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 et al.
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Case in brief
A 50-year-old man with colorectal cancer developed life-threatening grade 3–4 toxicity while receiving adjuvant XELOX (oxaliplatin and capecitabine). Routine DPYD genotyping found no pathogenic variants. Further exon sequencing identified three heterozygous variants: c.1627A>G, c.2194G>A and c.2766+3A>T. mRNA analysis of peripheral blood mononuclear cells showed that the intronic c.2766+3A>T variant caused exon 21 skipping. The patient had profound dihydropyrimidine dehydrogenase (DPD) deficiency; the authors concluded that this variant leads to non-functional DPD and is a likely cause of the severe fluoropyrimidine-related toxicity.
What made this case unusual
Routine DPYD genotyping was negative, but further sequencing identified an intronic variant whose functional effect—exon 21 skipping—was demonstrated by mRNA analysis.
Diagnostic / clinical pearl
A negative routine DPYD genotype does not exclude DPD deficiency; in this case, further sequencing and mRNA analysis identified a functionally consequential intronic variant.