Which pharmacogenomic and hereditary genetic blood tests should be ordered for the patient?

Pharmacogenomic and Hereditary Genetic Blood Tests to Order

Order a multi-gene pharmacogenomic panel that includes at minimum: CYP2D6, CYP2C19, CYP2C9, TPMT, NUDT15, HLA-B, and HLA-A, with testing methodology that can detect both single nucleotide variants (SNVs) and copy number variations (CNVs). 1

Core Pharmacogenomic Testing Approach

The 2022 ACMG guidelines establish that pharmacogenomic testing should be comprehensive rather than reactive single-gene testing. The evidence strongly supports panel-based testing because over 95% of the population carries at least one actionable pharmacogenomic variant 2, and panel testing is more cost-effective than sequential single-gene tests 3.

Essential Genes to Include

Your pharmacogenomic panel must include these high-priority genes based on FDA labeling and CPIC guidelines:

Drug Metabolism Genes:

• CYP2D6 - Critical for tamoxifen, codeine, antidepressants, antipsychotics. Must include CNV detection as deletions and duplications are common 1
• CYP2C19 - Essential for clopidogrel, proton pump inhibitors, antidepressants 1
• CYP2C9 - Required for siponimod dosing (contraindicated in *3/*3 genotype), warfarin, phenytoin. Include alleles *5, *6, *8, *11 which are common in African ancestry populations 1

Thiopurine Metabolism:

• TPMT - Test for *2, *3A, *3C alleles (account for 95% of reduced activity). Required before azathioprine, mercaptopurine, thioguanine to prevent life-threatening myelosuppression 1
• NUDT15 - Test for *3 allele. Also prevents myelosuppression with thiopurines 1

HLA Alleles for Severe Hypersensitivity:

• HLA-B*15:02 - Prevents Stevens-Johnson syndrome and toxic epidermal necrolysis with carbamazepine 1
• HLA-A*31:01 - Prevents drug reaction with eosinophilia and systemic symptoms (DRESS) with carbamazepine 1

Testing Methodology Requirements

Your laboratory must use methods that detect:

• Single nucleotide variants (SNVs)
• Copy number variations (CNVs) - particularly critical for CYP2D6 where deletions, duplications, and gene conversions are common 1
• Structural variants including gene conversions (CYP2D6/CYP2D7) 1

Targeted genotyping panels are acceptable but understand their limitation: they only detect variants specifically tested for. A negative result doesn't exclude the presence of other variants 1. Exome or genome sequencing can identify additional variants but may miss deep intronic variants unless specifically designed to capture them 1.

Critical Testing Considerations

When to Order Testing

Preemptive (screening) testing is superior to reactive testing because:

• Results are available before prescribing decisions need to be made
• Panel testing identifies actionable variants for multiple current and future medications
• 100% of tested patients have at least one actionable variant 3

Reactive testing is appropriate when:

• Patient is already prescribed or about to start a drug with FDA-required or recommended pharmacogenomic testing
• Patient has experienced unexplained adverse drug reactions or therapeutic failure
• Patient is on thiopurines, tamoxifen, clopidogrel, siponimod, carbamazepine, or abacavir 1, 4

Common Pitfalls to Avoid

1. Drug-drug interactions override genetics: A patient with normal CYP2D6 function who takes paroxetine (strong CYP2D6 inhibitor) will phenocopy as a poor metabolizer. Genetic testing doesn't account for this 1

2. Incomplete CYP2D6 testing: Over 140 CYP2D6 alleles exist. Testing must include no function (*4), decreased function (*10), and increased function (*2x2) alleles, plus CNVs 1

3. Population-specific variants: CYP2C9 alleles *5, *6, *8, *11 are common in African ancestry populations but often not included in standard panels 1

4. *Assuming 1 means normal: A *1 designation only means targeted variants weren't detected, not that the gene is definitively normal 1

Report Requirements

The laboratory report must include 1:

• Genotype and metabolizer phenotype (poor, intermediate, normal, rapid, ultrarapid)
• List of affected medications by the identified genotype
• Generalized therapeutic alternatives when appropriate
• Resources for actionable decisions (FDA tables, CPIC guidelines)
• Clear statement that drug-drug interactions can alter phenotype
• No patient-specific dosing recommendations - these are the prescriber's responsibility

Hereditary Cancer Testing Distinction

If your question refers to hereditary cancer genetic testing rather than pharmacogenomics, that's a separate category requiring different panels (BRCA1/2, Lynch syndrome genes, etc.). The context of your question suggests pharmacogenomic testing, but clarify if hereditary disease testing is needed instead.

Implementation Strategy

Order testing through a CAP-accredited laboratory that participates in proficiency testing programs 1. Verify the laboratory can detect CNVs, not just SNVs, particularly for CYP2D6 1. Results should be integrated into the electronic health record for longitudinal use, as pharmacogenomic results remain relevant throughout the patient's lifetime 5.