Cardiogenetics

17 pages, 991 KB

Open AccessArticle

Genetic Profile of Pediatric-Onset Cardiac Channelopathies

by Sara Giovani, Adelaide Ballerini, Alessia Gozzini, Michele Di Lorenzo, Davide Mei, Silvia Passantino, Mattia Zampieri, Alessia Tomberli, Alberto Marchi, Giovanni Battista Calabri, Gaia Spaziani, Giulio Porcedda, Elena Bennati, Silvia Favilli, Iacopo Olivotto and Francesca Girolami

Cardiogenetics 2025, 15(3), 25; https://doi.org/10.3390/cardiogenetics15030025 (registering DOI) - 12 Sep 2025

Abstract

This study investigates the genetic background of pediatric-onset cardiac channelopathies, a rare group of genetic disorders causing arrhythmias and sometimes sudden death, whose genetic background remains partially unknown. The research analyzed 59 pediatric patients (<18 years of age) diagnosed with different channelopathies (LQTS, [...] Read more.

This study investigates the genetic background of pediatric-onset cardiac channelopathies, a rare group of genetic disorders causing arrhythmias and sometimes sudden death, whose genetic background remains partially unknown. The research analyzed 59 pediatric patients (<18 years of age) diagnosed with different channelopathies (LQTS, BrS, CPVT, SQTS, and conduction disorders), along with 40 of their family members, using Next-Generation Sequencing (NGS) after genetic counseling. A causative genetic variant was found in 47% of cases, mainly in the KCNQ1 (42%), RYR2 (16%), CACNA1C (10%), and SCN5A (10%) genes. Notably, a de novo large deletion in KCNH2 was detected in an LQTS patient, and a pathogenic CALM1 variant was identified in a child. A compound heterozygous KCNQ1 was consistent with Jervell and Lange-Nielsen syndrome. In light of these data, genetic testing is crucial for diagnosis, prognosis, and treatment planning; cascade screening allowed early risk identification and preventive interventions for family members. Expanding NGS technologies and research on new candidate genes may enhance personalized therapies in the future. Full article

(This article belongs to the Section Molecular Genetics)

7 pages, 1560 KB

Open AccessCase Report

TNNC1 Gene Mutation in Ebstein’s Anomaly and Left Ventricular Hypertrabeculation: A Case Report of a New Causative Mutation?

by Irene Raso, Claudia Chillemi, Giorgia Prontera, Arianna Laoreti, Elisa Cattaneo, Valeria Calcaterra, Gian Vincenzo Zuccotti and Savina Mannarino

Cardiogenetics 2025, 15(3), 24; https://doi.org/10.3390/cardiogenetics15030024 - 26 Aug 2025

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Abstract

Background: Ebstein’s anomaly (EA) is a rare congenital heart defect characterized by failure of tricuspid valve delamination during embryogenesis. Left ventricular (LV) hypertrabeculation results from incomplete myocardial compaction during fetal development. EA is associated with LV hypertrabeculation in 0.14% of cases, and EA [...] Read more.

Background: Ebstein’s anomaly (EA) is a rare congenital heart defect characterized by failure of tricuspid valve delamination during embryogenesis. Left ventricular (LV) hypertrabeculation results from incomplete myocardial compaction during fetal development. EA is associated with LV hypertrabeculation in 0.14% of cases, and EA is the most common congenital heart disease in LV hypertrabeculation (up to 29%), suggesting a shared embryogenetic pathway. Case Report: We describe a female patient prenatally diagnosed with EA and a large ventricular septal defect. Postnatal echocardiography confirmed EA with moderate regurgitation and revealed previously unnoticed left ventricular excessive trabeculations. Whole exome sequencing revealed a heterozygous never-described variant of unknown significance in the TNNC1 gene. Discussion: The genetic link between EA and LV hypertrabeculation remains unclear, though variants in sarcomeric or cytoskeletal genes like MYH7, TPM1, and NKX2.5—essential for cardiac development—have been implicated. A developmental hypothesis suggests that aberrant contraction during endocardial-to-mesenchymal and epicardial-to-mesenchymal transformation (5th–8th gestational weeks) may affect valve delamination and ventricular compaction via parallel signaling pathways. TNNC1 encodes troponin C1, a subunit of the troponin complex involved in muscle contraction. Its mutations are known to alter calcium sensitivity and impair cardiac contractility. Conclusions: EA and LV hypertrabeculation patients diagnosed in infancy have a greater risk of negative outcomes. Early, especially prenatal, diagnosis is crucial. Genetic analysis can provide fundamental insight into cardiac development. This new and rare variant of TNNC1 gene supports the hypothesis that early cardiomyocytes dysfunction disrupts both valve delamination and left ventricular compaction and that the two diseases share a common genetic pathway related to cardiomyocyte contraction. Full article

