Massively parallel variant characterization identifies <i>NUDT15</i> alleles associated with thiopurine toxicity
Chase C. Suiter, Takaya Moriyama, Kenneth A. Matreyek, Wentao Yang, Emma Rose Scaletti, Rina Nishii, Wenjian Yang, Keito Hoshitsuki, Minu Singh, Amita Trehan, Christopher R. Parish, Colton Smith, Lie Li, Deepa Bhojwani, Liz Y. P. Yuen, Chi Kong Li, Chak-Ho Li, Yung‐Li Yang, G Walker, James Goodhand, Nicholas A. Kennedy, Federico Antillón‐Klussmann, Smita Bhatia, Mary V. Relling, Motohiro Kato, Hiroki Hori, Prateek Bhatia, Tariq Ahmad, Allen Eng Juh Yeoh, Pål Stenmark, Douglas M. Fowler, Jun J. Yang
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.