Characterization of a complex CYP2D6 genotype that caused an AmpliChip CYP450 Test® no-call in the clinical setting

Andrea Gaedigk; Amanda K. Riffel; Belén García Berrocal; Virginia García Solaesa; Ignacio Dávila; María Isidoro-García

doi:10.1515/cclm-2013-0943

Article

Characterization of a complex CYP2D6 genotype that caused an AmpliChip CYP450 Test^® no-call in the clinical setting

Andrea Gaedigk , Amanda K. Riffel , Belén García Berrocal , Virginia García Solaesa , Ignacio Dávila and María Isidoro-García

Published/Copyright: January 20, 2014

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From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 52 Issue 6

Abstract

Background: CYP2D6, a major drug-metabolizing enzyme, is encoded by a highly polymorphic and complex gene locus. We have identified a patient who failed to produce a CYP2D6 genotype with the AmpliChip P450 Test^® (AmpliChip), whereas his CYP2C19 genotype was readily determined. The aim of this investigation was to fully characterize the patient’s CYP2D6 gene locus to resolve the AmpliChip no-call.

Methods: The case, a brother, and son were genotyped with the AmpliChip and subsequently characterized using long-range (XL)-PCR coupled with TaqMan assay technology. Copy number variation was assessed by XL-PCR and quantitative PCR. Selected XL-PCR products were sequenced.

Results: The AmpliChip also produced a no-call for the son; the brother produced a result. The two alleles of the case were subsequently found to carry additional gene units that likely caused the AmpliChip no-calls. One was characterized as a CYP2D6*68+*4 tandem (CYP2D6*68 is a hybrid gene composed of 2D6 and 2D7), the other as a rare CYP2D6*13+*2 tandem (CYP2D6*13 is a 2D7/2D6 hybrid formerly known as CYP2D6*77). A novel CYP2D6*2 subvariant was identified in the son; the brother also carried the CYP2D6*68+*4 tandem.

Conclusions: The implementation of pharmacogenetics-guided drug therapy relies on accurate clinical-grade genotype analysis. Although the AmpliChip is deemed to be a reliable platform, numerous more recently discovered allelic variants and gene arrangements are not detected or trigger no-calls. Although such cases may be rare, the clinical/genetic testing community must be aware of the challenges of CYP2D6 testing on the AmpliChip platform and implications regarding accuracy of test results.

Keywords: AmpliChip CYP450 Test; CYP2D6; cytochrome CYP450; genotyping; pharmacogenetics

Corresponding author: Andrea Gaedigk, PhD, Division of Developmental Pharmacology and Therapeutic Innovation, Children’s Mercy Hospital and Clinics, 2401 Gilham Road, Kansas City, MO 64108, USA, Phone: +1-816-234-3059 (office), Fax: +1-816-855-1958, E-mail: agaedigk@cmh.edu; and Department of Pediatrics, University of Missouri-Kansas City, Kansas City, MO, USA

Acknowledgments

The authors are grateful to the technical assistance of Mrs. Pilar Carrero and Mr. Amador Crego.

Conflict of interest statement

Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

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Received: 2013-10-31

Accepted: 2013-12-10

Published Online: 2014-1-20

Published in Print: 2014-6-1

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Articles in the same Issue

https://doi.org/10.1515/cclm-2013-0943

Keywords for this article

AmpliChip CYP450 Test; CYP2D6; cytochrome CYP450; genotyping; pharmacogenetics