Thiopurine S-methyltransferase genotype-phenotype concordance: used as a quality assurance tool to help control the phenotype assay

Background: As part of the quality control system for our TPMT phenotyping service we monitor the genotype-phenotype concordance for patient samples with deficient and low TPMT activity. We have studied the genotype-phenotype concordance over the last year to demonstrate its effectiveness as a quality assurance tool. Methods: From July 2007 to July 2008 TPMT genotyping was performed on all routine samples analysed using our phenotypic assay with an activity of <= 40 nmol 6-MTG/gHb/h. The monthly genotype-phenotype concordance was calculated between: all deficient TPMT activity results and a homozygous mutant or compound heterozygote genotype, low TPMT activity and a heterozygote genotype, normal TPMT activity and a wild-type genotype. Results: A total of 14,832 samples were analysed by TPMT phenotyping and 1769 of these by genotyping. The monthly mean concordance between low TPMT activity and a mutant heterozygote genotype was 83%, ranging from 67-90%. The number of individuals with deficient TPMT activity identified by phenotyping was 44. For two of these individuals only one mutant allele was detected, and for one no common mutations were identified. Conclusions: Monitoring the genotype-phenotype concordance is an effective quality assurance tool for the TPMT phenotyping assay. As demonstrated in this study current genotyping assays risk missing some deficient patients.