Genetic Testing for Inherited Cardiovascular Diseases — AHA Scientific Statement 2020

Authors, Journal, Affiliations, Type, DOI

• Kiran Musunuru (Chair), Ray E. Hershberger (Vice Chair), Sharlene M. Day, N. Jennifer Klinedinst, Andrew P. Landstrom, Victoria N. Parikh, Siddharth Prakash, Christopher Semsarian, Amy C. Sturm; on behalf of the AHA Council on Genomic and Precision Medicine and three additional AHA councils
• Circulation: Genomic and Precision Medicine
• Affiliations: University of Pennsylvania, Ohio State University, Duke University, Stanford, University of Texas Health Science Center, University of Sydney, Geisinger Genomic Medicine Institute
• Type: AHA Scientific Statement (consensus/best-practice synthesis)
• DOI: 10.1161/HCG.0000000000000067

Overview

This 2020 AHA Scientific Statement consolidates best-practice frameworks for genetic testing across all major categories of inherited cardiovascular disease: cardiomyopathies, arrhythmic disorders, heritable thoracic aortic aneurysm and dissection (HTAD), and familial hypercholesterolemia (FH). Drawing on multiple society guidelines and ClinGen gene curation reports, it provides structured guidance on when to test, how to select appropriate gene panels, how to interpret variant classifications, and how to conduct cascade family testing. A key contribution is the integration of ClinGen curation findings that significantly narrow the gene lists with definitive evidence for arrhythmic diseases — notably that only SCN5A is definitively disease-causing for Brugada syndrome (of 21 evaluated genes), and only three genes (KCNQ1, KCNH2, SCN5A) have definitive evidence for typical LQTS. The document also addresses secondary and incidental findings management and outlines legal protections and limitations relevant to genetic testing in the US.

Keywords

AHA Scientific Statements, aneurysm, arrhythmia, cardiomyopathy, cardiovascular diseases, channelopathy, genetic testing, genetics

Key Takeaways

Decision to Perform Genetic Testing

• Two prerequisites before genetic testing: (1) rigorous disease-appropriate phenotyping and (2) comprehensive 3-generation family history
• Testing should ideally be initiated in the most clearly affected family member with the most severe phenotype — maximizes chance of identifying a causative variant useful for familial testing
• Genetic testing differs from standard laboratory testing: requires baseline genetics competence; referral to board-certified geneticists or genetic counselors recommended unless the provider is sufficiently qualified to choose, order, interpret, and counsel
• Mandatory pre-test genetic counseling: patient must understand benefits, risks, limitations, family implications, and uncertainties before consenting
• Mandatory post-test genetic counseling: full explanation of result implications for the patient and at-risk family members
• Panel selection: larger panels (exome/genome) increase VUS burden and risk of incidental findings without proportionately increasing clinically actionable results in adult patients; targeted panels aligned with ClinGen-curated gene lists are preferred for clinical practice
• Genetic Information Nondiscrimination Act (GINA): prohibits genetic discrimination in health insurance and employment but NOT life insurance, disability insurance, or long-term care insurance; does not apply to companies with <15 employees — counsel patients about these limitations before testing

Variant Interpretation

• ACMG/AMP 5-tier classification: Pathogenic (P), Likely Pathogenic (LP), VUS, Likely Benign, Benign — the universal standard for clinical reporting
• P/LP variants = positive result → cascade genetic testing recommended for at-risk family members
• VUS = not directly actionable for predictive cascade genetic testing in relatives; in HCM, VUS carriers have intermediate prognosis between P/LP-positive and genotype-negative sarcomere variant carriers (reflecting a mix of true pathogenic and true benign variants)
• VUS reclassification is expected over time; providers bear implicit responsibility for periodic recontact — reviewing updated lab interpretations, checking ClinVar, and recommending additional testing when warranted
• Non-European populations carry higher VUS rates due to underrepresentation in variant databases — a persistent health equity disparity
• ClinVar contains conflicting interpretations in a significant subset of variants across laboratories; standardisation efforts ongoing through ClinGen

Implications Beyond the Index Patient

• Privacy laws (HIPAA in US) restrict providers from directly contacting relatives without patient authorization; providers should give patients a family letter summarizing the genetic finding and directing relatives toward cascade evaluation
• Cascade clinical screening + genetic testing offered to first-degree family members once P/LP variant identified; cascade continues outward through extended family until all at-risk relatives have been offered testing and counselling
• At-risk relatives with no current disease signs: periodic clinical surveillance at disease-specific guideline-directed intervals based on the natural history of the condition
• Relatives testing negative for the familial P/LP variant: exonerated from further structured surveillance (risk returns to general population level); exception if clinical phenotype is atypical for the variant identified, oligogenic contribution is suspected, or penetrance questions remain
• Family members who decline genetic testing: uncertain genetic status; clinical surveillance recommended at same intervals as genotype-positive individuals
• Prenatal genetic testing and preimplantation genetic diagnosis (PGD): a confirmed familial P/LP variant enables prospective parents to consider these reproductive options

