BACKGROUND/AIM: Accurate genotyping of CYP2D6 is challenging due to its inherent genetic variation, copy number variation (duplications and deletions) and hybrid formation with highly homologous pseudogenes. Because a relatively high percentage (∼25%) of clinically prescribed drugs are substrates for this enzyme, accurate determination of its genotype for phenotype prediction is essential. METHODS: A cohort of 365 patient samples was genotyped for CYP2D6 using Sanger sequencing (as the gold standard), hydrolysis probe assays or pyrosequencing. RESULTS: A discrepant result between the three genotyping methods for the loss of function CYP2D6*3 (g.2549delA, rs35742686) genetic variant was found in one of the samples. This sample also contained the CYP2D6 g.2470T>C (rs17002852) variation, which had an allele frequency of 2.47% in our cohort. Redesign of the CYP2D6*3 pyrosequencing and hydrolysis probe assays to avoid CYP2D6 g.2470 corrected the anomaly. CONCLUSION: To evidence allele drop out and increase the accuracy of genotyping, intra-patient validation of the same genetic variation with at least two separate methods should be considered.
BACKGROUND/AIM: Accurate genotyping of CYP2D6 is challenging due to its inherent genetic variation, copy number variation (duplications and deletions) and hybrid formation with highly homologous pseudogenes. Because a relatively high percentage (∼25%) of clinically prescribed drugs are substrates for this enzyme, accurate determination of its genotype for phenotype prediction is essential. METHODS: A cohort of 365 patient samples was genotyped for CYP2D6 using Sanger sequencing (as the gold standard), hydrolysis probe assays or pyrosequencing. RESULTS: A discrepant result between the three genotyping methods for the loss of function CYP2D6*3 (g.2549delA, rs35742686) genetic variant was found in one of the samples. This sample also contained the CYP2D6 g.2470T>C (rs17002852) variation, which had an allele frequency of 2.47% in our cohort. Redesign of the CYP2D6*3 pyrosequencing and hydrolysis probe assays to avoid CYP2D6 g.2470 corrected the anomaly. CONCLUSION: To evidence allele drop out and increase the accuracy of genotyping, intra-patient validation of the same genetic variation with at least two separate methods should be considered.
Authors: Charity Nofziger; Amy J Turner; Katrin Sangkuhl; Michelle Whirl-Carrillo; José A G Agúndez; John L Black; Henry M Dunnenberger; Gualberto Ruano; Martin A Kennedy; Michael S Phillips; Houda Hachad; Teri E Klein; Andrea Gaedigk Journal: Clin Pharmacol Ther Date: 2019-12-09 Impact factor: 6.875
Authors: E Ricky Chan; Rajeev K Mehlotra; Karim A Pirani; Arsene C Ratsimbasoa; Scott M Williams; Andrea Gaedigk; Peter A Zimmerman Journal: Pharmacogenomics Date: 2022-03-01 Impact factor: 2.533
Authors: Helmi Pett; John Bradley; Joseph Okebe; Alassane Dicko; Alfred B Tiono; Bronner P Gonçalves; Will Stone; Ingrid Chen; Kjerstin Lanke; Mikko Neuvonen; Anna-Liina Mustaniemi; Alice C Eziefula; Roly Gosling; Umberto D'Alessandro; Chris Drakeley; Mikko Niemi; Teun Bousema Journal: Antimicrob Agents Chemother Date: 2019-09-23 Impact factor: 5.191
Authors: Gustav Kamenski; Seda Ayazseven; Anne Berndt; Waltraud Fink; Lukas Kamenski; Sonja Zehetmayer; Helene Pühringer Journal: Drugs Real World Outcomes Date: 2020-03
Authors: Christopher Taylor; Ian Crosby; Vincent Yip; Peter Maguire; Munir Pirmohamed; Richard M Turner Journal: Genes (Basel) Date: 2020-10-30 Impact factor: 4.096