PGX NUDT15 Genotyping For detection of NUDT15 variants affecting drug metabolism Clinical Background • NUDT15 is a negative regulator of thiopurine activation and toxicity. NUDT15 affects thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine. • NUDT15 catalyzes the conversion of cytotoxic thioguanine triphosphate (TGTP) metabolites to the less toxic thioguanine monophosphate. • Metabolizer phenotypes can be predicted by the NUDT15 genotype. • The clinical impact of the NUDT15 genotype is influenced by involvement of other metabolic pathways and other non-genetic factors. Epidemiology • NUDT15 variant frequency is ethnicity dependent. NUDT15*3 is present in approximately 7% of individuals of south/central Asian descent. NUDT15*5 is present in approximately 1% of individuals of East Asian descent. • The poor metabolizer phenotype is caused by two non-functional NUDT15 alleles. Genetics • The NUDT15 gene has three exons and is located on chromosome 13q14.2. • Inheritance is autosomal recessive. • Penetrance is drug-dependent. Indications for Ordering • Pre-therapeutic testing to identify individuals who should avoid, or may require unconventional doses of medications metabolized by NUDT15. Interpretation • If no NUDT15 variants are detected, this suggests *1 allele and normal enzymatic activity. • If one decreased functional or non-functional NUDT15 variant is detected, intermediate-to- normal NUDT15 enzymatic activity is predicted. Indiana University School of Medicine Genetics Testing Laboratories 975 W. Walnut St., IB350 Indianapolis, IN. 46202 Tel. 317-274-7597 • If two non-functional variants are present on opposite alleles, this predicts low NUDT15 enzymatic activity and a poor metabolizer phenotype. • Genotype results should be interpreted in the context of the individual clinical situation. Consultation with a clinical pharmacy professional is recommended. Methodology • Real-time polymerase chain reaction (PCR) and hydrolysis probe analysis. Variants in NUDT15 Assay Predicted enzyme Allele variant dbSNP activity *1 Assumed when no variant detected Normal *3 c.415C>T (also in *2 haplotype) rs116855232 No function *5 c.52G>A rs186364861 Uncertain function Indiana University School of Medicine Genetics Testing Laboratories 975 W. Walnut St., IB350 Indianapolis, IN. 46202 Tel. 317-274-7597 .