Constellation: tool for automated CYP2D6 phenotype assignment from WGS

A team from Children’s Mercy and the University of Missouri in Kanas City including Andrea Gaedigk and Greyson Twist published an article about a CYP2D6 phenotype assignment tool in Genomic Medicine (http://www.nature.com/articles/npjgenmed20157). Constellation, a probabilistic scoring system, enables automated ascertainment of CYP2D6 activity scores based on CYP2D6 diplotypes from whole-genome sequences (WGS).CYP2D6 is involved in the metabolism of about 25% of drugs in clinical use and genetic variations leading to functional consequences affecting drug efficacy and risk of adverse events.  The gene is highly polymorphic with over 100 allelic variants (star alleles) assigned including CYP2D6 copy number variations and rearrangements with the neighboring CYP2D7. This high degree of variation, high sequence similarity to CYP2D7 and CYP2D8, GC content, repetitive and low-complexity sequences are challenges in analyzing this locus.The performance of the developed algorithm is evaluated by comparing the CYP2D6 diplotype assigned by the probabilistic WGS analysis using Constellation with the diplotype determined by manual integration (consensus reference) of results obtained by quantitative copy-number assessment, a panel of TaqMan genotype assays, and Sanger sequencing of long-range genomic PCR in 61 samples. Phenotype prediction is consistent between the consensus reference and Constellation calls with the exception of three cases. Constellation was able to accurately identify all poor and ultrarapid metabolizers in WGS data. The authors anticipate Constellation to be extensible to identify variations in other pharmacogenomic-relevant genes, enabling future uses of WGS data.