The 2025 Editor’s Choice papers [1] are highly cited articles that reflect the breadth of contemporary cardiovascular genetics, spanning from the molecular diagnosis of rare monogenic cardiac disorders to the emerging use of polygenic risk scores (PRSs) in coronary artery disease (CAD). Together, these studies illustrate a field increasingly shaped by the integration of genetic data with clinical, histopathological, functional, and imaging findings to refine diagnosis, characterize disease phenotypes, improve risk stratification, and guide management and prevention strategies. This integrative approach is supported by advanced genomic technologies, enabling the translation of increasingly complex genetic information into clinically meaningful insights.
Five of the six studies addressed inherited, single-gene cardiac conditions such as PRKAG2-related disease, arrhythmogenic cardiomyopathies (ACMs), MELAS-related mitochondrial cardiac involvement, hypertrophic cardiomyopathy (HCM), and Brugada syndrome (BrS), exploring how specific genotypes translate into diagnostic criteria, clinical phenotypes, and adverse outcomes. The sixth study shifts the perspective from monogenic disorders to polygenic risk stratification, applying aggregate genetic scores to CAD. Together, these studies capture a central challenge in cardiovascular genetics: translating genetic information into clinically meaningful tools for diagnosis and risk prediction across rare monogenic and common multifactorial cardiovascular diseases.
The first three studies highlight the importance of integrating genetic, clinical, and imaging data to accurately diagnose rare cardiac conditions, which are often underdiagnosed and misclassified.
The case report “Integrating Genetic, Clinical, and Histopathological Data for Definitive Diagnosis of PRKAG2-related Disease” illustrates the importance of integrating genetic, clinical, and histopathological data to establish a definitive diagnosis in rare metabolic cardiomyopathies. In a 22-year-old man with mild left ventricular hypertrophy and conduction disease but no typical features of PRKAG2-related disease, the authors reclassified a rare heterozygous PRKAG2 variant from likely pathogenic to pathogenic. Endomyocardial biopsy demonstrating glycogen accumulation within cardiomyocytes provided functional evidence supporting the genetic finding and helped explain the mild clinical phenotype, underscoring the value of tissue biopsy when noninvasive findings are inconclusive (Contribution 1).
“Desmosomal Versus Non-Desmosomal Arrhythmogenic Cardiomyopathies: A State-of-the-Art Review” redefines ACM as broad spectrum of scarring myocardial disorders marked by fibro-fatty replacement, electrical instability, and elevated sudden cardiac death risk. The authors show how genetic etiology shapes presentation, with desmosomal variants typically driving right-ventricular or biventricular disease and non-desmosomal variants more often producing aggressive left-dominant involvement. For the substantial share of genotype-negative patients, imaging-based phenotyping remains essential for risk stratification. The authors call for integrating multiomics, rare-variant burden, and imaging biomarkers into dynamic, genotype-informed models. Until such tools mature, the authors note that management must remain grounded in individualized clinical judgment (Contribution 2).
The authors of “Cardiac Involvement in Patients with MELAS-related mtDNA 3243A>G variant” evaluated 22 adults with genetically confirmed MELAS, stratified according to electrocardiographic findings, and assessed by cardiac magnetic resonance (CMR) feature tracking. Despite preserved ejection fraction and ventricular volumes, patients with electrocardiographic abnormalities showed impaired mid-myocardial strain, whereas proBNP levels correlated with CMR tissue characterization and circumferential strain. These findings highlight the phenotypic heterogeneity of MELAS and suggest that integrating electrocardiogram, biomarkers, and CMR strain analysis improves the detection of early myocardial dysfunction and risk stratification (Contribution 3).
The authors of the next two studies examined whether specific gene variants translate into distinct, predictable clinical phenotypes.
The authors of “The Influence of Genotype on the Cardiopulmonary Test Response in Patients Affected by Hypertrophic Cardiomyopathy” investigated whether the presence and type of genetic variants influence exercise capacity in patients with asymptomatic or mildly symptomatic HCM. In 120 patients with HCM who underwent next-generation sequencing (NGS) and cardiopulmonary exercise testing (CPET), gene-positive patients showed lower age-adjusted exercise capacity than gene-negative patients. Thus, performing CPET at initial evaluation can reveal early functional deficits in genotype-positive patients with HCM and guide clinical management and risk stratification (Contribution 4).
