The variant c.2766+3A>T in DPYD leads to exon 21 skipping and is associated with DPD deficiency and severe fluoropyrimidine toxicity.

The intronic DPYD variant c.2766+3A>T causes exon 21 skipping, demonstrated on messenger RNA from peripheral blood mononuclear cells, yielding a non-functional DPD enzyme.

The authors report a 50-year-old man with colorectal cancer treated with adjuvant XELOX (oxaliplatin and capecitabine) who developed life-threatening grade 3-4 toxicity. Routine DPYD genotyping found no pathogenic variant; subsequent DPYD exon sequencing identified three heterozygous variants, c.1627A>G, c.2194G>A and c.2766+3A>T. The latter, a rare intronic variant, was shown to cause exon 21 skipping by messenger RNA analysis of peripheral blood mononuclear cells. The patient had profound DPD deficiency, and the authors conclude that c.2766+3A>T yields a non-functional enzyme and should be considered deleterious.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This case illustrates precisely the limitation of DPYD genotyping restricted to the recommended variants: a reassuring genotype says nothing about enzyme activity, and unexpected severe toxicity warrants full gene sequencing plus an RNA study rather than a conclusion of idiosyncratic susceptibility. The exon-skipping demonstration on RNA is convincing, but this is a single patient carrying three variants, so attributing the deficiency to the intronic variant alone rests on that functional result, not on family segregation or a cohort. In practice, treating the variant as deleterious seems reasonable for therapeutic decisions, while keeping phenotyping (plasma uracil or DPD activity) as a safety net independent of genotype.

Analysis by Dr Thibaut Benquey