What are the medical implications of a positive genetic test result for a pathogenic or likely pathogenic variant?

Medical Implications of a Positive Pathogenic or Likely Pathogenic Genetic Variant

A positive genetic test result for a pathogenic or likely pathogenic variant has significant medical implications including increased disease risk, need for specialized surveillance, cascade testing for family members, and potential targeted treatment options.

Disease Risk and Prognosis

• Pathogenic variants are associated with worse clinical outcomes in many conditions. For example, in hypertrophic cardiomyopathy (HCM), patients with pathogenic sarcomere variants have earlier disease onset, higher incidence of sudden cardiac death, higher rates of atrial fibrillation, ventricular arrhythmias, heart failure, and overall mortality compared to variant-negative patients 1.

• The specific implications vary by condition and gene involved. For instance, in HCM, the presence of sarcomeric variants in pediatric patients is more closely associated with sudden cardiac death risk 1.

• The penetrance (likelihood of developing the disease) varies significantly between different genetic disorders and specific variants, ranging from low to high penetrance 1.

Clinical Management Changes

• Identification of a pathogenic/likely pathogenic variant often leads to specialized surveillance protocols that differ from standard care. For example:

  • In HCM, genotype-positive individuals require regular clinical screening even if they don't yet show disease symptoms 1.
  • In hereditary cancer syndromes, enhanced screening protocols are implemented, such as earlier and more frequent cancer screening 1.

• Treatment decisions may be influenced by genetic findings:

  • Some genetic variants may indicate the need for specific treatments, such as enzyme replacement therapy in Fabry disease 1.
  • More aggressive clinical management may be warranted for conditions like Danon disease when pathogenic variants are identified 1.

• Risk stratification for life-threatening events may be affected, though genetic results alone are typically not sufficient for major interventions like implantable cardioverter-defibrillator placement in HCM 1.

Family Implications and Cascade Testing

• A positive genetic test enables cascade genetic testing in at-risk relatives, which can identify family members who carry the same variant and require surveillance 1.

• Family members who test negative for a known familial pathogenic variant can typically be released from ongoing clinical surveillance, as their risk reverts to that of the general population 1.

• For autosomal dominant conditions, each offspring of an affected individual has a 50% chance of inheriting the disease-causing variant, though penetrance may vary 1.

• Reproductive options become available, including prenatal genetic testing and preimplantation genetic diagnosis 1.

Ongoing Monitoring and Variant Reclassification

• Variant classifications may change over time as new evidence emerges. Studies show that approximately 7.7% of variants of uncertain significance are eventually reclassified, with most being downgraded to benign/likely benign (91.2%) and some being upgraded to pathogenic/likely pathogenic (8.7%) 2.

• Periodic reevaluation of variants is important, as reclassification may necessitate changes in clinical management. In one study, 11% of HCM variants were either upgraded or downgraded over a 6-year period 1.

• If a variant is downgraded from pathogenic/likely pathogenic to a variant of uncertain significance, family members previously released from surveillance may need to resume clinical screening 1.

Psychological and Insurance Implications

• Pretest genetic counseling is essential to ensure patients understand the potential psychosocial, ethical, and insurance implications of genetic testing 1.

• Posttest genetic counseling helps explain the findings and implications for both the individual and family members, regardless of whether a pathogenic variant is identified 1.

Practical Considerations for Different Clinical Scenarios

• For incidental findings (variants found during testing for another condition):

  • The American College of Medical Genetics and Genomics recommends returning pathogenic/likely pathogenic variants in 59 medically actionable genes, of which 30 are related to cardiovascular diseases 1.
  • These findings should prompt careful assessment of family history and appropriate phenotyping 1.

• For variants of uncertain significance (VUS):

  • VUS should not be used for clinical decision-making or predictive testing in family members 1.
  • In select circumstances, family testing may help clarify pathogenicity through segregation analysis 1.

• For prenatal testing:

  • Prenatal genetic counseling can help prospective parents understand options including preimplantation genetic diagnosis 1.
  • Reporting of VUS in prenatal settings requires careful consideration by multidisciplinary teams 3.

By understanding these implications, healthcare providers can better guide patients through the complex landscape of genetic testing results and ensure appropriate clinical management.