Profound Dihydropyrimidine Dehydrogenase Deficiency Resulting from a Novel Compound Heterozygote Genotype

摘要: A familial approach was used to elucidate the genetic determinants of profound and partial dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2) deficiency in an Alabama family. In 1988, our laboratory diagnosed DPD a breast cancer patient with grade IV toxicity after cyclophosphamide/methotrexate/5-fluorouracil chemotherapy (R. B. Diasio et al. , J. Clin. Investig., 81: 47–51, 1988). We now report analysis archived genomic DNA that reveals proband compound heterozygote for two different mutations, one each allele: ( ) G mutation GT 5′ splicing recognition sequence intron 14, which results 165-bp deletion (corresponding exon 14) mRNA DPYD*2A ); b T1679G (now designated DPYD*13 ), I560S substitution. Sequence revealed segregation both mutations son daughter inheriting mutation. Phenotype (DPD enzyme activity) confirmed children were partially deficient. Plasma uracil levels found be within normal limits children. conclude resulted from combination (one allele) heterozygosity either deficiency. Lastly, we identified variant alleles reported previously as being associated [T85C resulting C29R substitution DPYD*9A A496G (M166V) family member activity]. These data suggest are unrelated emphasize need perform detailed genotypic phenotypic while characterizing this pharmacogenetic syndrome.