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

BACKGROUND: Fluoropyrimidines are widely used for the treatment of solid tumours, but they carry a significant risk of severe toxicity in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. CASE PRESENTATION: We describe a 50-year-old male with colorectal cancer who received adjuvant XELOX (oxaliplatin and capecitabine) and developed life-threatening grade 3-4 toxicities. Routine DPYD genotyping showed no pathogenic variants. 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 demonstrated to cause exon 21 skipping by mRNA analysis of peripheral blood mononuclear cells (PBMCs). The patient presented a profound DPD deficiency. CONCLUSION: The c.2766+3A>T variant leads to a non-functional DPD enzyme and is a likely cause of severe fluoropyrimidine-related toxicity. This variant should be considered deleterious.