Direct-to-Consumer Genetic Testing for Cardiovascular Disease: A Scientific Statement From the American Heart Association

Authors, Journal, Affiliations, Type, DOI

• Authors: Leland E. Hull (Chair), Aaron W. Aday, Quan M. Bui, Jasmine A. Luzum, James M. Muchira, Hannah Wand, C. Anwar A. Chahal, Mina K. Chung, Anne E. Kwitek, Silvana Molossi, Pradeep Natarajan (Vice Chair); on behalf of the AHA Data Science and Precision Medicine Committee
• Journal: Circulation, 2025;151:e905–e917
• Affiliations: Massachusetts General Hospital, Vanderbilt University Medical Center, UC San Diego, University of Michigan, Stanford Health Care, Mayo Clinic, Cleveland Clinic, Medical College of Wisconsin, Texas Children's Hospital/Baylor College of Medicine
• Type: AHA Scientific Statement
• DOI: 10.1161/CIR.0000000000001304

Overview

Direct-to-consumer (DTC) genetic testing (GT) has expanded rapidly, with >33 million tests performed in 2022, yet insufficient evidence exists to support its routine use in cardiovascular clinical care. Cardiovascular clinicians increasingly face patient-initiated questions about DTC-GT results spanning monogenic disease, polygenic risk scores (PRS), and pharmacogenomics. This statement reviews the regulatory landscape, testing methodologies, cardiovascular disease categories covered, and the ACCE framework for test quality evaluation. A practical clinical algorithm for managing actionable DTC-GT results is provided, with emphasis on confirmatory CLIA-certified testing for all potentially actionable monogenic findings.

Keywords

AHA Scientific Statements, cardiovascular diseases, clinical laboratory services, genetic predisposition to disease, genetic testing

Key Takeaways

Evolution and Regulation of DTC-GT

• DTC-GT market grew rapidly post-Human Genome Project; >33 million DTC-GTs performed in 2022; driven by lower costs, internet marketplace, and demand for personalised medicine
• DTC-GTs are NOT classified as laboratory-developed tests (LDTs) because they are not intended for clinical use by the consumer — therefore avoided most FDA oversight historically
• FDA 2024 phased oversight rule for LDTs: Hybrid/clinician-mediated DTC models (where a clinician facilitates the process) DO fall under LDT definition and are now subject to greater oversight; purely direct-to-consumer tests remain largely unregulated
• 23andMe is the only DTC-GT company to receive FDA marketing authorisation — specifically for genetic health risks (thrombophilia, Alzheimer, Parkinson), carrier screening (Bloom syndrome), pharmacogenomics, and cancer predisposition (BRCA1/BRCA2); these are the only DTC-GTs evaluated by FDA for accuracy, reliability, and consumer comprehension
• CMS enforces Clinical Laboratory Improvement Amendments (CLIA) standards for analytical validity; FTC and state agencies also involved; ACMG has published position statements
• Regulatory gap: No regulation of third-party GT interpretation services; consumers can download raw data and multiple companies offer expanded (unsupported) interpretations
• GINA 2008 protects against discrimination in employment and health insurance but NOT life, disability, or long-term care insurance; DTC-GT companies are not covered by HIPAA

Testing Methodology and Scope

• Genotyping (SNP-chip): Examines specific variants (SNPs, short indels); lower cost; predominantly used in DTC-GT; higher false-negative rate for inherited CVD than sequencing because only selected variants are assessed; output includes specific SNP presence/absence and polygenic risk scores (PRS)
• Next-generation sequencing (NGS): Increasingly used in DTC as costs fall; ranges from single-gene to whole-exome/genome; variants classified using ACMG/AMP 5-tier system (pathogenic/LP/VUS/likely benign/benign)
• PRS: Aggregate weighted SNP scores representing relative risk for complex disease; may be reported by DTC products; NOT yet FDA cleared or clinically validated through standard regulatory pathway; genotyping array-based technology may not fully capture diversity needed for accurate PRS
• Variant pathogenicity may not be determinable for all sequenced variants — especially in non-European populations and for rare/family-specific variants; DTC curation methods may fall short of clinical-grade standards due to commercial cost considerations

