Abstract

Cytochrome P450 2D6, (CYP2D6) is highly polymorphic. CYP2D6-2D7 hybrid genes can be present in samples containing CYP2D6*4 and CYP2D6*10 alleles. CYP2D7-2D6 hybrid genes can be present in samples with duplication signals and in samples with homozygous genotyping results. The frequency of hybrid genes in clinical samples is unknown. 1390 samples were evaluated for undetected hybrid genes by PCR amplification, PCR fragment analysis, Taqman^® copy number assays, DNA sequencing and allele specific primer extension assay (ASPE). Of 508 CYP2D6*4-containing samples, 109 (21.5%) harbored CYP2D6*68 + *4-like, while 9 (1.8%) harbored CYP2D6*4N + *4-like. Of 209 CYP2D6*10-containing samples, 44 (21.1%) were found to have CYP2D6*36 + *10. Of 332 homozygous samples, 4 (1.2%) harbored a single CYP2D7-2D6 hybrid and of 341 samples with duplication signals, 25 (7.3%) harbored an undetected CYP2D7-2D6 hybrid. Phenotype before and after accurate genotyping was predicted using a method in clinical use. The presence of hybrid genes had no effect on the phenotype prediction of CYP2D6*4-and CYP2D6*10-containing samples. Four of 4 (100%) homozygous samples containing a CYP2D7-2D6 gene had a change in predicted phenotype and 23 of 25 (92%) samples with a duplication signal and a CYP2D7-2D6 gene had a change in predicted phenotype. Four novel genes were identified (CYP2D6*13A1 variants 1 and 2, CYP2D6*13G1 and a CYP2D6*13G2) and two novel hybrid tandem structures consisting of CYP2D6*13B + *68 X 2 + *4-like and CYP2D6*13A1 var 2 + *1 X N were observed.