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Tropomyosin 2-Related Disorders via the TPM2 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8805 TPM2 81479 81479,81479 $990 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8805TPM281479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Angela Gruber, PhD

Clinical Features and Genetics

Clinical Features

Mutations in TPM2 cause several distinct myopathic disorders (Tajsharghi et al. Neuromuscul Disord 22(11):923-933, 2012).

Nemaline myopathy (NEM) is a genetically and clinically heterogeneous disorder characterized by muscle weakness, hypotonia and the presence of nemaline bodies in skeletal muscle fibers. Muscle weakness is typically observed in affected neonates or infants, although later onset cases are reported (Ryan et al. Ann Neurol 50(3):312-320, 2001). The most severely affected muscle groups are proximal limb, facial, bulbar, and respiratory muscles. Deep tendon reflexes are absent or depressed. Histologically, NEM is characterized by type 1 fiber predominance and the presence of rod-like structures called nemaline bodies with Gomori trichrome staining of skeletal muscle (Ryan et al. Neurol 60(4):665-673, 2003). Six clinical types of NEM have been delineated based on age of onset, severity and distribution of weakness, and respiratory function (Ryan et al. 2001; North and Ryan. GeneReviews, 2012). Overlap among the six groups is significant, and adults are sometimes diagnosed only after a family member has presented with typical signs.

Distal arthrogryposis syndromes (DA) are a group of multiple congenital contracture disorders with distal joint involvement more common than proximal; variable clinical expression; and autosomal dominant inheritance (Bamshad et al. Am J Med Genet 65(4):277-281, 1996). Distal arthrogryposis type 1 (DA1) is characterized by talipes and camptodactyly, although the shoulders and hips may also be affected (Sung et al. Am J Hum Genet 72(3):681-690, 2003). The clinical phenotype of DA1 overlaps that of Freeman-Sheldon syndrome (FSS; Klemp and Hall. Am J Med Genet 55(4):414-419, 1995), and individuals with features in common to both DA1 and FSS have been found to have mutations in the TNNI2 gene (Sung et al., 2003). Autosomal dominant trismus-pseudocamptodactyly syndrome (distal arthrogryposis type 7, OMIM 158300) was previously thought to be caused by MYH8 gene mutations alone, however, a TPM2 mutation has been found to be causative for this disorder (Davidson et al. 2013 Brain 136 (Pt 2): 508–521).

An autosomal dominant distal myopathy with both cores and rods on muscle biopsy has also been associated with a TPM2 mutation in one family (Davidson et al., 2013).

Genetics

Tropomyosin 2 (TPM2; OMIM 190990) encodes the muscle isoform of tropomyosin 2, a regulator of actin-myosin interactions. TPM2-related myopathies are inherited as autosomal dominant disorders. Amino acid substitutions are the largest class of TPM2 mutations. An N-terminal amino acid deletion (p.Lys7del) has been found to be causative for a range of clinical phenotypes (Davidson et al., 2013: Mokbel et al. Brain 136(Pt 2): 494-507). Somatic mosaicism for a TPM2 mutation in an unaffected parent has been documented (Tasca et al. Acta Neuropathy 125(1):169-171, 2013).

Clinical Sensitivity - Sequencing with CNV PGxome

TPM2 mutations are a rare cause of nemaline myopathy and distal arthrogryposis. In a cohort of 66 unrelated nemaline myopathy patients, two were found to have TPM2 mutations (Donner et al. Neuromuscul Disord 12(2):151-158, 2002). One family with distal arthrogryposis has been found with a TPM2 mutation (Sung et al. Am J Hum Genet 72(3): 681-690, 2003).

Thus far, no gross deletions or duplications have been reported in TPM2 (Human Gene Mutation Databse).

Testing Strategy

This test provides full coverage of all coding exons of the TPM2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Individuals with clinical symptoms consistent with any of the TPM2-related disorders and with muscle biopsies positive for minicores and/or nemaline rods, or cap structures.

Gene

Official Gene Symbol OMIM ID
TPM2 190990
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Bamshad M. et al. 1996. American Journal of Medical Genetics. 65: 277-81. PubMed ID: 8923935
  • Davidson, A.E. et al. (2013). "Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies." Brain 136(Pt 2):508-521. PubMed ID: 23413262
  • Donner, K. et.al. (2002). "Mutations in the beta-tropomyosin (TPM2) gene- a rare cause of nemaline myopathy." Neuromuscul Disord 12(2): 151-158. PubMed ID: 11738357
  • Human Gene Mutation Database (Bio-base).
  • Klemp, P. and Hall, J.G. (1995). "Dominant distal arthrogryposis in a Maori family with marked variability of expression." Am J Med Genet 55(4): 414-419. PubMed ID: 7762579
  • Mokbel, N. et al. (2013). "K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity." Brain 136(Pt 2):494-507. PubMed ID: 23378224
  • North K, Ryan MM. 2002. Nemaline Myopathy. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301465
  • Ryan MM, Ilkovski B, Strickland CD, Schnell C, Sanoudou D, Midgett C, Houston R, Muirhead D, Dennett X, Shield LK, Girolami U De, Iannaccone ST, Laing NG, North KN, Beggs AH. 2003. Clinical course correlates poorly with muscle pathology in nemaline myopathy. Neurology 60: 665–673. PubMed ID: 12601110
  • Ryan MM, Schnell C, Strickland CD, Shield LK, Morgan G, Iannaccone ST, Laing NG, Beggs AH, North KN. 2001. Nemaline myopathy: a clinical study of 143 cases. Ann. Neurol. 50: 312–320. PubMed ID: 11558787
  • Sung S.S. et al. 2003. American Journal of Human Genetics. 72: 681-90. PubMed ID: 12592607
  • Tajsharghi, H. et al. (2012). "Myopathies associated with β-tropomyosin mutations." Neuromuscul Disord 22(11):923-933. PubMed ID: 22749895
  • Tasca, G. et al. (2013). "Somatic mosaicism in TPM2-related myopathy with nemaline rods and cap structures." Acta Neuropathol 125(1):169-171. PubMed ID: 23015096

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

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View Ordering Instructions

1) Select Test Method (Platform)


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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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