title: DPYD*2A mutation: the most common mutation associated with DPD deficiency.
abstract: BACKGROUND
  Dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the elimination of approximately 80% of administered dose of 5-FU. DPD deficiency has been associated with severe 5-FU toxicity. Syndrome of DPD deficiency manifests as diarrhea, stomatitis, mucositis, and neurotoxicity and in some cases death. This is a true pharmacogenetic syndrome, with symptoms being unrecognizable until exposure to the drug.
  
  
  METHODS
  A 75-year-old patient with metastatic pancreatic adenocarcinoma developed grade 4 thrombocytopenia, grade 3 coagulopathy, and grade 3 neurologic toxicity with a fatal outcome following administration of 5-FU. Due to pancytopenia, DPD activity could not be determined in peripheral blood mononuclear cells (PBMC) using a previously described radioassay. Therefore, screening and genotypic analysis of homozygous and heterozygous, known and unknown sequence variants, in the DPYD gene were performed using DHPLC as previously described. All DPYD sequence variants identified by DHPLC were confirmed by DNA sequencing using a dideoxynucleotide chain termination method and capillary electrophoresis on an ABI 310 Automated DNA Sequencer.
  
  
  RESULTS
  Genotyping analysis of the DPYD gene revealed the presence of the heterozygous mutation, IVS14 + 1 G > A, DPYD*2A.
  
  
  CONCLUSIONS
  Genotypic analysis using DHPLC can be employed to screen DPD deficiency in a patient with severe neutropenia. The mutation IVS14 + 1 G > A, DPYD*2A, is the most common mutation associated with DPD deficiency. A G > A base change at the splice recognition sequence of intron 14, leads to exon skipping and results in a 165-bp deletion in the DPD mRNA. We have previously demonstrated that a homozygote DPYD*2A genotype results in complete deficiency while the heterozygous DPYD*2A genotype results in partial deficiency of DPD.
authors.affiliation: Yale University School of Medicine, Section of Medical Oncology, 333 Cedar Street; FMP 116, New Haven, CT 06520, USA. wasif.saif@yale.edu
authors.forename: M W
authors.initials: MW
authors.lastname: Saif
authors.forename: Hany
authors.initials: H
authors.lastname: Ezzeldin
authors.forename: Katisha
authors.initials: K
authors.lastname: Vance
authors.forename: Sandra
authors.initials: S
authors.lastname: Sellers
authors.forename: Robert B
authors.initials: RB
authors.lastname: Diasio
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D017809:Fatal Outcome; D005472:Fluorouracil / Q000009:adverse effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil