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Cardiogenetics, Volume 16, Issue 1 (March 2026) – 6 articles

Cover Story (view full-size image): Sudden cardiac death (SCD) is a major global health concern, caused by cardiac conditions ranging from coronary artery disease in older adults to inherited cardiomyopathies and channelopathies in younger individuals. Despite thorough autopsy, many cases remain unexplained. Advances in genetic testing, including next-generation sequencing, have improved the identification of underlying causes. Structural disorders, like hypertrophic and arrhythmogenic cardiomyopathies, and electrical disorders, such as long QT and Brugada syndromes, increase arrhythmic risk. Molecular autopsy can reveal hidden inherited conditions, though uncertain variants remain common. Genetic testing also aids family screening, while polygenic factors may further influence SCD risk. View this paper

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22 pages, 1275 KB

Open AccessReview

The Genetic Architecture of Sudden Cardiac Death: A State-of-the-Art Review

by Sabrina Montuoro, Emanuele Monda, Gaetano Diana, Emanuele Bobbio, Vera Fico, Marta Rubino, Martina Caiazza, Adelaide Fusco, Annapaola Cirillo, Federica Verrillo, Francesca Dongiglio, Giuseppe Palmiero, Federica Barra, Giulia Frisso, Maria Giovanna Russo, Paolo Calabrò and Giuseppe Limongelli

Cardiogenetics 2026, 16(1), 6; https://doi.org/10.3390/cardiogenetics16010006 - 19 Mar 2026

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Abstract

Sudden cardiac death (SCD) is a major global health issue, defined as sudden natural death presumed to be of cardiac cause. While in the elderly SCD is commonly associated with coronary artery disease, in the younger population it is linked to inherited cardiomyopathies or channelopathies, even though SCD can remain unexplained even after a comprehensive autopsy in a substantial proportion of cases. In this context, genetic testing has gained importance, supported by the widespread availability of techniques such as next-generation and whole-exome/genome sequencing and their reduced costs. This state-of-the-art review summarizes the genetic bases of sudden cardiac death among cardiomyopathies, channelopathies and in sudden unexplained death presumed to be of arrhythmic cause. Among the structural causes, inherited cardiomyopathies such as hypertrophic, dilated, non-dilated left ventricular, arrhythmogenic right ventricular and restrictive ones represent major substrates for malignant ventricular arrhythmias mostly arising from variants in sarcomeric or desmosomal genes. Channelopathies (long or short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia) are caused by variants in genes encoding cardiac ion channels and/or regulatory proteins, which equally predispose to high risk of life-threatening ventricular arrhythmias. In sudden arrhythmic death syndrome, with a structurally normal heart, post-mortem genetic testing (molecular autopsy) can uncover an underlying inherited condition. However, variants of uncertain significance are detected in more than half of the cases, underscoring the need for a multidisciplinary approach. Genetic testing also plays a key role in cascade screening of first-degree relatives. While monogenic variants drive risk in inherited cardiac disorders, emerging evidence suggests that polygenic contributions may modulate SCD susceptibility, highlighting future roles for polygenic risk scores in risk stratification. Full article

(This article belongs to the Special Issue Genetic Insights into Sudden Cardiac Death: From Risk Stratification to Precision Prevention)

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12 pages, 621 KB

Open AccessReview

Influence of Genetic and Epigenetic Factors in Takotsubo Syndrome: Insights and Gaps of an Incompletely Understood Disease

by Giulio La Rosa, Gemma Pelargonio, Francesco Santoro, Sergio Conti, Francesco Campo and Giuseppe Sgarito

Cardiogenetics 2026, 16(1), 5; https://doi.org/10.3390/cardiogenetics16010005 - 12 Mar 2026

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Abstract

Takotsubo syndrome (TTS) is a temporary and reversible form of cardiomyopathy that clinically mimics acute coronary syndrome, typically triggered by intense physical or emotional stress. It mainly affects postmenopausal women and exhibits significant variation among individuals regarding its onset, progression, and outcomes. Although significant advances have been made since its initial description in 1990, the underlying pathophysiological mechanisms remain incompletely understood, limiting the development of effective prevention and targeted treatment strategies. A potential genetic predisposition has been suggested, supported by reports of familial clustering; however, a systematic and updated characterization of genetic and epigenetic factors associated with TTS is still lacking. This systematic and critical review aims to offer a comprehensive overview of current evidence on genetic susceptibility and epigenetic biomarkers potentially involved in the pathogenesis of TTS. Due to the heterogeneity and inconsistency of available findings, particular attention is also given to the methodological limitations of existing genetic studies. Finally, the review examines emerging multimodal approaches that may offer new perspectives for understanding the complex biological foundations of this syndrome. Full article