Types of Cardiovascular Genetic Health Information

Monogenic Disease Risk

• Most heritable CVDs exhibit age-dependent penetrance, incomplete penetrance, and variable expressivity; most are autosomal dominant but can be X-linked (Danon/GLA) or autosomal recessive (Jervell-Lange-Nielsen)
• Table 1 — Key DTC/commercial gene panel categories (ClinGen definitive/strong evidence):
  • Dyslipidemias: LDLR, APOB, PCSK9, LDLRAP1 (FH); ABCG5, ABCG8, LIPA, APOB (biallelic)
  • Cardiomyopathies — DCM: TNNT2, LMNA, FLNC, TTN, BAG3, DES, RBM20, TNNC1, SCN5A, MYH7, DSP, PLN
  • Cardiomyopathies — HCM: TNNC1, MYH7, MYBPC3, TNNI3, TPM1, MYL3, ACTC1, PRKAG2, MYL2, TNNT2, ALPK3
  • Cardiomyopathies — ARVC: PKP2, DSP, DSC2, TMEM43, DSG2, JUP
  • Storage disorders: TTR (ATTR amyloidosis), GLA (Fabry), GAA (Pompe), HFE (hemochromatosis)
  • Inherited arrhythmias — LQTS: KCNQ1, KCNH2, SCN5A, CALM1/2/3, TRDN
  • Inherited arrhythmias — BrS: SCN5A; CPVT: RYR2, CASQ2, TRDN, TECRL, CALM1
  • Thoracic aortic disease: FBN1 (Marfan), TGFBR1/2/TGFB2/3/SMAD3 (LDS), ACTA2/MYH11/PRKG1/MYLK (nsHTAD), COL3A1 (vascular EDS)
• All above genes are listed as ACMG SF v3.2 actionable secondary findings (except familial AF genes); ClinGen curation is the reference for gene-disease strength
• DTC-GT is not performed under clinical suspicion of disease — making individual risk prediction challenging; results may warrant further evaluation to determine clinical actionability

Polygenic Disease Risk (PRS)

• Genome-wide association studies (GWAS) identify common variants (allele frequency >0.1%) associated with cardiovascular traits; PRSs aggregate these into a weighted score
• PRSs are established at conception → maximal predictive performance earlier in life and for premature events; increasingly relevant for CAD risk in young adults
• DTC PRS limitations:
  1. No DTC PRS product has FDA clearance or approval — clinical validation lacking
  2. Array-based technology may miss important alleles; low-coverage WGS may address this but requires adequate imputation panels
  3. DTC PRS construction is often opaque with limited public benchmarking
  4. Ancestry integration highly variable — PRS performance depends on training population; non-European ancestry populations are substantially underrepresented
  5. Integrated risk scores incorporating clinical risk factors are desired (genetics should not be considered in isolation); such tools are emerging for clinical use
• Prior AHA Scientific Statement on PRS (Circulation 2022) provides comprehensive framework for cardiovascular PRS clinical translation

Pharmacogenomic Variation

• 99% of patients carry ≥1 actionable pharmacogenomic variant; over-the-counter DTC pharmacogenomic tests are now available in many pharmacies
• 23andMe DTC pharmacogenomic test: 33 variants in 8 genes; the only FDA-authorized DTC pharmacogenomic test; includes CYP2C19 (clopidogrel, citalopram), CYP2D6, SLCO1B1 (statins), CYP2C9, and others relevant to cardiovascular medications
• As of 2020: FDA no longer requires confirmatory clinical testing for 23andMe CYP2C19 results for clopidogrel and citalopram specifically
• Other hybrid/clinician-mediated DTC pharmacogenomic companies (Veritas Genetics, Genelex, Pathway Genomics) now fall under LDT definition subject to increased FDA oversight
• Third-party companies translate raw genetic data from DTC-GTs into pharmacogenomic reports (e.g., for CYP2C19 affecting cardiovascular and psychiatric medications)
• Clinical resource: CPIC pharmacogenomic guidelines (cpicpgx.org) and FDA pharmacogenomic biomarker tables

ACCE Framework for Evaluating DTC-GT Quality

• 44-question framework assessing: (A) Analytical validity (technical sensitivity/specificity), (C) Clinical validity (diagnostic sensitivity/specificity), (C) Clinical utility (leads to prevention/better treatment), (E) Ethical/legal/social issues
• Only a handful of DTC-GTs are FDA approved with demonstrated analytical and clinical validity; most DTC-GTs do NOT definitively indicate disease will or will not develop
• False positives → unnecessary procedures/therapies; false negatives → false reassurance and foregoing of evidence-based prevention
• Clinical utility evidence:
  • Gene-first FH screening: cost-effective in US adults ≤50 years
  • Neonatal HCM screening: may save lives but high surveillance cost due to variable penetrance
  • Behavioural change evidence from DTC-GT results: variable in studies
• ELSI (Ethical/Legal/Social Issues):
  • Benefits: consumer autonomy, accessibility, privacy from medical records
  • Harms: no genetic counselling, misinterpretation, data privacy risks
  • GINA protects health/employment insurance but NOT life/disability/LTC insurance
  • DTC companies not covered by HIPAA; consent forms may allow data sharing/research

Special Population Considerations

• Athletes: No evidence supports DTC-GT for athletic performance, injury prevention, or elite talent identification; small sample sizes and biased methodologies limit existing associations; NCAA mandated sickle cell trait testing (after Rice University lawsuit) but DTC-GT is NOT supported by prevailing consensus for sports genetics
• Adoptees/limited family history: DTC-GT can provide valuable genetic information; confirm positive results clinically; involve genetics professionals; disclosure considerations for relatives
• Aging populations: Interest in longevity genes (FOXO3, APOE for Alzheimer/lipid); high risk of misinterpretation without professional counselling; APOE ε4 has lipid metabolism implications
• Limited-resource communities: DTC-GT targets affluent consumers; inequity in access; insurance will not cover; digital divide (broadband/devices) compounds barriers; DTC-GT should not replace traditional screening

