A Lack of Complete Linkage Disequilibrium Between c.1236G>A and c.1129-5923C>G HapB3 Variants of DPYD: A Call to Revise European Pharmacogenetic Guidelines

Fluoropyrimidine derivatives can cause severe toxicity in patients with DPD deficiency. Regulatory agencies, such as the European Medicines Agency (EMA), recommend pre-emptive genotyping of the HapB3 haplotype, along with other variants. Historically, the two main HapB3 variants, the benign c.1236G>A and the pathogenic c.1129-5923C>G, have been assumed to be in complete linkage disequilibrium. Recent findings contradict this assumption, questioning the reliability of the HapB3 analysis through c.1236G>A, which could directly impact patient safety. The aim of this study is to assess the linkage disequilibrium between the c.1236G>A and c.1129-5923C>G variants, with the ultimate goal of revising genotyping guidelines. A total of 46 patients already heterozygous for the c.1236G>A variant have been carefully reviewed for the c.1129-5923C>G variant. From the 46 patients analyzed, 45 maintain complete linkage disequilibrium between both variants. However, there is one patient where this linkage disequilibrium is not complete, being heterozygous for c.1236G>A and homozygous for c.1129-5923C>G. These findings challenge the validity of c.1236G>A as a surrogate marker for pathogenic variant c.1129-5923C>G. This article highlights the need for a review of the recommendations of the EMA and suggests laboratories to analyze both variants, or at least the pathogenic one, to ensure accurate therapeutic decisions.