Should a patient undergo genetic testing?

Should a Patient Undergo Genetic Testing?

Genetic testing should be reserved for patients with a confirmed or suspected diagnosis of an inherited disease, those with a significant family history spanning at least 3 generations suggesting hereditary conditions, or individuals at high a priori risk from a previously identified pathogenic variant in their family—not for routine screening in asymptomatic individuals without these risk factors. 1

When Genetic Testing Is Appropriate

Cardiovascular Disease Context

• Genetic testing is indicated when rigorous disease-appropriate phenotyping combined with a comprehensive 3-generation family history establishes or strongly suggests an inherited cardiovascular disease (cardiomyopathies, arrhythmic disorders, thoracic aortic aneurysms, familial hypercholesterolemia). 1
• The family member with the most definitive and most severe phenotype should ideally be tested first to maximize the likelihood of identifying pathogenic variants useful for familial cascade testing, though practically the presenting patient is often tested first. 1

Cancer Susceptibility Context

• For BRCA-related cancer risk, women whose family history is associated with increased risk for potentially harmful BRCA1/BRCA2 mutations should be referred for genetic counseling and evaluation for testing, while routine referral is not recommended for those without such family history. 1
• For breast cancer patients, germline testing should be offered when there is personal or family history suggestive of genetic cancer susceptibility and when test results will influence medical management or treatment decisions. 1

Kidney Disease Context

• For living kidney donor candidates, genetic testing should be pursued through cascade testing—first testing the affected family member to establish a genetic diagnosis, then performing targeted testing on the asymptomatic donor candidate rather than screening donors directly without regard to familial disease. 1

Essential Pre-Testing Requirements

Mandatory Genetic Counseling

• Unless the ordering provider is sufficiently qualified to choose, order, interpret the genetic testing AND counsel the patient appropriately, referral to a genetics professional (board-certified geneticist or genetic counselor) is indicated before testing is ordered. 1
• Patients must receive pre-test genetic counseling covering: the purpose of testing, genes being tested, possible results (pathogenic/likely pathogenic variants, negative, VUS), implications for medical management, implications for family members, and legal/confidentiality concerns including insurance discrimination limitations. 1

Informed Consent Elements

• Patients must understand the potential benefits, risks, and limitations of genetic testing before consenting, including uncertainties in interpretation and the fact that testing may not reveal a cause or confirm diagnosis (yield remains <100% for most inherited diseases). 1
• Patients should understand that results have implications not just for their own health but for family members who might share genetic variants predisposing to disease. 1
• The Genetic Information Nondiscrimination Act protects against health insurance and employment discrimination but does NOT cover life insurance, disability insurance, or companies with <15 employees—asymptomatic individuals should obtain life and disability insurance before undergoing genetic testing. 1

When Genetic Testing Should NOT Be Performed

Inappropriate Screening Scenarios

• Routine genetic testing is NOT recommended for individuals without confirmed/suspected inherited disease, significant family history, or known familial pathogenic variants. 1
• Testing should not proceed if the patient does not express a preference for screening or is uncertain about the decision (such patients should be referred to a provider experienced in clinical cancer genetics). 1
• Minors should not undergo genetic testing until they can understand the implications and provide informed consent themselves. 1

Scope of Testing Considerations

• Avoid the temptation to test more genes or all genes simply because next-generation sequencing is affordable—larger panels including limited-evidence genes increase the burden of variants of uncertain significance (VUS), particularly in individuals of non-European ancestry. 1
• Disease-focused or targeted gene panels limited to the disease phenotype are preferred over comprehensive panels to limit the burden of identified variants to disease-relevant genes. 1

Post-Testing Responsibilities

Result Interpretation and Follow-Up

• All genetic testing results must be accompanied by post-test genetic counseling so patients fully understand implications for their health and family members' health. 1
• Providers have implicit responsibility to ensure genetic testing interpretations remain up-to-date through periodic recontact with patients, reviewing updated interpretations (variants can be reclassified over time), and recommending additional testing when warranted. 1

Family Cascade Testing

• Once a patient tests positive for a pathogenic or likely pathogenic variant, providers should recommend the patient share genetic risk information with all at-risk biological relatives, as any relative might share the same variant. 1
• Cascade clinical screening and genetic testing should be offered to first-degree family members with genetic counseling, continuing until all extended at-risk family members have been offered evaluation. 1

Critical Pitfalls to Avoid

• Do not order genetic testing without adequate pre-test counseling about benefits, risks, limitations, and family implications—this differs fundamentally from traditional laboratory testing. 1
• Do not assume negative genetic testing rules out inherited disease—the diagnostic yield remains incomplete for most conditions, and patients may have unidentified genetic determinants. 1
• Do not fail to consider DNA banking as an alternative when patients decline testing after counseling—this preserves samples until more is known about disease genetics and allows future informed counseling even after the patient is unavailable. 1
• Do not neglect legal protections and their limitations—clearly explain that genetic discrimination protections do not extend to all insurance types or employment situations. 1