What is genetic testing (Genesite testing) used for and how are the results interpreted?

Genetic Testing: Purpose and Interpretation of Results

Genetic testing is used for screening, diagnosis, and prognosis of diseases with genetic etiology, and to guide drug therapy to improve efficacy and avoid adverse effects (pharmacogenomics). 1

Types and Purposes of Genetic Testing

Genetic testing involves analyzing human chromosomes, genes, or proteins to detect heritable diseases for clinical purposes. The main applications include:

Diagnostic Testing

• Confirms or rules out suspected genetic disorders based on clinical evidence or family history
• Used for diagnosing rare Mendelian disorders
• Helps identify genetic causes of complex traits (e.g., APOL1-associated chronic kidney disease) 1

Pharmacogenomic Testing

• Guides drug therapy selection and dosing
• Identifies individuals who may:
  • Metabolize drugs faster or slower than average
  • Be non-responders to certain medications
  • Be at risk for severe adverse drug reactions 1
• Example: Warfarin dosing is significantly affected by CYP2C9 and VKORC1 genetic variants:
  • Patients with CYP2C9*2 variant require 17% less warfarin
  • Patients with CYP2C9*3 variant require 37% less warfarin
  • About 55% of warfarin dose variability can be explained by these genetic factors 2

Predictive/Presymptomatic Testing

• Identifies genetic variants associated with disease risk before symptoms appear
• Particularly important for inherited cardiovascular diseases and cancer predisposition 1

Carrier Testing

• Identifies individuals carrying genetic variants that may not affect them but could be passed to offspring
• Used for reproductive planning 1

Interpretation of Genetic Test Results

Variant Classification

Genetic variants are classified into five categories according to ACMG guidelines:

• Pathogenic
• Likely pathogenic
• Variant of uncertain significance (VUS)
• Likely benign
• Benign 1

Clinical Implications

• Positive result (pathogenic/likely pathogenic variant): Confirms diagnosis or indicates increased disease risk
• Negative result: May rule out certain genetic conditions but doesn't eliminate all genetic causes
• VUS: Insufficient evidence to determine if variant affects disease risk; requires periodic reassessment as knowledge evolves 1

Important Considerations

1. Test limitations:

   • Genetic testing rarely has 100% diagnostic yield
   • People of non-European ancestry are more likely to receive VUS results due to less diverse reference databases 1

2. Result interpretation challenges:

   • Penetrance varies (not everyone with a pathogenic variant will develop disease)
   • Expressivity varies (severity differs among individuals with same variant)
   • Multiple genes and environmental factors often contribute to disease risk 1

3. Pharmacogenomic implications:

   • Results can guide initial drug selection and dosing
   • May help avoid adverse effects or ineffective treatments
   • Particularly valuable for medications with narrow therapeutic windows 1, 2

Pitfalls and Caveats

1. Overinterpretation of results:

   • VUS should not be used for clinical decision-making
   • Direct-to-consumer tests may have limited clinical validity and utility 1

2. Ethical and psychological considerations:

   • Potential for insurance discrimination (though GINA provides some protection)
   • Psychological impact of learning about disease risk 1

3. Provider knowledge gaps:

   • Many providers feel unprepared to interpret genetic test results
   • Lack of confidence in explaining implications to patients 3

4. Test selection:

   • Expanded test panels may increase VUS findings
   • Whole-genome/exome sequencing increases chance of incidental findings 1

Best Practices for Genetic Testing

1. Pre-test counseling:

   • Discuss purpose, benefits, limitations, and potential outcomes
   • Consider psychological impact and family implications

2. Test selection:

   • Choose tests with strong evidence for clinical validity and utility
   • Consider targeted testing before broader panels when appropriate 1

3. Result interpretation:

   • Consult with genetics professionals when needed
   • Consider periodic reinterpretation as knowledge evolves 1

4. Post-test counseling:

   • Explain results and implications clearly
   • Discuss management plans and follow-up
   • Address cascade testing for family members when appropriate 1

Genetic testing technology continues to advance rapidly, making it increasingly important for healthcare providers to understand its applications and limitations to provide optimal patient care.