Ordering genetic testing in cardiology: pre-test checklist and consent

Germline testing for suspected inherited CVD. Not for somatic variants (CHIP), polygenic risk scores or direct-to-consumer tests (outside this guideline's scope).

STEP 1. Define the purpose and who is being tested

• Patient analysis (affected proband, gene panel or full-gene sequencing) vs cascade screening (relative, single-variant Sanger test once a family variant is known).
• Decide: if the person is a relative and the proband has no pathogenic/likely pathogenic (P/LP) variant, there is no variant to cascade. Offer clinical surveillance instead.

STEP 2. Confirm there is an indication

• Follow the disease-specific guideline for indications (e.g. HCM, LQTS, Marfan, FH). Insurance-covered diseases are listed in REFERENCE.md.
• Ask whether the result would change surveillance, treatment, prevention or family management (actionability). Many inherited CVD are autosomal dominant and actionable, so benefit usually outweighs the limitations.
• Decide: order if clinically phenotyped and the result is useful. If the test's usefulness is unestablished, it belongs in an ethics-approved research setting, not routine care.

STEP 3. Check age and symptom status

• Adult presymptomatic testing for adult-onset disease: only with the subject's own autonomous decision.
• Minors (<18 y): consent from parents plus assent from the child. Testing for later-adult-onset disease is controversial, so postpone until the child can decide. Exception: actionable diseases that can present with sudden death (e.g. congenital LQTS, Marfan), where testing from childhood is internationally accepted. Do this after counseling with a medical geneticist or an experienced cardiologist.
• Decide: test now, or defer to adulthood.

STEP 4. Pre-test counseling and written informed consent (mandatory)

Explain in plain language, giving enough time:

1. Results are lifelong and shared with blood relatives, and can predict future disease, but not its timing, severity or age of onset.
2. A negative result does not exclude disease: the gene may not be in the panel, or the variant may be undetectable.
3. VUS may be reported and cannot guide decisions alone.
4. No gene correction therapy exists, and psychological and insurance/discrimination burdens are possible.
5. How secondary findings will be handled, who will see the results, and cost and insurance coverage.

• Action: obtain written consent, record it in the chart, and record the patient's wishes about disclosure and about the right not to know.
• Refer to a clinical geneticist or certified genetic counselor for pre-test counseling where available (a medical genetics department is advisable). If none is available, use the national genetic medicine department directory.

STEP 5. Choose the test and the laboratory

• Usual choice: NGS panel with a gene list justified by ClinGen gene-disease validity. Add MLPA/CNV analysis when large deletions are plausible. Chromosomal microdeletions (22q11.2, Williams) need FISH or array. Enzyme assay for Fabry/Pompe.
• Use a certified clinical laboratory or hospital laboratory with quality control (ISO 15189 or CAP is recommended). Research-laboratory results are not clinical results.
• Decide: send to the certified laboratory and ask for a report that states limitations (non-coding or deep-intronic regions not covered).

STEP 6. Plan secondary findings before sending

• Set a process in advance: which findings will be disclosed, and by whom. Reference list: ACMG secondary findings genes (see REFERENCE.md).
• Action: tell the patient at consent whether secondary findings will be reported.

STEP 7. Return the result

• Interpret in the clinical context (genotype and phenotype, family segregation). Classify: P/LP, VUS, likely benign/benign.
• P/LP: confirm the diagnosis, plan treatment and surveillance, offer cascade screening with counseling.
• VUS: not diagnostic and not for cascade testing decisions. Consider co-segregation or functional work, and re-review later.
• Negative: continue clinical surveillance of relatives if hereditary disease is suspected from the phenotype.
• Offer genetic counseling at disclosure, and again at life changes (marriage, pregnancy).

STEP 8. Privacy

• Record the result in the chart. Do not disclose to relatives or third parties without the patient's consent. Exception: possible only with ethics committee approval if clinically useful for relatives and no alternative exists.

Guardrails

• Do not equate a variant with disease in relatives: penetrance varies (high: Marfan, CPVT, LMNA; moderate: HCM, LQTS; low: TTN). Diagnosis needs clinical findings.
• Do not treat VUS as pathogenic, and do not tell the patient a negative panel excludes a genetic cause.
• Do not test minors for adult-onset non-actionable disease without counseling.
• Do not disclose to family without consent.
• Do not use unaccredited research results for clinical decisions without confirming validity.
• Prenatal testing and PGT are specialist and ethics matters. Refer.
• Insurance does not cover asymptomatic-relative testing or counseling without testing (Japan, as of 2023). Tell the family the cost up front.

Example

A 16-year-old whose father has a pathogenic KCNQ1 variant for LQTS. Step 1: cascade screening. Step 3: a minor, but LQTS is actionable, so test. Step 4: written parental consent plus the teen's assent, with a geneticist counseling session. Step 5: single-variant Sanger test. Step 7: if positive, ECG and beta-blocker decision, and sports advice. If negative, the relative is not a carrier of the family variant.

Source: JCS/JCC/JSPCCS 2024 Guideline on Genetic Testing and Counseling in Cardiovascular Disease. Imai Y, Kusano K, Aiba T, et al. J Cardiol 2025;85:115-176. doi:10.1016/j.jjcc.2024.10.002