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Cardiogenetics, Volume 15, Issue 4 (December 2025) – 6 articles

Cover Story (view full-size image): Clinical variability within families harboring disease-causing genetic variants hamper clinical care and risk stratification. We studied a family with sinus bradycardia and long QT syndrome type 2 (LQTS2). The family harbored a variant in KCNH2, which co-segregated with the LQTS2. While sinus bradycardia has been reported in some LQTS subtypes, its association with LQTS2 is limited. Thorough analysis revealed that the sinus bradycardia and more severe LQTS2 were limited to one side of the family. We hypothesized that this family harbored a second genetic variant. This resulted in further genetic assessment and functional assessment of the identified variants. This study highlights the importance of additional genetic testing when discordant features are present, thereby enabling more accurate diagnosis, risk prediction, and management. View this paper

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18 pages, 665 KB

Open AccessReview

The Hidden Face of Danon Disease: Unique Challenges for Female Patients

by Laura Torlai Triglia, Federico Barocelli, Enrico Ambrosini, Alberto Bettella, Filippo Luca Gurgoglione, Michele Bianconcini, Angela Guidorossi, Francesca Russo, Antonio Percesepe and Giampaolo Niccoli

Cardiogenetics 2025, 15(4), 32; https://doi.org/10.3390/cardiogenetics15040032 - 4 Dec 2025

Viewed by 1659

Abstract

Danon Disease (DD) is a rare X-linked autophagic vacuolar myopathy caused by pathogenic variants in the lysosome-associated membrane protein 2 (LAMP-2) gene. Alternative splicing of the terminal exon 9 leads to the creation of three different isoforms, each with essential roles in regulating autophagy. DD is characterized by cardiomyopathy, skeletal myopathy, cognitive impairment, and retinal disorders, with cardiac involvement being the primary cause of morbidity and mortality. Muscle biopsy may reveal signs of vacuolar myopathy, but the diagnosis is typically confirmed through sequencing and deletion/duplication analysis of the LAMP-2 gene using peripheral blood. Although few genotype–phenotype correlations have been described, with most being limited to isoform 2B of exon 9, the most significant prognostic indicator remains sex. The disease manifests earlier and with a more severe systemic presentation in males due to their hemizygous status, whereas in females, the typical presentation is late-onset hypertrophic or dilated cardiomyopathy, generally without extracardiac involvement. Cases of severely affected women have been described, potentially due to non-random or defective X-inactivation. The less typical and delayed clinical presentation in females can result in incorrect or missed diagnoses. The aim of this narrative review is to summarize the natural history, diagnostic criteria, management strategies, and recent advancements in the understanding of DD in women. Full article

(This article belongs to the Section Rare Disease-Genetic Syndromes)

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15 pages, 2866 KB

Open AccessArticle

Sinus Bradycardia and Long QT Syndrome: Double Heterozygosity for Variants in KCNH2 and HCN4

by Jaël S. Copier, Fenna Tuijnenburg, Karolina Andrzejczyk, Alex V. Postma, Saskia N. van der Crabben, Oussama Najih, Caroline Pham, Leander Beekman, Arie O. Verkerk, Ahmad S. Amin and Elisabeth M. Lodder

Cardiogenetics 2025, 15(4), 31; https://doi.org/10.3390/cardiogenetics15040031 - 13 Nov 2025