Secondary / Incidental Findings

• ACMG 59 medically actionable genes (list subsequently updated): 30 are cardiovascular-related and reportable when P/LP variants are identified during exome/genome sequencing
• Key CVD genes in the ACMG reportable list (Table 2):
  • Marfan/Loeys-Dietz/HTAD: FBN1, TGFBR1, TGFBR2, SMAD3, ACTA2, MYH11
  • HCM/DCM: MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL3, ACTC1, PRKAG2, GLA, MYL2, LMNA
  • CPVT: RYR2
  • ARVC: PKP2, DSP, DSC2, TMEM43, DSG2
  • LQTS/BrS: KCNQ1, KCNH2, SCN5A
  • FH: LDLR, APOB, PCSK9
  • Vascular Ehlers-Danlos: COL3A1
• On confirming incidental CVD variant: perform ≥3-generation family history + rigorous disease-appropriate phenotyping; if phenotype identified → treat as primary finding + cascade testing; if no phenotype + no family history → individualize surveillance based on age, expected penetrance; do NOT routinely pursue family-based cascade evaluation when neither the individual nor pedigree shows any disease evidence
• Research sequencing findings must be confirmed by CLIA-certified clinical sequencing before management changes

Disease-Specific Gene Panel Table (AHA 2020 Table 3 — Condensed)

Disease-Specific Guidance: Arrhythmic Disorders

• LQTS: genetic testing recommended for strong clinical suspicion, and for idiopathic QT prolongation with QTc >480 ms (prepuberty) or >500 ms (adults), even when asymptomatic; ClinGen 2020 confirmed only KCNQ1, KCNH2, SCN5A as definitively associated with typical LQTS; CALM1/2/3 and TRDN confirmed for atypical LQTS
• Brugada syndrome: ClinGen 2019 evaluated 21 candidate genes — only SCN5A has definitive disease-causing evidence; findings in other genes should NOT be used to inform clinical management (may be useful in research); genetic testing is NOT indicated for isolated type 2 or type 3 BrS ECG patterns (these are not diagnostic for BrS)
• CPVT: RYR2 is a major diagnostic criterion; CASQ2 also tested; cascade genetic testing recommended once P/LP variant identified
• Short-QT syndrome: KCNH2, KCNQ1, KCNJ2 tested
• Out-of-hospital cardiac arrest survivors: genetic testing only when clinical index of suspicion for a specific cardiomyopathy or channelopathy; not indicated as a routine workup for all cardiac arrest survivors
• Postmortem genetic testing: collect tissue samples for possible future testing; select panels guided by autopsy findings and surviving family clinical testing results; cascade testing recommended if genetic cause identified
• Atrial fibrillation: genetic testing NOT recommended per HRS/EHRA 2011; evolving evidence may warrant testing in selected patients (e.g., early-onset AF with cardiomyopathy-gene variants)

Disease-Specific Guidance: HTAD

• ClinGen 2018 (Renard): 11 genes with definitive/strong evidence for highly penetrant HTAD: ACTA2, COL3A1, FBN1, MYH11, SMAD3, TGFB2, TGFBR1, TGFBR2, MYLK, LOX, PRKG1
• 8 additional potentially diagnostic genes frequently included in commercial panels: EFEMP2, ELN, FBN2, FLNA, NOTCH1, SLC2A10, SMAD4, SKI
• Gene identification provides clinically actionable information: guides surgical timing, scope of aortic/vascular surveillance, and identifies risk of additional vascular diseases
• ACTA2 pathogenic variants → elevated risk for early-onset stroke/MI from vascular occlusive lesions and moyamoya disease (beyond aortic disease)
• 70% of HTAD families without systemic features (Marfan/Loeys-Dietz phenotype) test negative on current panels — additional undiscovered genes suspected; refer panel-negative HTAD families to research studies
• 2010 AHA/ACC HTAD guideline: individualized prophylactic interventions based on gene-specific risks (e.g., more aggressive surveillance thresholds for TGFBR1/2 vs. FBN1 carriers)

