Identification of rare defective allelic variants in cases of thiopurine S-methyltransferase deficient activity.

Abstract

Aim: To assess rare TPMT variants in patients carrying a deficient phenotype not predicted by the fourmore frequent genotypes (*2, *3A, *3B and *3C). Materials & methods: Next-generation sequencing of TPMT in 39 patients with a discordant genotype. Results: None of the variants identified explained the discordances assuming that they are of uncertain significance according to the Clinical Pharmacogenetics Implementation Consortium classification.Two unknown variants were detected and predicted to result in a splicing defect. We show that TPMT*16and TMPT*21 are defective alleles, and TPMT*8 and TPMT*24 are associated with a normal activity. Conclusion: Whole-exon sequencing for rareTPMT mutations has a low diagnostic yield. A reassessment of the functional impact of rare variants of uncertain significance is a critical issue.