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 four more 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*16 and TMPT*21 are defective alleles, and TPMT*8 and TPMT*24 are associated with a normal activity. Conclusion: Whole-exon sequencing for rare TPMT mutations has a low diagnostic yield. A reassessment of the functional impact of rare variants of uncertain significance is a critical issue.

Keywords::

• defective allelic variant
• discordance
• genotype
• next-generation sequencing
• phenotype
• thiopurines
• TPMT

Author contributions

A Chansavang and N Pallet made substantial contributions to the conception or design of the work, the acquisition, analysis and interpretation of data for the work, drafting the work, approved the final approval of the version and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. S Maalej, C Narjoz and M Loriot made substantial contributions to the acquisition, analysis and interpretation of data for the work, drafting the work, approved the final approval of the version and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.