Interpreting Incidentally Identified Variants in Genes Associated With Heritable Cardiovascular Disease

Authors, Journal, Affiliations, Type, DOI

• Authors: Andrew P. Landstrom MD PhD (Chair), Anwar A. Chahal MBChB PhD (Vice Chair), Michael J. Ackerman MD PhD, Sharon Cresci MD, Dianna M. Milewicz MD PhD, Alanna A. Morris MD, Georgia Sarquella-Brugada MD PhD, Christopher Semsarian MBBS PhD, Svati H. Shah MD, Amy C. Sturm MS LCGC; on behalf of the AHA Data Science and Precision Medicine Committee
• Journal: Circulation: Genomic and Precision Medicine, April 2023; 16:e000092
• Affiliations: Multi-institutional (Duke, UPenn, Mayo, Washington University, UT Houston, Emory, Hospital Sant Joan de Deu Spain, University of Sydney, Geisinger)
• Type: AHA Scientific Statement
• DOI: 10.1161/HCG.0000000000000092

Overview

As exome (ES) and genome sequencing (GS) expand beyond targeted diagnostic contexts — into research biobanks, direct-to-consumer testing, and unrelated clinical indications — clinicians increasingly receive incidentally identified variants in CVD-associated genes. The variant burden in the general population far exceeds actual disease prevalence, making interpretation of these results non-trivial. This AHA Scientific Statement establishes a Bayesian probabilistic framework to guide clinicians: establish a pretest probability via comprehensive clinical and ≥3-generation family evaluation, modify it by the strength of gene-variant-disease association (LP/P per ACMG criteria and ClinGen curation), and arrive at a posttest probability that determines management, follow-up interval, and cascade family testing. Multidisciplinary cardiovascular genetics specialty centre involvement is considered essential throughout.

Keywords

AHA Scientific Statements · aortic diseases · cardiomyopathies · cardiovascular diseases · channelopathies · dyslipidemias · genomics · patient care team

Key Takeaways

Reporting Framework for Incidental Variants

• Incidental variants = variants not related to the phenotype for which testing was ordered; includes ACMG-defined "secondary findings" plus variants identified through research or DTC testing
• ACMG SF v3.1 contains 78 actionable genes — 42 (54%) are CVD-related, spanning dyslipidemias, cardiomyopathies (ACM, DCM, HCM, RCM), inherited arrhythmias (LQTS1/2/3, BrS, CPVT), thoracic aortic disease, Fabry disease, Pompe disease, and haemochromatosis
• Only LP/P variants in ACMG-78 genes should be communicated if the patient has consented to receiving such results
• VUSs are generally not communicated to patients; however, VUSs found through DTC testing or patient-initiated broad testing may still be presented to clinicians
• CDC 3-tier system: Tier 1 (sufficient evidence to alter management — only FH currently for CVD); Tier 2 (moderate evidence for decision-making); Tier 3 (insufficient/not ready for routine use); HCM genes expected to move to Tier 1

Pretest/Posttest Genetic Counselling

• Pretest counselling before GS/ES should cover: likelihood of incidental results, types communicated, benefits/risks, family implications, insurance concerns, distinction between clinical and research testing, recontact policies
• Patients should be asked whether they wish to receive secondary results
• Telehealth and digital tools can support counselling scalability
• Certified genetic counsellors are central to the process

A Bayesian Framework for Variant Interpretation

• Step 1 — Pretest probability: Comprehensive medical history + ≥3-generation family history + physical examination + disease-specific clinical testing
  • Channelopathies: ECG + ≥24h Holter + exercise stress test
  • Cardiomyopathy: ECG + echocardiogram (CMR with tissue characterisation can be considered)
  • Thoracic aortic disease: echocardiogram (CT or MRI to evaluate aorta can be considered)
  • Familial hypercholesterolaemia: serum lipid panel (CT coronary angiography if appropriate)
  • Congenital/structural heart disease: ECG + echocardiogram (CMR in selected cases)
• Step 2 — Modification by variant pathogenicity: Re-evaluate the LP/P classification assigned by the testing laboratory using ClinVar, ClinGen, ACMG 2015 criteria; do not rely solely on laboratory interpretation — pathogenicity assertions differ between labs and change over time; incorporation of clinical phenotype into variant interpretation may aid reclassification
• Step 3 — Posttest probability: Integrates steps 1 and 2; drives clinical management, follow-up interval, and cascade testing decisions
  • High posttest probability (confirmed LP/P + positive clinical findings) → ongoing longitudinal surveillance per disease-specific guidelines + cascade testing of first-degree relatives
  • Low posttest probability (disputed gene, absent phenotype) → infrequent or no further follow-up

