Clinical Functional Assignment of TPMT and NUDT15 Alleles by the Clinical Pharmacogenetics Implementation Consortium Pharmacogene Curation Expert Panel.

TPMT and NUDT15 govern thiopurine metabolism; the function assigned to each star allele determines the predicted metabolizer phenotype and hence the dose administered.

The CPIC Pharmacogene Curation Expert Panel re-evaluated the star alleles of TPMT and NUDT15, two genes central to the metabolism of thiopurines used in cancer and autoimmune disease. Assignments rest on a standardised framework combining clinical data on thiopurine tolerance and toxicity, in vitro protein activity, ex vivo enzymatic measurements and in silico variant effect prediction. The work delivers the first designation of decreased function alleles for both TPMT and NUDT15, based on new clinical data showing partial loss of enzymatic activity and reduced dose tolerance. Several alleles previously assigned uncertain or unknown function are reclassified. The authors present these updates as a gain in genotype-to-phenotype mapping precision supporting more personalised thiopurine therapy.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is allele curation, not a clinical study: its strength is only that of the underlying data, often thin for rare alleles, and CPIC's authority is no substitute for it. The practical contribution is nevertheless immediate, since this table determines the phenotype a laboratory reports and therefore the starting thiopurine dose. The open question is a dosing one: the decreased function category creates intermediate diplotypes whose translation into a specific dose reduction still needs to be spelled out, where existing recommendations were built on a normal versus no-function dichotomy.

Analysis by Dr Thibaut Benquey