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

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13 pages, 1337 KB

Open AccessArticle

Association Between Angiotensinogen Gene M235T and Renin–Angiotensin System Insertion/Deletion Variants and Risk of Cardiovascular Disease in North African and Middle Eastern Populations: A Systematic Review and Meta-Analysis

by Rajaa El Mansouri, Hind Dehbi and Rachida Habbal

Cardiogenetics 2025, 15(3), 23; https://doi.org/10.3390/cardiogenetics15030023 - 8 Aug 2025

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Abstract

Background: The renin–angiotensin system (RAS) is pivotal in regulating cardiovascular function, while cardio-genomics offers insights into genetic factors influencing cardiovascular disease (CVD) susceptibility. Aim: This study investigates the relationship between the angiotensin-converting enzyme insertion/deletion variant (ACE I/D) and the angiotensinogen gene M235T variant [...] Read more.

Background: The renin–angiotensin system (RAS) is pivotal in regulating cardiovascular function, while cardio-genomics offers insights into genetic factors influencing cardiovascular disease (CVD) susceptibility. Aim: This study investigates the relationship between the angiotensin-converting enzyme insertion/deletion variant (ACE I/D) and the angiotensinogen gene M235T variant (AGT M235T) in Mediterranean, North African, and Middle Eastern populations. Methods: A systematic review and meta-analysis, encompassing studies until December 2023, were conducted utilizing the PubMed and Scopus databases. The study followed the PICO checklist to enroll in the review process. The meta-analysis results were obtained using CMA software V2. Results: An analysis of 12 studies (2984 participants) for ACE I/D and 7 studies (2275 participants) for AGT M235T revealed significant associations between these gene variants and increased CVD risk in Mediterranean and North African populations. Conclusions: These findings underscore the utility of cardio-genomics in delineating CVD susceptibility among these groups, emphasizing targeted interventions and personalized treatment strategies Full article

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24 pages, 649 KB

Open AccessReview

Desmosomal Versus Non-Desmosomal Arrhythmogenic Cardiomyopathies: A State-of-the-Art Review

by Kristian Galanti, Lorena Iezzi, Maria Luana Rizzuto, Daniele Falco, Giada Negri, Hoang Nhat Pham, Davide Mansour, Roberta Giansante, Liborio Stuppia, Lorenzo Mazzocchetti, Sabina Gallina, Cesare Mantini, Mohammed Y. Khanji, C. Anwar A. Chahal and Fabrizio Ricci

Cardiogenetics 2025, 15(3), 22; https://doi.org/10.3390/cardiogenetics15030022 - 1 Aug 2025

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Abstract

Arrhythmogenic cardiomyopathies (ACMs) are a phenotypically and etiologically heterogeneous group of myocardial disorders characterized by fibrotic or fibro-fatty replacement of ventricular myocardium, electrical instability, and an elevated risk of sudden cardiac death. Initially identified as a right ventricular disease, ACMs are now recognized [...] Read more.

Arrhythmogenic cardiomyopathies (ACMs) are a phenotypically and etiologically heterogeneous group of myocardial disorders characterized by fibrotic or fibro-fatty replacement of ventricular myocardium, electrical instability, and an elevated risk of sudden cardiac death. Initially identified as a right ventricular disease, ACMs are now recognized to include biventricular and left-dominant forms. Genetic causes account for a substantial proportion of cases and include desmosomal variants, non-desmosomal variants, and familial gene-elusive forms with no identifiable pathogenic mutation. Nongenetic etiologies, including post-inflammatory, autoimmune, and infiltrative mechanisms, may mimic the phenotype. In many patients, the disease remains idiopathic despite comprehensive evaluation. Cardiac magnetic resonance imaging has emerged as a key tool for identifying non-ischemic scar patterns and for distinguishing arrhythmogenic phenotypes from other cardiomyopathies. Emerging classifications propose the unifying concept of scarring cardiomyopathies based on shared structural substrates, although global consensus is evolving. Risk stratification remains challenging, particularly in patients without overt systolic dysfunction or identifiable genetic markers. Advances in tissue phenotyping, multi-omics, and artificial intelligence hold promise for improved prognostic assessment and individualized therapy. Full article

