Pathogenic variants in either the TSC1 or TSC2 gene

Inheritance

Autosomal dominant
Approximately 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, cognitive disability, autism spectrum disorder, and infantile spasm. However, there is variable expressivity and clinical overlap between TSC1 and TSC2 variants.

Test Interpretation

Methodology

This test is performed using the following sequence of steps:

Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as NGS) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline.
Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.

Clinical Sensitivity

95% for TSC

TSC1: Approximately 26%
TSC2: Approximately 69%
Unknown: Approximately 5%

Analytic Sensitivity

For massively parallel sequencing:

Variant Class	Analytic Sensitivity (PPA) Estimate^a (%) and 95% Credibility Region (%)	Analytic Specificity (NPA) (%)
SNVs	>99 (96.9-99.4)	>99.9
Deletions 1-10 bp^b	93.8 (84.3-98.2)	>99.9
Insertions 1-10 bp^b	94.8 (86.8-98.5)	>99.9
Exon-level^c deletions	97.8 (90.3-99.8) [2 exons or larger] 62.5 (38.3-82.6) [Single exon]	>99.9
Exon-level^c duplications	83.3 (56.4-96.4) [3 exons or larger]	>99.9
^aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA). ^bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced. ^cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp. bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants

Results

Result	Variant(s) Detected	Clinical Significance
Positive	One TSC1 or TSC2 pathogenic variant detected	Consistent with a diagnosis of TSC
Negative	No TSC1 or TSC2 pathogenic variants detected	Diagnosis of TSC is unlikely but not excluded
Uncertain	TSC1 or TSC2 variant of unknown clinical significance detected	It is unknown whether variant is benign or pathogenic

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
The following may not be detected:
- Deletions/duplications/insertions of any size by massive parallel sequencing
- Large duplications less than 3 exons in size
- Noncoding transcripts
- Some variants due to technical limitations in the presence of pseudogenes, repetitive or homologous regions
- Low-level somatic variants

References

GeneReviews - Tuberous Sclerosis Complex

Northrup H, Koenig MK, Pearson DA, et al. Tuberous sclerosis complex. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Revised Dec 2021; accessed Jun 2022.

24053982

Northrup H, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4):243‐254.

2039137

Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci. 1991;615:125‐127.

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