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Abstract

Introduction: Clinical variability within families harbouring disease-causing genetic variants hampers clinical care and risk stratification. We studied a multigenerational family presenting with sinus bradycardia and long QT syndrome type 2 (LQTS2). The family harboured a pathogenic variant in KCNH2, which co-segregated with the observed LQTS2. We studied the genetic cause of the high occurrence of sinus bradycardia in this family. Methods: Clinical data was collected, including heart rate, QT-interval, symptoms, and echocardiographic parameters. QTc was calculated using the Bazett and the Fridericia formula. Sanger sequencing of HCN4 was performed, followed by segregation analysis of the identified variant with sinus bradycardia. The biophysiological consequences of two variants, KCNH2-p.L69P (c.206T>C) and HCN4-p.R666W (c.1996C>T), were assessed by patch-clamp experiments. Therefore, a heterologous model was generated by transfection of HEK293A or CHO-k1 cells, respectively. Results: Sanger sequencing of HCN4 identified HCN4-p.R666W (c.1996C>T), which has a stronger segregation with the observed sinus bradycardia than KCNH2-p.L69P. Patch-clamp experiments revealed that KCNH2-p.L69P and HCN4-p.R666W lead to a decrease in the corresponding current densities, which explains the LQTS and sinus bradycardia observed in the patients. Carriers of both genetic variants have a more severe LQTS2 phenotype, reflected in longer QT and higher incidence of syncope. Conclusions: We identified two (likely) pathogenic variants, KCNH2-p.L69P and HCN4-p.R666W, co-segregating with LQTS2 and sinus bradycardia, respectively. Patients carrying both variants showed a more severe phenotype. These findings highlight the importance of additional genetic testing when discordant features are present, thereby enabling more accurate diagnosis, risk prediction, and management. Full article

(This article belongs to the Section Molecular Genetics)

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6 pages, 1074 KB

Open AccessCase Report

Integrating Genetic, Clinical, and Histopathological Data for Definitive Diagnosis of PRKAG2-Related Disease

by Martina Caiazza, Emanuele Monda, Francesco Loffredo, Rossana Bussani, Vera Fico, Emanuele Bobbio, Chiara Cirillo, Anna Murredda, Immacolata Viscovo, Alessandra Scatteia, Santo Dellegrottaglie, Diego Colonna, Berardo Sarubbi, Maria Giovanna Russo, Paolo Golino, Gianfranco Sinagra and Giuseppe Limongelli

Cardiogenetics 2025, 15(4), 30; https://doi.org/10.3390/cardiogenetics15040030 - 4 Nov 2025

Cited by 2 | Viewed by 1913

Abstract

Background: PRKAG2-related disease is an autosomal dominant disorder caused by pathogenic variants in the PRKAG2 gene, leading to glycogen accumulation in cardiomyocytes. It is characterized by left ventricular hypertrophy (LVH), ventricular pre-excitation, and conduction disease. Due to the rarity of the condition and the frequent occurrence of private variants, functional or pathological testing is required for definitive pathogenicity classification. Case Presentation: We describe a 22-year-old male referred for evaluation after experiencing exertional dyspnea and a syncopal episode. Family history revealed sudden cardiac deaths and conduction disease requiring pacemaker implantation. The patient exhibited mild LVH on imaging, conduction abnormalities on electrophysiological study, and a heterozygous PRKAG2 variant (c.1643C>T; p.Ser548Leu), classified as likely pathogenic according to ACMG guidelines. Cascade screening identified the variant in three family members, one of whom exhibited a positive phenotype. Endomyocardial biopsy revealed glycogen accumulation, providing histopathological confirmation of PRKAG2-related disease. Conclusions: This case underscores the importance of integrating genetic, clinical, and histopathological data in variant interpretation. Endomyocardial biopsy can provide definitive evidence to reclassify a PRKAG2 variant as pathogenic, thereby guiding management and family screening. Full article

(This article belongs to the Section Rare Disease-Genetic Syndromes)

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23 pages, 1720 KB

Open AccessReview

From Genetics to Phenotype: Understanding the Diverse Manifestations of Cardiovascular Genetic Diseases in Pediatric Populations

by Jule Leonie Gutmann, Alina Spister and Lara Baticic

Cardiogenetics 2025, 15(4), 29; https://doi.org/10.3390/cardiogenetics15040029 - 11 Oct 2025

