Identification of CYP2D6 Haplotypes that Interfere with Commonly Used Assays for Copy Number Variation Characterization.

Document Type


Publication Date



DOI: 10.1016/j.jmoldx.2021.01.013


Cytochrome P450 2D6 (CYP2D6) copy number (CN) variation affects the metabolism of numerous prescribed drugs. Sequence variation within primer or probe target regions of hydrolysis probe CN assays can generate false-positive calls for CN loss. Furthermore, CYP2D6-CYP2D7 hybrids and gene conversions can cause difficult to interpret discordant CN calls. The identification of haplotypes with CN variations and structural arrangements is important to predict phenotype accurately. During clinical testing with hydrolysis probe assays targeting three CYP2D6 regions (intron 2, intron 6, and exon 9), samples with haplotypes causing inconsistent CN calls were identified. To resolve these cases, next-generation sequencing and allele-specific Sanger sequencing was performed. Sequence analysis of 16 samples, all but one from subjects of African descent, identified six novel suballeles containing single-nucleotide polymorphisms, which cause false-positive calls for CN loss in introns 2 and 6. Five samples with an exon 9 CN loss contained CYP2D6/CYP2D7 hybrids (∗13 or ∗36) and one sample was found to have a novel haplotype, CYP2D6∗141. Interestingly, CYP2D6∗141 contains a CYP2D7-derived exon 9 conversion and core single-nucleotide polymorphisms that are otherwise found in CYP2D6∗17 and ∗27. Although these variants are rare, they can cause inconsistent CN calls that typically are reported as no calls or indeterminant, and thus may deprive patients, particularly those of African descent, from taking full benefit of pharmacogenetic testing.

Journal Title

The Journal of molecular diagnostics : JMD





First Page


Last Page


Library Record