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Updated: Aug 15, 2026

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
The variant c.2766+3A>T in DPYD leads to exon 21 skipping and is associated with DPD deficiency and severe
Sara Salvador-Martín1, Irene Taladríz-Sender1, Paula Zapata-Cobo1
1Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
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.
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