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

Authors

Sara Salvador-Martín, Irene Taladríz-Sender, Paula Zapata-Cobo, Gina Hernández-Osio, Javier Soto-Alsar, José Luis Revuelta-Herrero, Pilar García-Alfonso, Fabienne Thomas, María Sanjurjo-Sáez, Luis A López-Fernández, Xandra García-González

Published in

British journal of clinical pharmacology. Aug 13, 2026. Epub Aug 13, 2026.

Abstract

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.
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.
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.

PMID:
42596594
Bibliographic data and abstract were imported from PubMed on 14 Aug 2026.

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