2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Development and validation of an NGS assay for the detection of clinically actionable genetic variants in DPYD and UGT1A1

Pdf Summary

This document discusses the development and validation of a Next-Generation Sequencing (NGS) assay for the detection of clinically actionable genetic variants in two drug metabolizing enzymes, DPYD and UGT1A1. The NGS assay was designed to detect any loss or decreased function of these enzymes, which can impact the response to certain medications. <br /><br />The authors implemented a novel calling algorithm to address an issue called "stutter" created by DNA polymerase in repeats. The accuracy of the assay was confirmed by comparing the calls of TA repeat polymorphisms with orthogonal methods such as PCR amplified capillary electrophoresis and Sanger sequencing.<br /><br />The performance of the assay was evaluated using metrics such as Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA). The results showed high agreement between the NGS assay and the orthogonal methods.<br /><br />DPYD and UGT1A1 are important enzymes involved in the metabolism of drugs such as 5-fluorouracil (5-FU), irinotecan, and sacituzumab. Loss or decreased function of these enzymes can affect the effectiveness and toxicity of these medications.<br /><br />The assay was able to accurately detect genetic polymorphisms in DPYD and UGT1A1, which are associated with poor metabolizer variants. This information can be useful in identifying patients who may require dose adjustments or alternative treatment options.<br /><br />Overall, the NGS assay developed in this study provides a reliable and efficient method for detecting clinically actionable genetic variants in DPYD and UGT1A1. This information can help personalize treatment plans and improve patient outcomes in a range of cancers treated with drugs metabolized by these enzymes.

Asset Subtitle

Presenting Author - Robert Huether, PhD; Co-Author - Kyung Choi, Pharm.D.; Co-Author - Ian Zavitz, MS; Co-Author - Yan Yang, Ph.D.; Co-Author - Christopher N. Vlangos, PhD, FACMG; Co-Author - Rachel Star, BS; Co-Author - Francisco De La Vega, PhD;

Meta Tag

Bioinformatics

NextGen Sequencing

Pharmacogenomics

Therapy

Co-Author Kyung Choi, Pharm.D.

Co-Author Ian Zavitz, MS

Co-Author Yan Yang, Ph.D.

Co-Author Christopher N. Vlangos, PhD, FACMG

Co-Author Rachel Star, BS

Co-Author Francisco De La Vega, PhD

Presenting Author Robert Huether, PhD

Keywords

Next-Generation Sequencing

NGS assay

clinically actionable genetic variants

drug metabolizing enzymes

DPYD

UGT1A1

stutter

orthogonal methods

Positive Percent Agreement

Negative Percent Agreement