Predictive Testing

Predictive testing is genetic testing of an asymptomatic individual to estimate future risk of disease or differential drug response. It is distinct from diagnostic testing, which evaluates a symptomatic patient to confirm or rule out a suspected condition. Two main contexts dominate practice: (1) hereditary disease predictive testing in at-risk relatives of a proband with a known familial pathogenic variant, and (2) pharmacogenetic testing to predict drug response or adverse reactions.

Used when a familial pathogenic variant has been identified in a proband, and unaffected at-risk relatives elect to learn their carrier status. Cascade testing extends from the proband outward through first-degree relatives.

• Huntington disease (HTT CAG repeat expansion): the prototypical predictive test. Adult-onset, autosomal dominant, untreatable at present. International guidelines (Huntington's Disease Society of America, International Huntington Association/World Federation of Neurology) require a structured multi-visit protocol:
  • In-person pre-test counseling over multiple sessions (typically 2-3 visits).
  • Partner or support person involvement strongly encouraged.
  • Neurologic and psychiatric assessment, including suicide risk screening (elevated around result disclosure).
  • No predictive testing of asymptomatic minors (defers autonomy until adulthood; testing only if results would change clinical management).
  • In-person disclosure with arranged follow-up.
• Hereditary Breast and Ovarian Cancer (BRCA1, BRCA2): cascade testing of relatives once a familial variant is known. Implications include enhanced surveillance (breast MRI starting at 25-30, alternating with mammography), risk-reducing salpingo-oophorectomy (typically 35-40 for BRCA1, 40-45 for BRCA2), and consideration of risk-reducing mastectomy.
• Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM): cascade testing drives colonoscopy every 1-2 years starting at 20-25 (or 2-5 years before earliest family case), endometrial surveillance, and risk-reducing hysterectomy/BSO discussions after childbearing.
• Other examples: familial adenomatous polyposis (APC), familial hypercholesterolemia (LDLR), hereditary cardiomyopathies and channelopathies, von Hippel-Lindau, MEN syndromes.

Counseling principles: address uncertainty of penetrance and age of onset, surveillance options, risk-reducing surgery, reproductive implications (PGT-M, prenatal diagnosis), insurance considerations (GINA covers health insurance and employment but not life, disability, or long-term care), and psychological impact of a positive or negative result (including survivor guilt).

Genotyping to predict drug efficacy or adverse reaction risk. Increasingly delivered as preemptive panels (tested before any prescription) rather than reactive testing (after a treatment failure or adverse event). CPIC (Clinical Pharmacogenetics Implementation Consortium) guidelines are the standard interpretive resource, providing peer-reviewed gene-drug prescribing recommendations with leveled actionability.

Pharmacogenomic genes fall into a small number of mechanism categories. Knowing the category predicts the kind of failure: metabolizing-enzyme variants alter drug exposure (toxicity vs subtherapeutic), transporters alter tissue distribution, drug-target variants alter sensitivity, and HLA variants drive immune-mediated hypersensitivity.

The HLA pharmacogenomic alleles share a mechanism: drug-modified peptides bind specific HLA pockets and trigger cytotoxic T-cell responses. See HLA & MHC for the underlying antigen-presentation framework and the broader HLA-disease association catalog.