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