Clinical Approach to DTC-GT Results

Reviewing the Test Report

• ClinGen consortium: Primary resource for evaluating gene-disease validity and variant pathogenicity; expert panels for cardiomyopathies, arrhythmias, aortopathies, and dyslipidemias; FDA-recognized database
• ClinVar: Public repository where laboratories publish variant evidence; DTC variants can be queried to understand evidence level
• Clinicians should obtain DTC company evidence curation protocols and assess adoption of expert standards (ClinGen/ACMG/AMP criteria)

Nonactionable Results

• No further follow-up needed if: no health risk information, low complex disease risk PRS, no pharmacogenomic results relevant to the patient, or negative for monogenic disease variants — provided no additional personal/family history or phenotypic features warrant investigation
• Most DTC users without prior known disease risk will receive nonactionable monogenic results (rare disease prevalence)

Confirmation of Potentially Actionable Results

• Confirmatory CLIA-certified testing is recommended for ALL health-related monogenic DTC-GT results — due to limited assay coverage (SNP-chip cannot capture all pathogenic variants), false positives, and accuracy concerns
• Consumer must discuss DTC-GT results with a clinician before adjusting any therapy
• Raw genotyping data may be downloadable from DTC companies; consumers should be aware this does not replace clinical-grade testing

Management of Actionable DTC-GT Results (Table 2)

• History and physical examination with attention to signs/symptoms of disease
• 3-generation family history
• Confirmation with CLIA-certified retesting if necessary
• Consider cascade testing for family members if indicated
• Additional testing: lipid panel, ECG, exercise treadmill test, cardiac imaging (TTE/CMR/PET), vascular imaging, surveillance imaging, specialist referral

Cascade Testing After DTC-GT

• Cascade testing adoption rate in traditional clinical genetics workflows <50%; specific frequency for DTC-GT is uncertain
• DTC companies generally do NOT actively facilitate cascade testing
• PRS cascade testing not strongly indicated (not mendelian) but may be considered given high concordance between relatives with high PRS (Reid et al., Circ Genom Precis Med 2021)
• No current guidelines on cascade screening after DTC-GT — this represents a major gap; misclassified variants could lead to unnecessary procedures/financial burdens if cascade testing is initiated inappropriately

Engaging Genetic Counselors (GCs)

• GC: master's degree minimum; can evaluate family history, counsel/consent/guide GT, communicate results; cannot diagnose or prescribe
• Three pathways for DTC-GT genetic counselling: (1) clinician/GC referral within health system, (2) DTC company telehealth GC (variable scope), (3) independent telehealth GC companies

Limitations of the Document

• No primary RCT data — descriptive/framework document; clinical utility evidence for DTC-GT in CVD is limited across the board
• DTC-GT market is rapidly evolving; specific company offerings become outdated quickly (e.g., 23andMe filed for bankruptcy in 2025 after this statement was written)
• Table 1 gene lists reflect ClinGen curation at time of writing; ClinGen is continuously updated
• No formal cost-effectiveness analysis of confirmatory testing strategies
• Framework is US-centric; regulatory and access landscape varies substantially by country
• Statement does not address next-generation DTC modalities (RNA, proteomics, wearable-integrated genomics)

Key Concepts Mentioned

• concepts/DTC-Genetic-Testing — primary concept introduced by this source
• concepts/Genetic-Testing-in-Cardiomyopathy — DTC cardiomyopathy gene panels, limitations vs clinical testing
• concepts/Familial-Hypercholesterolemia — gene-first FH screening cost-effectiveness
• concepts/Cascade-Family-Screening — cascade testing challenges in DTC context
• concepts/ASCVD-Risk-Assessment — DTC PRS limitations, population-ancestry bias

Key Entities Mentioned

• entities/HCM — sarcomeric HCM genes in DTC panels; confirmatory testing required
• entities/DCM — DCM genes (LMNA, TTN, FLNC, SCN5A, PLN) in DTC panels
• entities/Long-QT-Syndrome — KCNQ1/KCNH2/SCN5A/CALM1-3/TRDN in DTC panels
• entities/Brugada-Syndrome — SCN5A in DTC panels
• entities/ATTR-Amyloidosis — TTR in DTC panels; ACMG actionable secondary finding
• entities/Anderson-Fabry-Disease — GLA in DTC panels; X-linked; ACMG actionable

Wiki Pages Updated

• wiki/sources/consumer-genetictest-aha-2025.md — created (this file)
• wiki/concepts/DTC-Genetic-Testing.md — created
• wiki/concepts/Genetic-Testing-in-Cardiomyopathy.md — added DTC-GT context section
• wiki/concepts/Familial-Hypercholesterolemia.md — added DTC gene-first screening evidence
• wiki/concepts/Cascade-Family-Screening.md — added DTC cascade testing challenges
• wiki/concepts/ASCVD-Risk-Assessment.md — added DTC PRS limitations
• wiki/wikiindex.md — DTC-Genetic-Testing concept added
• wiki/sourceindex.md — source entry added
• wiki/log.md — ingest entry appended