What are the recommendations for genetic testing and gene therapy for genetic disorders?

Recommendations for Genetic Testing and Gene Therapy for Genetic Disorders

Genetic testing should be performed in specific clinical scenarios based on established guidelines, while gene therapy remains an emerging treatment with limited approved applications that requires careful consideration of risks and benefits.

Genetic Testing Recommendations

When to Perform Genetic Testing

The American College of Medical Genetics and Genomics (ACMG) has established clear guidelines for genetic testing in various clinical scenarios:

First-Tier Testing:

• All children with autism spectrum disorder (ASD) should undergo chromosomal microarray (CMA) testing 1
• Testing for specific genetic disorders when clinical presentation suggests their presence:
  • Alpha-1 antitrypsin deficiency testing for individuals with:
    • Early-onset emphysema (age ≤45 years)
    • Emphysema without recognized risk factors
    • Emphysema with basilar hyperlucency
    • Unexplained liver disease
    • Necrotizing panniculitis
    • Anti-proteinase 3-positive vasculitis
    • Family history of related conditions 1

Second-Tier Testing:

For children with ASD, additional testing should include:

• Fragile X testing in all males
• MECP2 sequencing in all females and in males with suggestive clinical presentation
• PTEN sequencing in children with macrocephaly 1

Early-Onset Autosomal Dominant Alzheimer's Disease Testing

Testing for genes associated with early-onset autosomal dominant Alzheimer's disease should be offered in:

• Symptomatic individuals with early-onset AD in families with dementia history
• Families with autosomal dominant dementia history with early-onset cases
• Relatives of individuals with confirmed mutations 1

Genetic Testing Approach

The ACMG emphasizes that genetic testing should follow a structured approach:

1. Ideally, test an affected family member first
2. Provide thorough genetic counseling before and after testing
3. Consider psychological impact and potential discrimination risks 1

Gene Therapy Considerations

Current Status of Gene Therapy

Gene therapy has progressed from theoretical concept to clinical reality:

• First products have been licensed in the European Union for:
  • Immune deficiency
  • Spinal muscular atrophy
  • Hemophilia
  • Retinal dystrophy
  • Rare neurotransmitter disorders
  • Some hematological cancers 2

Safety Concerns with Gene Therapy

Important safety considerations include:

• Immune reactions to:
  • The vector
  • Foreign DNA
  • New proteins resulting from gene therapy
• Low but persistent cancer risk from insertional mutagenesis 2
• Unintended biological consequences 3

Ethical Considerations

Gene therapy raises significant ethical questions:

• When and why to use such technology versus alternative treatments
• Balancing benefits against risks and costs
• Ensuring fair access to potentially life-saving treatments 3
• Distinguishing between somatic and germline interventions 3

Clinical Utility of Genetic Testing

The ACMG position statement on clinical utility emphasizes that utility extends beyond direct medical management:

• Effects on diagnostic or therapeutic management
• Implications for prognosis
• Health and psychological benefits to patients and relatives
• Economic impact on healthcare systems
• Value a diagnosis brings to individuals, families, and society 1

Special Considerations for Pharmacogenomic Testing

For patients receiving anthracycline chemotherapy:

• Pharmacogenomic testing should be performed in all childhood cancer patients receiving doxorubicin or daunorubicin therapy for specific genetic variants (RARG rs2229774, SLC28A3 rs7853758, and UGT1A6*4 rs17863783)
• Testing is not currently recommended for adult patients or children receiving other anthracyclines 1

Practical Implementation Challenges

Economic Evaluation of Genetic Testing

Economic evaluations of genetic testing should:

• Consider test performance characteristics (sensitivity/specificity)
• Conduct sensitivity analyses for key parameters
• Evaluate the impact of uncertainty in model inputs 1

Incidental Findings

The ACMG recommendations for handling incidental findings from whole genome/exome sequencing:

• Specific gene panels should be evaluated as part of testing
• Pathogenic variants should be reported regardless of patient age
• Focus on highly penetrant disorders for which treatment or prevention is available 1

Conclusion

Genetic testing has established clinical utility in specific scenarios with clear guidelines, while gene therapy represents a promising but still developing treatment approach that requires careful evaluation of risks and benefits. The decision to pursue either should be guided by evidence-based recommendations from professional societies, with consideration of both clinical outcomes and broader impacts on patients and families.