Follow-Up of Variants Over Time

• Variant pathogenicity classification is dynamic: LP/P or likely benign variants reclassify at a rate of 1–8%/year per variant, predominantly toward VUS
• VUSs themselves reclassify at even higher rates over time
• Recommended follow-up interval for variant re-evaluation: every 1–3 years, paired with clinical follow-up; interval individualized to variant and patient
• Follow-up should reassess personal and family history, repeat clinical testing, and reintegrate new genetic evidence
• Genetic specialists in CVD genetics must take an active and consistent role in variant review

Cascade Family Genetic Testing from Incidental Variants

• LP/P incidental variants — once confirmed by the Bayesian framework as disease-associated — can and should trigger cascade genetic testing in first-degree relatives (and recursively in their relatives if positive)
• Cascade testing must NOT be performed on VUS variants, regardless of whether the proband is clinically affected
• Family members found to be genotype-positive should undergo the same clinical evaluation framework
• Genotype-positive relatives with no phenotypic evidence of disease still require longitudinal follow-up (as per guideline-directed intervals)

Special Populations

Diverse Populations

• Most large GS studies performed in populations of European ancestry; non-European populations (African, Latin American, Indigenous) markedly underrepresented
• Higher VUS rates in non-European ancestry; benign variants more likely misclassified as LP/P due to inadequate control databases
• Urgent need to include diverse and underrepresented populations in human genomics research
• Same Bayesian framework applies but special attention to variant re-evaluation over time

Direct-to-Consumer Testing

• DTC testing bypasses clinician gatekeeping; ACMG published minimum requirements for DTC-GT
• When a LP/P variant is found in an ACMG-recommended gene, referral to an inherited CVD specialist centre should be considered
• Most DTC testing does not undergo FDA review for analytical reliability or clinical validity

Pharmacogenomic Incidental Findings

• Each patient in the NIH Undiagnosed Diseases Program had ≥1 pharmacogenomic incidental finding; ~1% had findings related to current medications
• No uniform standards exist for reporting incidental findings from pharmacogenomic testing
• Consistent pretest counselling before pharmacogenomic testing is needed

Pediatric Populations

• Frequency of incidental CVD gene variants in children markedly exceeds prevalence of actual disease — careful interpretation in multidisciplinary setting is essential
• Parents/guardians should be counselled about incidental CVD variant possibility before ES/GS
• Assent from children capable of understanding should be sought
• Adolescents should be offered private discussion
• Timely referral to paediatric multidisciplinary centres is recommended

Limitations of the Document

• Expert-based consensus framework without randomised trial evidence; practice heterogeneity across centres is acknowledged
• The reclassification rate data (1–8%/year) is cited from single-centre or disease-specific studies, not a systematic multi-centre registry
• No specific management algorithms for every CVD subtype — relies on existing disease-specific guidelines
• DTC-specific guidance is limited and non-prescriptive

Key Concepts Mentioned

• concepts/Incidental-Cardiovascular-Variants — primary framework described in this source
• concepts/Variant-Reclassification — 1–8%/year reclassification rate; VUS follow-up
• concepts/Cascade-Family-Screening — LP/P-only cascade testing rule; posttest-probability-driven
• concepts/Cardiogenetic-Centers — multidisciplinary centre role in incidental variant evaluation
• concepts/DTC-Genetic-Testing — DTC context and ACMG minimum requirements
• concepts/Genetic-Testing-in-Cardiomyopathy — cardiomyopathy gene evaluation framework
• concepts/Genetic-Testing-in-AF — incidental AF gene findings
• concepts/Familial-Hypercholesterolemia — only CVD condition in CDC Tier 1 actionable genomics

Key Entities Mentioned

• entities/HCM — ACMG-78 HCM genes; expected to move to CDC Tier 1
• entities/DCM — ACMG-78 DCM genes
• entities/ARVC — ACMG-78 ACM/ARVC genes
• entities/Long-QT-Syndrome — KCNQ1, KCNH2, SCN5A; CALM1/2/3 and TRDN as ClinGen definitive
• entities/Brugada-Syndrome — SCN5A incidental findings
• entities/CPVT — RYR2, CASQ2, TRDN; cascade testing rules
• entities/ATTR-Amyloidosis — TTR as ACMG-78 gene (restrictive/infiltrative cardiomyopathy)
• entities/Anderson-Fabry-Disease — GLA as ACMG-78 gene

Wiki Pages Updated

• wiki/sources/incident-gene-aha-2023.md (created)
• wiki/concepts/Incidental-Cardiovascular-Variants.md (created)
• wiki/concepts/Variant-Reclassification.md (updated)
• wiki/concepts/Cascade-Family-Screening.md (updated)
• wiki/concepts/Cardiogenetic-Centers.md (updated)
• wiki/concepts/DTC-Genetic-Testing.md (updated)
• wiki/wikiindex.md (updated)
• wiki/sourceindex.md (updated)