Highlights
- Variants of uncertain significance (VUS) enriched in individuals of African ancestry confer measurable risk for cardiomyopathy and arrhythmias.
- PKP2 p.Val558Ile variant is strongly associated with increased risk of ventricular arrhythmias and sudden cardiac death and meets likely pathogenic criteria.
- Cardiovascular risk factors potentiate earlier onset and increased severity of heart failure and arrhythmias among variant carriers.
- Genetic ancestry influences the pathogenicity of variants, underscoring the need for ancestry-specific genetic testing interpretation.
Background
Cardiomyopathies and arrhythmias comprise a heterogeneous group of cardiac disorders characterized by structural and electrical abnormalities of the heart, frequently inherited in Mendelian patterns. Genetic testing increasingly informs diagnosis, prognosis, and management. However, individuals of African ancestry remain underrepresented in genetic studies, which contributes to a disproportionate burden of variants of uncertain significance (VUS) and limits diagnostic yield in this population. This underrepresentation exacerbates health disparities, as many variants enriched in African ancestry lack robust pathogenicity classification and actionable interpretation.
The increasing availability of large-scale biobanks with linked genomic and clinical data offers an unprecedented opportunity to reexamine the clinical impact of ancestry-enriched variants. This is critical to improve diagnostic precision, risk stratification, and personalized care for minority populations at elevated cardiovascular risk.
Key Content
Ancestry-Enriched VUS and Cardiovascular Risk: Evidence from Large Biobanks
The landmark study by Abe et al. (2026) examined 18 cardiomyopathy and arrhythmia genes to identify VUS with allele frequencies at least two-fold higher in individuals of African ancestry than in non-Finnish Europeans, requiring allele frequency >0.05% within African ancestry groups. Analyzing 96,897 African ancestry individuals from the All of Us and BioVU biobanks, the authors identified 82 such variants and conducted fixed-effects meta-analysis to assess associations with cardiovascular phenotypes stratified by heart failure (HF) status and cardiovascular risk factors.
Ten variants showed association with a composite cardiovascular endpoint in exploratory analysis. Four variants demonstrated significant associations with specific phenotypes across cohorts:
– PKP2 p.Val558Ile showed a 4-fold increased risk of ventricular arrhythmias or sudden cardiac death (aOR 4.02; P=0.004).
– ELAC2 p.Ile396Val was associated with heart failure (aOR 1.67; P=0.02) and atrial arrhythmias (aOR 1.88; P=0.02).
– FLNC p.Gly11Ser and PKP2 p.Val842Ile associated with heart failure (aOR ~1.96 and 1.99 respectively).
Importantly, cardiovascular risk factors (hypertension, diabetes, etc.) were linked to earlier HF onset (adjusted hazard ratio 1.71) and atrial arrhythmias (adjusted hazard ratio 1.17) in variant carriers, highlighting gene-environment interactions. Notably, PKP2 p.Val558Ile met American College of Medical Genetics and Genomics (ACMG) criteria for likely pathogenic classification, affecting an estimated 24,000 Black adults in the U.S.
Genetic Ancestry Modifies Variant Associations: Comparative Insights
Insights from other studies underscore that the impact of variants differs by ancestry. For example, the genomics-first evaluation of TTN truncating variants (TTNtvs) by Liu et al. (2019) demonstrated that hiPSI TTNtvs strongly correlate with dilated cardiomyopathy (DCM) in European ancestry cohorts but not in African ancestry individuals, despite comparable disease prevalence. This illustrates the complexity of variant pathogenicity modulated by genetic background.
Similarly, SCN5A, encoding the voltage-gated sodium channel Na_v1.5, harbors variants influencing electrocardiographic traits and arrhythmia susceptibility in African-descent populations (Chen et al., 2011). Variants such as SCN5A p.Gln1832Glu increase arrhythmia burden particularly in heart failure patients, as also corroborated in the biobank analyses.
Impacts on Clinical Practice and Variant Classification
The identification of ancestry-enriched variants associated with cardiovascular risk has immediate clinical implications. Variants historically labeled as VUS in African ancestry individuals may be reclassified as likely pathogenic with clinical data integration. This enhances the yield of genetic testing and informs personalized management strategies.
Moreover, understanding the interplay of genetic variants with conventional risk factors supports a more nuanced approach to screening and intervention. For example, carriers of FLNC or PKP2 variants with elevated blood pressure or diabetes might benefit from earlier and closer monitoring.
Methodological Advances and Research Domains
Large-scale biobank analyses combining genomic data with rich electronic health records enable assessment of genetic variant impact in real-world, diverse populations. Stratified meta-analytic approaches allow integration across cohorts and adjustment for confounders such as heart failure status and traditional cardiovascular risk factors. This domain advances precision medicine by contextualizing genetic findings within clinical phenotypes and environmental exposures.
Expert Commentary
The evolving evidence highlights critical gaps addressed by integrating large population-based genomic data from ancestrally diverse cohorts. The disproportionate underrepresentation of African ancestry individuals in prior genetic studies has hampered variant interpretation leading to health inequities. The present findings by Abe et al. fundamentally shift this paradigm by reclassifying common variants previously labeled as uncertain into actionable categories.
Mechanistically, variants such as PKP2 p.Val558Ile implicate plakophilin-2 dysfunction, a key component of cardiac desmosomes, in arrhythmogenesis and sudden cardiac death. Similarly, ELAC2 and FLNC variants affect RNA processing and cytoskeletal function respectively, linking molecular defects to cardiac phenotype. The modulation of risk by concomitant cardiovascular comorbidities suggests additive or synergistic pathophysiological pathways.
Guidelines for genetic testing in cardiomyopathy may increasingly incorporate ancestry-specific allele frequency thresholds and functional data to refine pathogenicity classifications. The precision cardiology community must address the challenge of variant interpretation in admixed and understudied populations and develop frameworks accommodating genetic diversity.
Limitations include the observational nature of biobank data, potential misclassification of clinical phenotypes, and the need for functional validation of variants to confirm causality. Further prospective studies and biological characterization are warranted.
Conclusion
This comprehensive review synthesizes new and prior evidence demonstrating that common ancestry-enriched variants confer significant cardiovascular risk in African ancestry populations, especially when compounded by traditional risk factors. The recognition and reclassification of such variants minimize disparities in genetic testing outcomes and enhance personalized medicine. Future research should expand diverse genomic databases, integrate multi-omics data, and develop ancestry-informed clinical algorithms to optimize cardiovascular care.
References
- Abe TA, Lancaster MC, Roden DM. Association of Common Ancestry-Enriched Variants With Cardiomyopathy and Arrhythmias. Circulation. 2026 May 27;153(24):1915-1927. PMID: 42200287.
- Liu Y et al. Genomics-First Evaluation of Heart Disease Associated With Titin-Truncating Variants. Circulation. 2019 Jul 2;140(1):42-54. PMID: 31216868.
- Chen L et al. SCN5A variation is associated with electrocardiographic traits in the Jackson Heart Study. Circ Cardiovasc Genet. 2011 Apr;4(2):139-44. PMID: 21325150.