The authors of “Brugada Syndrome and GPD1L: Definite Genotype-Phenotype Association?” gathered all rare variants in the GPD1L gene that were previously linked to patients with a definitive or suspected diagnosis of BrS. Reviewing 15 published articles, 10 variants were identified and reanalyzed using the current ACMG/AMP guidelines to determine their pathogenicity. Based on this updated classification, five variants are likely benign, and five are variants of unknown significance, with none classified as pathogenic/likely pathogenic. The current evidence is therefore insufficient to prove a definitive causal link between GPD1L and BrS (Contribution 5).
Finally, shifting the focus from monogenic to polygenic architecture, the last study “Polygenic Risk Scores and Coronary Artery Disease” provides an overview of the role of PRSs in CAD risk stratification, highlighting their potential for quantifying inherited cardiovascular susceptibility. Genome-wide PRSs may improve risk assessment in younger adults before traditional risk factors accumulate, potentially identifying individuals who would benefit from earlier statin therapy and lifestyle interventions. However, their clinical implementation remains limited by the lower predictive accuracy in non-European populations, largely reflecting the Eurocentric GWAS bias. Moreover, combining PRSs with coronary artery calcium imaging appears to provide limited additional value beyond calcium scoring alone. Thus, PRSs may currently be best considered as a complementary tool for risk refinement rather than a standalone clinical test (Contribution 6).
In summary, these papers show how genetic characterization (whether at the level of a single causative variant or an aggregate polygenic score) continues to reshape the diagnostic and prognostic landscape of cardiovascular disease. A multimodality approach to patients, as illustrated across these contributions, remains essential for translating genetic discovery into meaningful patient care, from accurate diagnosis of rare cardiomyopathies to the risk stratification of coronary disease.
Conflicts of Interest
The author declares no conflicts of interest.
List of Contributions
- Caiazza, M.; Monda, E.; Loffredo, F.; Bussani, R.; Fico, V.; Bobbio, E.; Cirillo, C.; Murredda, A.; Viscovo, I.; Scatteia, A.; et al. Integrating Genetic, Clinical, and Histopathological Data for Definitive Diagnosis of PRKAG2-Related Disease. Cardiogenetics 2025, 15, 30. https://doi.org/10.3390/cardiogenetics15040030.
- Galanti, K.; Iezzi, L.; Rizzuto, M.L.; Falco, D.; Negri, G.; Pham, H.N.; Mansour, D.; Giansante, R.; Stuppia, L.; Mazzocchetti, L.; et al. Desmosomal Versus Non-Desmosomal Arrhythmogenic Cardiomyopathies: A State-of-the-Art Review. Cardiogenetics 2025, 15, 22. https://doi.org/10.3390/cardiogenetics15030022.
- Vuorinen, A.-M.; Lehmonen, L.; Auranen, M.; Weckström, S.; Kivistö, S.; Holmström, M.; Heliö, T. Cardiac Involvement in Patients with MELAS-Related mtDNA 3243A>G Variant. Cardiogenetics 2025, 15, 16. https://doi.org/10.3390/cardiogenetics15020016.
- Gagliardi, M.F.; Malfatto, G.; Baratto, C.; Giglio, A.; Rella, V.; Cerea, P.; Mariani, D.; Salerno, S.; Ravaro, S.; Castelletti, S.; et al. The Influence of Genotype on the Cardiopulmonary Test Response in Patients Affected by Hypertrophic Cardiomyopathy. Cardiogenetics 2025, 15, 12. https://doi.org/10.3390/cardiogenetics15020012.
- Greco, A.; Martínez-Barrios, E.; Cruzalegui, J.; Cesar, S.; Chipa, F.; Díez-Escuté, N.; Cerralbo, P.; Zschaeck, I.; Loredo, P.; Sarquella-Brugada, G.; et al. Brugada Syndrome and GPD1L: Definite Genotype-Phenotype Association? Cardiogenetics 2025, 15, 9. https://doi.org/10.3390/cardiogenetics15010009.
- Ansari, S.; Lakshmanan, S.; Budoff, M.J. Polygenic Risk Scores and Coronary Artery Disease. Cardiogenetics 2025, 15, 27. https://doi.org/10.3390/cardiogenetics15040027.
Reference
- Cardiogenetics|Editor’s Choice Articles in 2025. Available online: https://www.mdpi.com/journal/cardiogenetics/announcements/18671 (accessed on 21 September 2026).
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