Massively parallel variant characterization identifies<i>NUDT15</i>alleles associated with thiopurine toxicity

TLDR

Pharmacogenetics exemplifies genomics‑guided precision medicine, yet the rapid discovery of novel variants and the lack of scalable interpretation hinder progress, with NUDT15 polymorphisms being a major cause of hematopoietic toxicity during thiopurine therapy. The study aimed to develop a massively parallel assay to preemptively characterize 91.8 % of all possible missense variants in NUDT15 to inform clinical actions. A massively parallel assay was used to preemptively characterize 91.8 % of all possible missense variants in NUDT15. Function‑based variant classification accurately predicted thiopurine toxicity risk alleles, enabling improved genotype‑guided thiopurine therapy and demonstrating the value of high‑throughput variant effect screens.

Abstract

Significance Pharmacogenetics is a prototype of genomics-guided precision medicine. While there is a rapid expansion of novel pharmacogenetic variants discovered by genome sequencing, the lack of variant interpretation in a scalable fashion is a formidable barrier in this field. NUDT15 polymorphism is a major genetic cause for hematopoietic toxicity during thiopurine therapy. Motivated by the need to understand NUDT15 variant effects for clinical actions, we developed a massively parallel assay to preemptively characterize 91.8% of all possible missense variants in NUDT15 . Our function-based variant classification accurately predicted thiopurine toxicity risk alleles in patients. These results vastly improved the ability to implement genotype-guided thiopurine therapy and illustrated the value and potential of a high-throughput variant effect screen in general.