Viewed by 3022

Abstract

Congenital genetic heart defects are major contributors to pediatric morbidity and mortality, underscoring the importance of early detection and individualized therapeutic strategies. This review aimed to summarize current knowledge on a spectrum of inherited cardiovascular disorders, with a focus on their genetic etiology, molecular pathogenesis, and phenotypic presentation in children. Conditions discussed include Marfan syndrome, Noonan syndrome, various cardiomyopathies, Duchenne muscular dystrophy, DiGeorge syndrome, and the tetralogy of Fallot. These six conditions were selected to represent the spectrum of pediatric cardiovascular genetic diseases, encompassing connective tissue disorders, multisystem syndromes, primary myocardial diseases, neuromuscular cardiac involvement, and structural congenital defects, thereby illustrating how distinct genotypes lead to diverse phenotypes. For each disorder, the underlying genetic mutations, associated molecular pathways, cardiovascular involvement, clinical features, and approaches to diagnosis and management are examined. Emphasis is placed on the role of timely diagnosis, genetic counseling, and personalized treatment in improving patient outcomes. The review concludes by highlighting emerging research directions and novel therapeutic interventions aimed at enhancing care for these complex pediatric conditions. Full article

(This article belongs to the Section Inherited Heart Disease-Children)

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18 pages, 762 KB

Open AccessSystematic Review

MicroRNA and DNA Methylation Adaptation Mechanism to Endurance Training in Cardiovascular Disease: A Systematic Review

by Jil Delhez, Jeanne Ougier, Francisco Xavier de Araujo, Raphael Martins de Abreu and Camilo Corbellini

Cardiogenetics 2025, 15(4), 28; https://doi.org/10.3390/cardiogenetics15040028 - 11 Oct 2025

Cited by 1 | Viewed by 2077

Abstract

Background: Regular endurance training induces physiological changes in cardiac structure and function. The precise epigenetic mechanisms by which cardiovascular adaptations are mediated are still unclear. This review seeks to clarify the role of epigenetic regulation in exercise-induced cardiovascular adaptation. Methods: This systematic review was conducted in accordance with the PRISMA guidelines up to 30 April 2025, using the databases PubMed, VHL, and LILACS Plus. Studies were included if they focused on microRNA expression and DNA methylation in individuals with cardiovascular disease who underwent endurance training. Results: Six articles, including 384 participants with heart failure, coronary artery disease, and hypertension, were included in the final analysis. Changes in DNA methylation and microRNA expression of specific genes involved in cardiovascular structural and functional adaptation were observed. Significant improvements were found in body composition, VO_2peak, systolic and diastolic blood pressure, and left ventricular function and structure. Conclusions: Endurance training has a positive impact on epigenetic mechanisms related to cardiovascular structural and functional adaptation. A clear causal link between epigenetic modifications and clinical outcomes remains to be established. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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10 pages, 383 KB

Open AccessReview

Polygenic Risk Scores and Coronary Artery Disease

by Salman Ansari, Suvasini Lakshmanan and Matthew J. Budoff

Cardiogenetics 2025, 15(4), 27; https://doi.org/10.3390/cardiogenetics15040027 - 26 Sep 2025

Cited by 1 | Viewed by 6137

Abstract

Background: Polygenic risk scores (PRSs) aggregate the effects of many common genetic variants and are being investigated as tools to refine coronary artery disease (CAD) risk prediction beyond traditional clinical models. Methods and Results: We review the development of PRS from early unweighted scores to contemporary genome-wide models and summarize evidence from major studies. We identified key studies through PubMed searches using the terms “polygenic risk score,” “genetic risk prediction,” and “coronary artery disease,” supplemented by citation chaining of highly cited articles and recent reviews. Large cohorts, such as the UK Biobank, show that individuals in the highest PRS percentiles have a 3–5-fold higher risk of CAD, and may gain the greatest benefit from statin therapy. PRS can also reclassify younger adults at borderline or intermediate risk and may complement coronary artery calcium (CAC) scoring. Conclusions: PRSs hold promise for lifetime risk stratification and targeted prevention in CAD but are limited by ancestry bias in GWAS, underrepresentation of diverse populations, inconsistency in individual estimates, and lack of standardized reporting. Future research should focus on expanding multi-ancestry databases, standardizing methods, prospective validation, and effective communication strategies to support equitable and evidence-based clinical use. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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