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Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) Disease via the TYMP 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
11783 TYMP 81405 81405,81479 $990 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11783TYMP81405 81405,81479 $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

  • Kym Bliven, PhD

Clinical Features and Genetics

Clinical Features

The mitochondrial DNA depletion syndromes (MDSs) form a group of clinically and genetically heterogeneous diseases characterized by a quantitative abnormality of the mitochondrial genome in specific tissues (Suomalainen et al. 2010; El-Hattab and Scaglia 2013).

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease is an inherited, multi-systemic MDS that manifests with a combination of gastrointestinal, neurological, and ocular symptoms (Garone et al. 2011; Hirano 2016). MNGIE disease is characterized by gastrointestinal dysmotility, peripheral neuropathy, leucoencephalopathy, cachexia, ptosis, and progressive external ophthalmoplegia. Other features may include severe hypokalaemia, infections (due to either aspiration or rupture of diverticuli), short stature, cardiopathy, anaemia, amenorrhea, pigmentary retinopathy, dry mouth/eyes, psoriasis, and coarse bronze skin. In a subset of patients, disease progression can be further complicated by endocrine or exocrine pancreatic insufficiency. In addition to mtDNA depletion, MNGIE is often associated with the accumulation of multiple mtDNA deletions in various tissues over time.

MNGIE symptoms may manifest at any time between infancy to the third decade of life, but average age at onset generally occurs between 15 to 20 years (Garone et al. 2011). Allogeneic haematopoetic stem cell transplantation is a potentially promising enzyme replacement therapy for MNGIE disease, although this treatment requires timely and accurate diagnosis.

Genetics

MNGIE disease, which is inherited in an autosomal recessive manner, is caused primarily by pathogenic variants in the TYMP gene (Nishino et al. 1999; Nishino et al. 2000; Copeland 2012; Hirano 2016). TYMP has 9 coding exons that encode thymidine phosphorylase, an enzyme involved in the pyrimidine salvage pathway. Defects of this enzyme cause a marked accumulation of deoxythymidine and deoxyuridine, resulting in mitochondrial DNA instability and respiratory chain dysfunction.

Genetic defects in the TYMP gene include pathogenic missense, nonsense, and splicing variants, in addition to numerous small deletions and/or insertions (Human Gene Mutation Database). Only one gross deletion, encompassing the entire TYMP gene and several neighboring genes, has been reported in a patient with MNGIE (Vondráčková et al. 2014). Although much less frequently reported, defects in RRM2B have also been associated with a MNGIE-like phenotype (Shaibani et al. 2009).

Clinical Sensitivity - Sequencing with CNV PGxome

In one large cohort study, compound heterozygous or homozygous pathogenic variants in TYMP were identified in 92 out of 102 unrelated individuals (~ 90%) with clinical presentations suggestive of MNGIE disease (Garone et al. 2011).

Only one gross deletion, encompassing the entire TYMP gene and several neighboring genes, has been reported in a patient with MNGIE (Vondrácková et al. 2014). Although we can not precisely estimate clinical sensitivity at this time, large deletions or insertions in TYMP appear to be a rare cause of MNGIE.

Testing Strategy

This test provides full coverage of all coding exons of the TYMP 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

Candidates for this test are patients with MNGIE disease. Testing is also indicated for family members of patients who have known pathogenic variants in TYMP. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in TYMP.

Gene

Official Gene Symbol OMIM ID
TYMP 131222
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Copeland W.C. 2012. Critical Reviews in Biochemistry and Molecular Biology. 47:64-74. PubMed ID: 22176657
  • El-Hattab A.W. and Scaglia F. 2013. Neurotherapeutics. 10:186-98. PubMed ID: 23385875
  • Garone C. et al. 2011. Brain. 134:3326-32. PubMed ID: 21933806
  • Hirano M. 2016. Mitochondrial Neurogastrointestinal Encephalopathy Disease. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(Ž), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301358
  • Human Gene Mutation Database (Bio-base).
  • Nishino I. et al. 1999. Science. 283:689-92. PubMed ID: 9924029
  • Nishino I. et al. 2000. Annals of Neurology. 47:792-800. PubMed ID: 10852545
  • Shaibani A. et al. 2009. Archives of Neurology. 66:1028-32. PubMed ID: 19667227
  • Suomalainen A. and Isohanni P. 2010. Neuromuscular Disorders. 20:429-37. PubMed ID: 20444604
  • Vondrá?ková A. et al. 2014. European Journal of Human Genetics. 22:431-4. PubMed ID: 23838601

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)


1) Select Test Type


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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