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Homocystinuria, cblG Type, via the MTR 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
11841 MTR 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11841MTR81479 81479(x2) $890 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 backbone).

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

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

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days 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

  • McKenna Kyriss, PhD

Clinical Features and Genetics

Clinical Features

Cobalamin (Cbl or vitamin B12) is an important cofactor in homocysteine metabolism and in branched-chain amino acid and odd-chain fatty acid catabolism. A series of inherited inborn errors of cobalamin metabolism have been identified, designated cblA through cblJ. In the cblE and cblG disorders, the formation of methionine via methylation of homocysteine is disrupted. Clinically and biochemically, the cblE and cblG disorders are indistinguishable (Watkins and Rosenblatt 2014).

The cblG disorder leads to homocystinuria, hyperhomocystinemia, and hypomethioninemia without methylmalonic aciduria. Clinically, most patients have presented within the first two years of life with megaloblastic anemia and severe developmental delay. Some patients have also exhibited ataxia, cerebral atrophy, neonatal seizures and blindness (Watkins and Rosenblatt 2014; Wilson et al. 1998). A few cases of adult onset cblG disorder have been reported (Watkins and Rosenblatt 2014; Watkins et al. 2002). The cblG disorder can be enzymatically distinguished from the cblE disorder as the activity of methionine synthase from cblG patients is deficient under all conditions tested, whereas the activity of methionine synthase from cblE patients is only deficient under limited reducing conditions (Wilson et al. 1998). In most cblG patients, normal accumulation of labeled cobalamin is observed. A few "variant" patients with severe clinical features have been identified; these patients were found to have nearly undetectable methionine synthase activity as well as reduced accumulation of labeled cobalamin (Wilson et al. 1998). Importantly, some cblD variant patients may have a very similar biochemical and clinical profile to cblE and cblG patients. These three disorders are best distinguished by complementation studies or direct gene sequencing (Carrillo-Carrasco et al. 2013).

Some cblG individuals may be identified by newborn screening programs, although this depends on the methods used by the screening laboratory and their ability to detect low levels of methionine (Carrillo-Carrasco et al. 2013). Therefore, complementation analysis and/or molecular genetic testing should still be considered for symptomatic individuals, even if newborn screening results were reported to be normal (Carrillo-Carrasco et al. 2013). A variety of treatment options have been explored for cblG patients, including folinic acid, vitamins B6 and B12, betaine and methionine. However, the outcome of treatment varies with each patient and even with early treatment, no therapy has been found that completely alleviates all symptoms.

Genetics

Homocystinuria, cblG type is an autosomal recessive disorder, and MTR is the only gene that is involved. To date, approximately 20 causative variants have been reported in the MTR gene (Human Gene Mutation Database). The majority of reported pathogenic variants are missense and small deletions that lead to premature protein termination, although splice variants, small insertions and indels have also been reported. The variants are spread throughout the gene, with no reported mutational hotspots. The most commonly reported variant is Pro1173Leu, and most other pathogenic variants are private (Watkins et al. 2002).

The cblG disorder is caused by defects in the Methionine Synthase enzyme, which is responsible for the methylation of homocysteine, resulting in conversion to methionine. The clinical features of this disorder are thought to be caused by the accumulation of homocysteine and low levels of methionine in the blood as well as the "trapping" of the methyl donor 5-methyltetrahydrofolate (5-MTHF) in the Methionine Synthase enzyme. A lack of adequate levels of methionine leads to a decrease in the cellular level of the critical and widely used methyl group donor S-adenosylmethionine, and "trapping" of 5-MTHF prevents this metabolite from being available for other folate-dependent reactions (Watkins et al. 2002).

Clinical Sensitivity - Sequencing with CNV PGxome

Overall, the clinical sensitivity of this test is expected to be relatively high as the majority of confirmed cblG patients identified to date have been found to have MTR variants that are detectable via DNA sequencing. In the largest study of cblG patients to date, Watkins et al. (2002) studied 24 confirmed cblG patients. Full-gene sequencing was performed on 21 of these patients. Two pathogenic variants were identified in ~71% of the patients and a single variant was identified in the remaining ~29%, for an overall detection rate of ~86% (36 of 42 alleles).

To date, no large deletions or duplications have been described in the MTR gene, although most studies of cblG patients were not reported to include deletion and duplication analysis.

Testing Strategy

This test provides full coverage of all coding exons of the MTR 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 a positive newborn screening result for homocystinuria are good candidates for this test, particularly if they were also found to exhibit hypomethioninemia. Additionally, individuals that exhibit biochemical and clinical symptoms of cblG disorder are good candidates, as are family members of patients known to have MTR variants. We will also sequence the MTR gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
MTR 156570
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Carrillo-Carrasco N, Adams D, Venditti CP. 2013. Disorders of Intracellular Cobalamin Metabolism. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301503
  • Human Gene Mutation Database (Bio-base).
  • Watkins and Rosenblatt. 2014. Inherited Disorders of Folate and Cobalamin Transport and Metabolism. In: Valle D, Beaudet A.L., Vogelstein B, et al., editors. New York, NY: McGraw-Hill. OMMBID.
  • Watkins D. et al. 2002. American Journal of Human Genetics. 71: 143-53. PubMed ID: 12068375
  • Wilson A. et al. 1998. American Journal of Human Genetics. 63: 409-14. PubMed ID: 9683607

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


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


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.
Total Price: $
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