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

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11 pages, 2277 KB

Open AccessFeature PaperArticle

How to Enhance Diagnosis in Fabry Disease: The Power of Information

by Maria Chiara Meucci, Rosa Lillo, Margherita Calcagnino, Giampaolo Tocci, Eustachio Agricola, Federico Biondi, Claudio Di Brango, Vincenzo Guido, Valentina Parisi, Francesca Giordana, Veronica Melita, Mariaelena Lombardi, Angela Beatrice Scardovi, Li Van Stella Truong, Francesca Musella, Francesco di Spigno, Benedetta Matrone, Ivana Pariggiano, Paolo Calabrò, Roberto Spoladore, Stefania Luceri, Stefano Carugo, Francesca Graziani and Francesco Burzotta Show full author list Hide full author list

Cardiogenetics 2025, 15(3), 21; https://doi.org/10.3390/cardiogenetics15030021 - 31 Jul 2025

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Abstract

Background: Cardiac involvement is common in Fabry disease (FD) and typically manifests with left ventricular hypertrophy (LVH). Patients with FD are frequently misdiagnosed, and this is mainly related to the lack of disease awareness among clinicians. The aim of this study was to [...] Read more.

Background: Cardiac involvement is common in Fabry disease (FD) and typically manifests with left ventricular hypertrophy (LVH). Patients with FD are frequently misdiagnosed, and this is mainly related to the lack of disease awareness among clinicians. The aim of this study was to determine whether providing a targeted educational intervention on FD may enhance FD diagnosis. Methods. This research was designed as a single-arm before-and-after intervention study and evaluated the impact of providing a specific training on FD to cardiologists from different Italian centers, without experience in rare diseases. In the 12-month period after the educational intervention, the rate of FD screening and diagnosis was assessed and compared with those conducted in the two years preceding the study initiation. Results: Fifteen cardiologists participated to this study, receiving a theoretical and practical training on FD. In the two previous two years, they conducted 12 FD screening (6/year), and they did not detect any cases of FD. After the training, they performed 45 FD screenings, with an eight-fold rise in the annual screening rate. The screened population (age: 61 ± 11 years, men: 82%) was mainly composed of patients with unexplained LVH (n = 43). There were four new FD diagnoses and, among of them, three had a late-onset GLA variant. After the cascade genetic screening, 11 affected relatives and 8 heterozygous carriers were also detected. Conclusions: A targeted educational intervention for cardiologists allowed the identification of four new families with FD. Enhancing FD awareness is helpful to reduce the diagnostic and therapeutic delay. Full article

(This article belongs to the Section Education in Cardiogenetics)

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15 pages, 1506 KB

Open AccessReview

Dilated Cardiomyopathy and Sensorimotor Polyneuropathy Associated with a Homozygous ELAC2 Variant: A Case Report and Literature Review

by Francesco Ravera, Filippo Angelini, Pier Paolo Bocchino, Gianluca Marcelli, Giulia Gobello, Giuseppe Giannino, Guglielmo Merlino, Benedetta De Guidi, Andrea Destefanis, Giulia Margherita Brach Del Prever, Carla Giustetto, Guglielmo Gallone, Stefano Pidello, Antonella Barreca, Silvia Deaglio, Gaetano Maria De Ferrari, Claudia Raineri and Veronica Dusi

Cardiogenetics 2025, 15(3), 20; https://doi.org/10.3390/cardiogenetics15030020 - 31 Jul 2025

Viewed by 356

Abstract

Variants in ELAC2, a gene encoding the mitochondrial RNase Z enzyme essential for mitochondrial tRNA processing, have been associated with severe pediatric-onset mitochondrial dysfunction, primarily presenting with developmental delay, hypertrophic cardiomyopathy (HCM), and lactic-acidosis. We hereby report the case of a 25-year-old [...] Read more.

