Full Gene Sequencing for DPD Deficiency Testing

Key Messages

What Is DPYD Genotyping Using Full Gene Sequencin?

• Dihydropyrimidine dehydrogenase (DPD) deficiency is the partial or complete loss of function of the DPD enzyme. Reduced DPD enzyme activity has an important effect on fluoropyrimidine (FP) treatment metabolism, which can increase the risk of experiencing treatment-related toxicity. DPD deficiency testing methods include DPYD genotyping and DPD phenotyping. Full DPYD gene sequencing is a genotyping approach that provides comprehensive sequencing of the entire DPYD gene rather than a targeted approach that only identifies a select panel of common deficient DPYD Comprehensive DPYD genotyping using full gene sequencing (FGS) provides an opportunity to identify additional rare coding variants with potentially decreased or no functional activity that may not be captured using standard targeted DPYD genotyping.

What Is the Purpose of This Recommendation and Evidence Review?

• Canada’s Drug Agency (CDA-AMC) published a Health Technology Review on DPD testing for patients treated with 5-fluorouracil and capecitabine in 2025. Newfoundland and Labrador Health Services subsequently requested updated information and a recommendation to support decision-making for the adoption and implementation of DPYD genotype testing in its jurisdiction. This request is singularly focused on 1 DPYD genotype testing strategy: using FGS through next-generation sequencing, as compared to no testing. The evidence review did not assess the comparative evidence of FGS versus other testing strategies for DPD deficiency (e.g., targeted panels for 4 or 7 common DPYD variants).

How Did CDA-AMC Assess DPYD Genotyping Using FGS?

• CDA-AMC conducted a review of the published literature to identify clinical outcomes and provide a simplified economic evaluation associated with DPYD genotype testing using FGS. This evidence review included a description of the context and evidence need; identified, appraised, and summarized the clinical utility, clinical validity, and diagnostic test accuracy evidence; provided considerations for cost outcomes and assessed the economic value; and identified and described some social and ethical considerations related to DPYD genotyping using FGS. This evidence review informed deliberations by the Health Technologies and Systems Expert Committee (HTSEC) to make recommendations on the use of FGS for DPD deficiency testing.

What Did We Find?

• Five nonrandomized studies were identified that provided outcomes for the clinical utility and clinical validity of DPYD genotype testing using FGS. Overall, DPYD genotype testing using FGS identified rare and novel DPYD variants, including confirmed pathogenic variants among the cohorts included within the studies, compared with no testing. Rare and novel pathogenic variants were associated with severe adverse events, including FP-related toxicities and mortality. DPYD genotyping using FGS provided predictive value measures for determining individuals at risk for experiencing severe FP-related toxicities and may offer clinical utility above targeted variant panel testing for identifying people who have variants associated with reduced or no DPD enzyme function who are at risk for adverse events. No evidence regarding outcomes associated with diagnostic test accuracy for DPYD genotyping using FGS was identified in the literature.
• FGS testing with whole exome sequencing adds modest lifetime costs ($388 per patient) and small (0.0117) quality-adjusted life-year gains compared with no testing. It would be considered cost-effective if the public health care system were willing to pay at least $33,281 per quality-adjusted life-year gained. These results are highly sensitive to assumptions about the prevalence of patients with poor or intermediate FP metabolism and the average intensive care unit use for such patients upon hospitalization. The cost-effectiveness of FGS is expected to improve as additional clinically actionable variants — ones that only FGS can detect — are shown to have clear, useful effects on treatment decisions.
• Evidence for the clinical utility of standard targeted DPYD testing is mainly focused on variants that have been most frequently identified in populations with predominately European ancestry. Limiting DPYD genotype testing to a targeted select panel of common DPYD variants based on such evidence has the potential to exacerbate health and racial inequities in populations with racially or ethnically diverse genetic backgrounds.
• Adequate and informed consent that outlines possible outcomes of the test, potential harms or benefits for patients and families, and privacy and confidentiality should be required when providing DPD deficiency testing.

What Is HTSEC?

• The mandate of HTSEC is advisory in nature and is to participate in the development of guidance or recommendations for CDA‑AMC projects on medical devices, diagnostic tests, and clinical interventions, inclusive of models and programs of care.
• HTSEC comprises 7 core members (1 chair, 1 ethicist, 1 health economist, 1 patient member, 2 health care practitioners, and 1 health technology assessment specialist) who serve for all topics under consideration during their term of office. In addition to these core members, HTSEC also includes up to 5 expert members appointed to provide their expertise on a specific topic. To develop the recommendations for the use of FGS for DPD deficiency testing uptake, HTSEC appointed 1 clinician with expertise in oncology, 1 with expertise in pathology and laboratory medicine, and 1 member who was able to speak to the perspective of a patient with lived experience.