Genotyping and sequencing NUDT15, TPMT and CEP72

DNA strand for Precision Medicine

Genotyping and sequencing NUDT15, TPMT and CEP72

Comprehensive Cascade Testing

Test Information

The CNT (CEP72, NUDT15, and TPMT) and NT (NUDT15 and TPMT) cascade testing detects known and novel clinically relevant genetic variants in these actionable pharmacogenetics (PGx) genes in a tiered fashion.

Tier 1 genotyping test investigates CEP72, NUDT15 and TPMT genes for common clinically relevant variants. Tier 2 reflex test (launch in October, 2020) using next generation sequencing (NGS) technology detects all known PGx-relevant haplotypes as well as novel single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) in NUDT15 and TPMT.

By investigating exhaustively all the clinically relevant variants in CEP72, NUDT15 and TPMT, our comprehensive cascade testing yields thorough dosing guidance for thiopurines and vincristine with higher accuracy.

Webinar

PGx of Thiopurines Toxicity: Make the Case for Precision Medicine

Speaker: Dr. Jun Yang, PhD.  St Jude Children’s Research Hospital

Clinical Value

The tests provides clinically relevant information to help clinicians determine effective therapies and dosing for patients with acute lymphoblastic leukemia (ALL) or inflammatory bowel disease (IBD).

TPMT and NUDT15 are two important PGx genes recommended in the latest CPIC guidelines to guide proper dosing of thiopurines, including azathioprine, mercaptopurine, and thioguanine. Thiopurines are  commonly used drugs to treat acute lymphoblastic leukemia (ALL), autoimmune diseases, and inflammatory bowel disease (IBD), or to prevent rejection after organ transplant.1 Variants in TPMT and NUDT15 are associated with increased risk of life-threatening myelosuppression induced by thiopurines.1,2,3

Whereas TPMT variants are primarily found in those of European descent, genetic variants in NUDT15 are found in many populations (Figure 1).2

CNT Pane NUDT15 Diplotype Variants

One genetic variant of CEP72 has been associated with vincristine-related peripheral neuropathy. Thus, genotyping of CEP72 is recommended to guide safer dosing of vincristine.4

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Webinar Recording

Learn how TPMT and NUDT15 PGx reduces thiopurines-related ADRs.

KEY ADVANTAGES

Covers CPIC guideline-recommended genes in one test

Analyze both CPIC guideline-recommended genes, TPMT and NUDT15, for thiopurines in a single test.

Test all clinically relevant variants

Test all clinically relevant variants of TPMT, NUDT15, and CEP72 to enhance accuracy and eliminate guesswork.

Rapid turnaround time (TAT)

Highly accurate clinical results are delivered within 3-5 days to support potentially life-saving clinical decision making.

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NT PanelCNT PanelGenesAlleles Detected by Tier 1 Genotyping Assay Alleles Detected by Tier 2 NGS Reflex Test DrugsIndications
X XTPMT*1, *2, *3A, *3B, *3C, *4, *8, *24 *5, *6, *7, *9, *10, *11, *12, *13, *14, *15, *16, *17, *18, *19, *20, *21, *22, *23, *25, *26, *27, *28, *29, *30, *31, *32, *33, *34, *35, *36, *37, *38, *39, *40, *41, *42, *43, *44, plus novel single nucleotide variants (SNVs) and small insertions/deletions (in/dels) ThiopurinesAcute Lymphoblastic Leukemia,
Inflammatory Bowel Disease,
Autoimmune Diseases,
Organ Transplant
X XNUDT15*1, *2, *3, *4, *5, *6, *7, *8, *9 *10, *11, *12, *13, *14, *15, *16, *17, *18, *19, *20, plus novel single nucleotide variants (SNVs) and small insertions/deletions (in/dels)
XCEP72SNP rs924607: C, SNP rs924607: TVincristineAcute Lymphoblastic Leukemia

Testing for individual gene (NUDT15, CEP72 or TPMT)  is also available. Contact us for more information.

Comprehensive Cascade Testing WorkFlow

 

1. The tier 2 NGS test might be performed (approximately 10% of the individuals may need tier 2 test) for the following reasons:
  • no call on single nucleotide polymorphism
  • genotype/phenotype discord
  • ambiguous genotype result
  • requested by Laboratory Director
  • requested to review an old case
Gene Details

NUDT15

Download NUDT15 Spec Sheet

NUDT15 encodes an enzyme (nudix hydrolase) which is a negative regulator of thiopurines (e.g., 6-mercaptopurine, azathioprine, thioguanine, etc.) activation and toxicity. Genetic variants in the NUDT15 gene can modulate enzymatic activity and the metabolism of thiopurines.1,2,3

Pharmacogenetic testing for these variants can identify individuals who may fail to respond to standard dosages of drugs metabolized by NUDT15 or be at an increased risk of adverse drug reactions.

The latest CPIC guidelines recommend testing for NUDT15 and TPMT to guide the dosing of thiopurines. Read more.

A recent landmark study shows NUDT15 variants are associated with thiopurine-induced myelosuppression in patients with IBD. Read more.

Read more about NUDT15.

Single gene testing for NUDT15 is also available. Please contact us for more information.

TPMT

Download TPMT Spec Sheet

TPMT encodes an enzyme that is a negative regulator of thiopurines (e.g., 6-mercaptopurine, azathioprine, thioguanine, etc.) activity. Genetic variants of the TPMT gene can modify enzymatic activity and the ability to metabolize thiopurines.1 Pharmacogenetic testing for these variants can identify individuals who may have an increased risk of having adverse drug reactions or may fail to respond to standard dosages of drugs metabolized by TPMT.

Read more about TPMT.

The latest CPIC guidelines recommend testing for NUDT15 and TPMT to guide the dosing of thiopurine. Read more.

CEP72

Download CEP72 Spec Sheet

CEP72 encodes a protein that is essential for microtubule formation. The chemotherapeutic drug vincristine exerts its cytotoxic effects by interfering with microtubule formation and mitotic spindle dynamics, leading to mitotic arrest and cell death. One specific sequence variant in CEP72 (T/T genotype) is associated with an increased risk and severity of vincristine-related peripheral neuropathy in individuals ALL.4

REFERENCES
  1. Relling MV, et al. CPIC Guideline for Thiopurines and TPMT and NUDT15. Clin Pharmacol Ther. 2019 May;105(5):1095-1105.
  2. Moriyama T, et al. NUDT15 Polymorphisms Alter Thiopurine Metabolism and Hematopoietic Toxicity. Nat Genet. 2016 Apr;48(4):367-73.
  3. Schaeffeler, E. et al. Impact of NUDT15 Genetics on Severe Thiopurine-related Hematotoxicity in Patients with European Ancestry. Genetics in Medicine. Feb 2019. [Ahead of ePub].
  4. Stock W, et al. Clin Pharmacol Ther. 2017;101(3):391-95.

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