What is genetic testing and how does it impact medical decision-making?

GeneSight Testing: An Overview of Pharmacogenomic Testing

GeneSight is a commercial pharmacogenomic test that analyzes genetic variants affecting drug metabolism, but its clinical utility remains limited by insufficient evidence demonstrating improved patient outcomes, and it should not replace standard clinical decision-making or therapeutic drug monitoring.

What GeneSight Testing Is

GeneSight represents a type of pharmacogenomic panel testing that analyzes genetic variants associated with drug metabolism, particularly for psychotropic medications 1. The test examines genes encoding drug-metabolizing enzymes (primarily cytochrome P450 enzymes) to predict how patients may respond to various medications 1.

• The test falls under the broader category of direct-to-consumer and clinical pharmacogenomic testing that has proliferated as next-generation sequencing has become more affordable 1
• These panels genotype multiple pharmacogenomic variants simultaneously, providing results that theoretically guide drug selection and dosing 1

Critical Limitations and Concerns

Lack of Demonstrated Clinical Utility

The fundamental problem with tests like GeneSight is the absence of robust evidence demonstrating that their use improves clinical outcomes compared to standard care 1.

• Major challenges include lack of demonstrated clinical validity and utility for most genetic variants identified in such panels 1
• Alternative approaches often exist with lower costs and better evidence, such as monitoring actual drug blood levels rather than adjusting based on genetic predictions alone 1
• The American Journal of Kidney Diseases guidelines emphasize that only a limited number of variants have strong evidence for preemptive screening, mostly in specific pharmacogenomic contexts 1

Interpretation Complexity

• Pharmacogenomic test results are highly technical and complex, requiring specialized knowledge for proper interpretation 1
• Results provide probabilistic information about drug metabolism, not definitive answers about whether a medication will work or cause adverse effects 1
• The clinical significance of many variants remains uncertain, and test results must be integrated with patient-specific factors including medical history, concurrent medications, and clinical response 1

Appropriate Use Framework

When Genetic Testing May Be Considered

Genetic testing should be reserved for specific clinical scenarios with established evidence, not as routine screening 1.

• Testing requires rigorous clinical phenotyping and comprehensive evaluation first 1
• The decision must consider whether results will actually alter clinical management or provide actionable information 1, 2
• For pharmacogenomics specifically, testing may be most appropriate when there is strong evidence from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for specific drug-gene pairs 1

Essential Requirements Before Testing

Board-certified genetics professionals or genetic counselors should be involved in the testing process 1.

• Pre-test genetic counseling is essential to ensure patients understand the purpose, benefits, limitations, and implications of testing 1, 2
• Patients must understand that results may not provide definitive answers and could identify variants of uncertain significance 1
• The testing laboratory must be CLIA-accredited and meet strict standards for clinical testing 1

Specific Concerns with Direct-to-Consumer Pharmacogenomic Testing

• The FDA has issued warning letters to direct-to-consumer genetic testing companies, stating that some tests require approval as medical devices prior to marketing 1
• Major safety concerns include incorrect test ordering, misinterpretation of results, and lack of appropriate follow-up 1
• Results may become actionable years after testing when medications are prescribed, creating potential for harm if healthcare providers lack proper context 1
• Educational initiatives are essential to improve health literacy among both healthcare providers and the public regarding these tests 1

Privacy and Legal Considerations

• The Genetic Information Nondiscrimination Act (GINA) provides some protections against discrimination in health insurance and employment, but does not cover life insurance, disability insurance, or companies with fewer than 15 employees 1
• Patients should understand who will have access to results, what happens to DNA samples after testing, and whether data will be shared with third parties 1
• Results have implications not just for the patient but for biological family members who may share genetic variants 1, 2

Alternative Approaches

In most clinical scenarios, traditional therapeutic drug monitoring and careful clinical observation provide more reliable guidance than pharmacogenomic testing 1.

• Measuring actual drug blood levels is often more cost-effective and clinically useful than genetic predictions 1
• Standard dose titration based on clinical response and side effects remains the gold standard for most medications 1
• Incorporating genetic testing into electronic medical records could facilitate appropriate use when evidence supports it, but this infrastructure is often lacking 1

Common Pitfalls to Avoid

• Do not treat variants of uncertain significance as definitively pathogenic or benign, as this leads to inappropriate clinical management 2
• Avoid ordering genetic tests without adequate pre-test counseling and a clear plan for how results will be used 2
• Do not fail to recognize the limitations of genetic testing, including possibilities of false positives and false negatives 2
• Avoid neglecting the need for periodic reassessment, as variant interpretations may change over time as evidence accumulates 2

Bottom Line for Clinical Practice

For tests like GeneSight, the evidence does not currently support routine use in clinical practice 1. When pharmacogenomic testing is considered, it should be limited to scenarios with strong supporting evidence from professional guidelines, involve appropriate genetic counseling, and never replace careful clinical assessment and monitoring 1. The burden of competing morbidities and shorter life expectancy in some patients may further reduce any potential benefit from such testing 1.