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Test Category: Specialist Biochemistry

Investigation Name:NUDT15 (Nudix Hydrolase 15) Genotyping

Alias or Abbreviation:NUDT15, Nudix Hydrolase 15

Accreditation:Awaiting accreditation due to relocation.

Intro:

NOTE: changes to reporting from 01/08/25

NUDIX hydrolase 15 (NUDT15) is a nucleoside diphosphatase enzyme directly involved in the metabolism of thiopurines, a class of immunosuppressive drugs widely used in the treatment of inflammatory and autoimmune disease, leukaemias and post-organ transplant to prevent rejection. NUDT15 catalyzes the conversion of active metabolites, cytotoxic 6-thioguanine triphosphate (6-thio-GTP and 6-thio-dGTP), into less toxic metabolites, thioguanine monophosphate (6-thio-GMP and 6-thio-dGMP).

Loss of function NUDT15 genetic variants result in reduced or absent enzyme activity, which leads to an accumulation of 6-thio-GTP and 6-thio-dGTP metabolites and risk increased haematopoietic toxicity at standard doses.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Thiopurine Dosing were updated in 2018 to include NUDT15 Genotype. Pre-emptive testing of NUDT15 allows for dose customization, reducing the likelihood of adverse effects.

NUDT15*3/*6/*9 variant alleles are screened for in BCPS. These account for up to 65% of all NUDT15 variant alleles associated with thiopurine-related leukopenia, neutropenia or myelosuppression.

NUDT15*3: rs116855232; c415C>T, p. Arg139Cys; loss of function. Allele frequency of 6% for East Asians and 6.7 % South Asians, also prevalent in those with Hispanic and Native American ancestry. The ALLtogether study protocol states that all patients of Asian ancestry aged 1-45 years with newly diagnosed acute lymphoblastic leukaemia should be screened for NUDT15*3 and NUDT15*2 (NUDT15*3 and *6) variant alleles.

NUDT15*6: rs746071566; c.55_56insGAGTCG, p. Val18_Val19insGV; uncertain function. Second most frequent variant allele, 1.3 % for East Asians.

NUDT15*9: rs746071566; c.50delGAGTCG, p.G17_V18del; loss of function. Rare, frequency of 0.18% in Europeans.

Results are reported with updated interpretative comments as per CPIC Guideline for Thiopurines and TPMT and NUDT15. Poor metabolisers are at increased risk of thiopurine toxicity at standard doses. Significantly reduced doses, or alternative agents should be considered. Intermediate metabolisers have some reduction in NUDT15 activity and are at increased risk of thiopurine toxicity. Reduced doses should be considered.

Pathology Laboratory:TPMT Laboratory

Requestable Seperately?Yes

Units:Qualitative

Minimum Sample Volume:1mL

Expected Turnaround Time:14 working days

Test Code:NUDT

Sample Type:

EDTA whole blood

Complex Reference Range:NOTE: changes to reporting from 01/08/25

NUDT15 genotype results are expressed as follows:
*1/*1 - No NUDT15 variant alleles detected (wild type). Likely normal metabolizer

*1/*3, *1/*9 - Heterozygote for NUDT15*X variant allele. Likely intermediate metabolizer

*1/*6 - Heterozygote for NUDT15*6 variant allele. Possible intermediate metabolizer. There may be an increased risk of thiopurine-related leukopenia, neutropenia or myelosuppression.

*3/*3, *9/*9 - Homozygote for the NUDT15*X variant allele. Likely poor metabolizer.

*3/*6, *6/*9 - Heterozygote for NUDT15*X and *X variant alleles. Intermediate or possible intermediate metabolizer. There may be an increased risk of thiopurine-related leukopenia, neutropenia or myelosuppression.

*3/*9 - Heterozygote for the NUDT15*3 and NUDT15*9 variant alleles. Likely poor metabolizer.

*6/*6 - Homozygote for NUDT15*6 variant allele. The likely phenotype of this genotype is not known. There may be an increased risk of thiopurine-related leukopenia, neutropenia or myelosuppression.

NB: X in place of specific variant allele for demonstration purposes where comment applicable to several possible results.

Collection Conditions / Other Information:Patients must give consent for genetic testing prior to sample collection.

Referred to Another Laboratory?No

Storage Requirements:Do not freeze, store at 4°C prior to dispatch.

Posting Address / Requirements:First class post at ambient temperature
Sandwell Health Campus,
Specialist Chemistry,
Pathology Department,
Lyndon, B71 4HJ

NPEX / PDF Reporting Available:Yes

EQA Scheme:We participate in an interlaboratory sample exchange.
GenQa: Pharmacogenomics - TPMT and NUDT15

Lead Contact Details:Consultant Clinical Scientist, Dr Hayley Sharrod-Cole,
Email: hayley.sharrod-cole@nhs.net

Email Address For Chasing Results:rwh-tr.bcpsspecialistchemistryenquiries@nhs.net

Site Sample Tested:Sandwell Health Campus

Cost:Please email: bcpspathology.info@nhs.net for further details

Contact Number:Tel: 0121 507 5162