Disease-Specific Guidance: Familial Hypercholesterolemia

• FH genes: LDLR, APOB, PCSK9; phenotypic overlap genes: LDLRAP1, LIPA, ABCG5, ABCG8, APOE
• Genetic testing should be offered (recommended):
  • Children with persistent LDL-C ≥160 mg/dL or adults with LDL-C ≥190 mg/dL (no secondary cause) + ≥1 first-degree relative with similar LDL-C or premature CAD, or when family history is unavailable (e.g., adoption)
  • Children with persistent LDL-C ≥190 mg/dL or adults with persistent LDL-C ≥250 mg/dL (no secondary cause), even without positive family history
• Genetic testing may be considered:
  • Children with LDL-C ≥160 mg/dL + parent LDL-C ≥190 mg/dL or family history of hypercholesterolemia + premature CAD
  • Adults without pre-treatment LDL-C data but with personal premature CAD + family history of both hypercholesterolemia and premature CAD
  • Adults with LDL-C ≥160 mg/dL + family history of hypercholesterolemia + personal or family history of premature CAD
• Premature CAD threshold: males ≤55 years, females ≤65 years
• Cascade genetic testing offered to all at-risk relatives once P/LP variant identified
• Expected benefits of FH genetic testing: higher diagnosis rate, more effective cascade testing, earlier therapy initiation, and more accurate risk stratification

Future Outlook

• Reliable variant classification remains the preeminent challenge; ClinGen gene-specific curation and high-throughput functional platforms (e.g., saturation genome editing) are critical tools for resolution
• Statement focused on monogenic disorders; oligogenic and multigenic disease mechanisms are increasingly recognized
• Polygenic risk scores for complex CVD (CAD, AF): extreme-score individuals (~top few percent) have risk equivalent to some monogenic disorders — clinical actionability remains to be determined

Limitations of the Document

• Evidence base is predominantly expert consensus and guideline synthesis — few clinical trials exist for genetic testing in cardiovascular medicine
• Published 2020: disease-specific gene curation and guidelines have continued to evolve (LQTS ClinGen reappraisal, ACMG secondary findings list expansion, DTC-GT landscape)
• US-centric legal discussion (GINA, HIPAA) — international applicability limited
• Does not address polygenic disorders or actionability of polygenic risk scores in clinical practice (acknowledged as future frontier)
• Variant interpretation framework based on ACMG 2015 criteria; ClinGen gene-specific adaptation incomplete for most cardiovascular genes at time of publication

Key Concepts Mentioned

• concepts/Genetic-Testing-in-Cardiomyopathy — comprehensive framework; gene panels by cardiomyopathy subtype
• concepts/Cascade-Family-Screening — principles and implementation of cascade genetic and clinical testing
• concepts/Variant-Reclassification — ACMG classification; VUS management; re-evaluation responsibility
• concepts/Incidental-Cardiovascular-Variants — ACMG 59 CVD genes; management of secondary findings
• concepts/Familial-Hypercholesterolemia — FH genetic testing criteria; cascade screening
• concepts/Cardiogenetic-Centers — expertise model for genetic testing and counselling

Key Entities Mentioned

• entities/HCM — definitive gene panel (8 genes); ClinGen curation; genotype-guided management
• entities/DCM — comprehensive gene panel; TTR testing in RCM
• entities/ARVC — gene panel; DCM panel overlap recommended
• entities/Brugada-Syndrome — SCN5A only definitively causal (of 21 evaluated); type 2/3 ECG not indication for testing
• entities/Long-QT-Syndrome — KCNQ1/KCNH2/SCN5A definitive; QTc thresholds for testing indication
• entities/CPVT — RYR2/CASQ2 panel; major diagnostic criterion
• entities/ATTR-Amyloidosis — TTR testing in RCM; prevalence in elderly Black patients (10% carry p.Val142Ile)
• entities/Anderson-Fabry-Disease — GLA as HCM genocopy; actionable enzyme replacement therapy
• entities/LMNA — DCM + ARVC panels; highest malignant VA risk
• entities/TTN — most common DCM gene; must be included in DCM gene panels

Wiki Pages Updated

• wiki/concepts/Genetic-Testing-in-Cardiomyopathy.md — added arrhythmic disorder and HTAD gene testing sections; incremented source_count
• wiki/concepts/Cascade-Family-Screening.md — added AHA 2020 general legal/institutional principles section; incremented source_count
• wiki/concepts/Familial-Hypercholesterolemia.md — added AHA 2020 FH genetic testing criteria (Table 4 content); incremented source_count
• wiki/entities/Brugada-Syndrome.md — added note that type 2/3 ECG is not an indication for genetic testing; incremented source_count
• wiki/entities/Long-QT-Syndrome.md — added AHA 2020 QTc thresholds for testing indication; incremented source_count
• wiki/sourceindex.md — added new entry