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Test Category: Specialist Biochemistry

Investigation Name:NUDT15-(Genotyping of Nudix Hydrolase 15)

Alias or Abbreviation:NUDT15, Nudix Hydrolase 15

Accreditation:Awaiting accreditation due to relocation.

Intro:

Nudix hydrolase 15 (NUDT15) is a nucleoside diphosphatase enzyme, and part of the nudix hydrolase superfamily. It is involved in the metabolism of thiopurine drugs e.g. azathioprine, mercaptopurine and thioguanine, which are widely used in the treatment ofinflammatory and autoimmune disease, leukaemias and post-organ transplant to prevent rejection. NUDT15 catalyses the metabolism of cytotoxic thioguanine nucleotide metabolites into less toxic forms.

Various NUDT15 genetic polymorphisms have been identified. The most extensively studied variant is caused by a single nucleotide transition (c.415C>T, p.Arg139Cys) within exon 3. This variant is found in haplotypes NUDT15*3 and NUDT15*2. For NUDT15*2 there is also an insertion of a repeat ‘GGAGTC’ sequence within exon 1, so that 4 copies of this repeat sequence are present instead of the 3 copies that are present in the wild type (NUDT15*1).

Individuals who are homozygous or compound heterozygous for NUDT15*3 or NUDT15*2 (*3/*3, *2/*2 or *2/*3) have significantly reduced NUDT15 activity and are described as “poor metabolisers”. These individuals are at increased risk of thiopurine toxicity at standard doses.
Heterozygous individuals (*1/*3 or *1/*2) are “intermediate metabolisers” with some reduction in NUDT15 activity. These individuals may also be at an increased risk of thiopurine toxicity, especially if another variant is present.
The frequency of the single nucleotide variant c.415C>T is highest in Asian individuals. The frequencies of C/C, C/T and T/T are reportedly 80%, 20% and 1-5%, respectively (2). The variant is also more prevalent in those with Hispanic and Native American ancestry. NUDT15 variants are rarely found in European populations (<1%).
Indications for testing
Pre-emptive NUDT15 genotyping is recommended in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, particularly for Asian patients. The genotyping results should be used to guide starting doses of thiopurine medications. “Intermediate metabolisers” should be considered for a reduced dose, and “poor metabolisers” should be started on a significantly reduced dose or alternative agent.

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*2 and NUDT15*3. Homozygote individuals should be started on a significantly reduced dose of 6-mercaptopurine, which may be carefully titrated up if tolerated. The guidelines do not recommend a pre- emptive dose reduction for heterozygous patients.

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:Results are expressed as follows:
• No mutation detected (c.415C>T)
• Heterozygous (c.415C>T)
• Homozygous (c.415C>T)
A standard interpretative comment is added to state that the mutation is associated with haplotypes NUDT15*2 and NUDT15*3.

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