Variants in ELAC2, a gene encoding the mitochondrial RNase Z enzyme essential for mitochondrial tRNA processing, have been associated with severe pediatric-onset mitochondrial dysfunction, primarily presenting with developmental delay, hypertrophic cardiomyopathy (HCM), and lactic-acidosis. We hereby report the case of a 25-year-old young woman presenting with dilated cardiomyopathy (DCM) and peripheral sensorimotor polyneuropathy, harboring a homozygous variant in ELAC2. The same variant has been reported only once so far in a case of severe infantile-onset form of HCM and mitochondrial respiratory chain dysfunction, with in vitro data showing a moderate reduction in the RNase Z activity and supporting the current classification as C4 according to the American College of Medical Genetics (ACMG) criteria (PS3, PM2, PM3, PP4). Our extensive clinical, imaging, histological, and genetic investigations support a causal link between the identified variant and the patient’s phenotype, despite the fact that the latter might be considered atypical according to the current state of knowledge. A detailed review of the existing literature on ELAC2-related disease is also provided, highlighting the molecular mechanisms underlying tRNA maturation, mitochondrial dysfunction, and the variable phenotypic expression. Our case further expands the clinical spectrum of ELAC2-related cardiomyopathies to include a relatively late onset in young adulthood and underscores the importance of comprehensive genetic testing in unexplained cardiomyopathies with multisystem involvement. Full article

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

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33 pages, 4016 KB

Open AccessArticle

Integrated Deep Learning Framework for Cardiac Risk Stratification and Complication Analysis in Leigh’s Disease

by Md Aminul Islam, Jayasree Varadarajan, Md Abu Sufian, Bhupesh Kumar Mishra and Md Ruhul Amin Rasel

Cardiogenetics 2025, 15(3), 19; https://doi.org/10.3390/cardiogenetics15030019 - 15 Jul 2025

Viewed by 416

Abstract

Background: Leigh’s Disease is a rare mitochondrial disorder primarily affecting the central nervous system, with frequent secondary cardiac manifestations such as hypertrophic and dilated cardiomyopathies. Early detection of cardiac complications is crucial for patient management, but manual interpretation of cardiac MRI is labour-intensive [...] Read more.

Background: Leigh’s Disease is a rare mitochondrial disorder primarily affecting the central nervous system, with frequent secondary cardiac manifestations such as hypertrophic and dilated cardiomyopathies. Early detection of cardiac complications is crucial for patient management, but manual interpretation of cardiac MRI is labour-intensive and subject to inter-observer variability. Methodology: We propose an integrated deep learning framework using cardiac MRI to automate the detection of cardiac abnormalities associated with Leigh’s Disease. Four CNN architectures—Inceptionv3, a custom 3-layer CNN, DenseNet169, and EfficientNetB2—were trained on preprocessed MRI data (224 × 224 pixels), including left ventricular segmentation, contrast enhancement, and gamma correction. Morphological features (area, aspect ratio, and extent) were also extracted to aid interpretability. Results: EfficientNetB2 achieved the highest test accuracy (99.2%) and generalization performance, followed by DenseNet169 (98.4%), 3-layer CNN (95.6%), and InceptionV3 (94.2%). Statistical morphological analysis revealed significant differences in cardiac structure between Leigh’s and non-Leigh’s cases, particularly in area (212,097 vs. 2247 pixels) and extent (0.995 vs. 0.183). The framework was validated using ROC (AUC = 1.00), Brier Score (0.000), and cross-validation (mean sensitivity = 1.000, std = 0.000). Feature embedding visualisation using PCA, t-SNE, and UMAP confirmed class separability. Grad-CAM heatmaps localised relevant myocardial regions, supporting model interpretability. Conclusions: Our deep learning-based framework demonstrated high diagnostic accuracy and interpretability in detecting Leigh’s disease-related cardiac complications. Integrating morphological analysis and explainable AI provides a robust and scalable tool for early-stage detection and clinical decision support in rare diseases. Full article

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Cardiogenetics, Volume 15, Issue 3 (September 2025) – 7 articles

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