(This article belongs to the Section Biomarkers)

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22 pages, 580 KB

Open AccessReview

Exploring the Genetic Architecture of Myocarditis and Inherited Cardiomyopathies

by Sukruth Pradeep Kundur, Ali Malik, Rasi Mizori and Sanjay Sivalokanathan

Cardiogenetics 2026, 16(1), 4; https://doi.org/10.3390/cardiogenetics16010004 - 10 Mar 2026

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Abstract

Myocarditis is a complex inflammatory myocardial disease. Although traditionally regarded as exclusively immune-mediated, recent evidence highlights the significant role of underlying genetics on susceptibility, phenotypic variability, and long-term prognosis. This narrative review examines the evolving genetic architecture of myocarditis and its relationship to inherited cardiomyopathies, integrating mechanistic insights from molecular, imaging, and clinical studies. Variants in desmosomal genes such as desmoplakin (DSP) and plakophilin-2 (PKP2) are increasingly linked to recurrent myocarditis that may evolve into arrhythmogenic cardiomyopathy, supporting the concept of a genetically predisposed myocardium in which inflammatory stressors can act as triggers. Truncating variants in titin (TTN) and Filamin C (FLNC) are associated with fulminant or dilated phenotypes. Conversely, mutations in Lamin A/C (LMNA), Desmin (DES), and BCL2-Associated Athanogene 3 (BAG3) contribute to inflammatory myocardial remodeling and other forms of inherited cardiomyopathies. These findings collectively have the potential to redefine myocarditis as an inflammatory disorder influenced by genetic factors. Furthermore, advancements in genetic testing and multi-omics approaches show promise in enhancing diagnostic accuracy and informing management strategies. Full article

(This article belongs to the Section Molecular Genetics)

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14 pages, 2724 KB

Open AccessSystematic Review

Genetic Variants as a Potentially Arrhythmogenic Substrate in Mitral Annular Disjunction: Case Report and a Systematic Review of the Literature

by Lorenzo Bianchi, Marialaura Buscemi, Domenico Coviello, Massimiliano Cecconi, Andrea Minghini, Stefano Cornara, Matteo Astuti, Francesco Pentimalli, Pietro Bellone, Emmanuel Androulakis and Alberto Somaschini

Cardiogenetics 2026, 16(1), 3; https://doi.org/10.3390/cardiogenetics16010003 - 26 Feb 2026

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Abstract

Mitral annular disjunction (MAD) is associated with an increased risk of ventricular arrhythmias and sudden cardiac death, yet its genetic background remains poorly defined. We report the case of a 50-year-old man with MAD who survived cardiac arrest and carries three variants of unknown significance (VUS) in genes involved in cardiomyopathy pathogenesis. To explore the genetic basis of non-syndromic MAD, we performed a systematic review of the literature, identifying five case reports and one retrospective cohort study. The case reports described patients with MAD harboring four pathogenic variants and ten VUS. Two pathogenic variants were linked to cardiomyopathies, involving proteins of the nuclear envelope and cytoskeleton, while two were associated with channelopathies. The retrospective cohort study identified a recurrent variant in a gene involved in intercellular adhesion segregating within a family affected by MAD. Overall, available evidence suggests that genetic factors may hypothetically modulate susceptibility to MAD, not only in connective tissue disorders but also in isolated mitral valve disease. Variants associated with arrhythmogenic cardiomyopathies and channelopathies appear to cluster in families with non-syndromic MAD and arrhythmic phenotypes, suggesting a role in the arrhythmic substrate. However, in absence of definitive functional, segregation, or longitudinal data, the contribution of genetic variants to MAD should be interpreted with caution. Further genomic studies are needed to clarify their genetic contribution and prognostic implications. Full article

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

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14 pages, 1155 KB

Open AccessReview

Non-Lysosomal Glycogen Storage Cardiomyopathy with Hypertrophic Phenotype Due to PRKAG2 c.905G>A (p.Arg302Gln): Case Report and Narrative Review

by Pasquale Crea, Alice Moncada, Francesco Catanzariti, Graziella Agnelli, Michela Navarra, Claudia Rubino, Irene Scimè, Lucio Teresi, Maurizio Cusmà Piccione, Luigi Colarusso, Roberto Licordari, Giuseppe Dattilo and Gianluca Di Bella

Cardiogenetics 2026, 16(1), 2; https://doi.org/10.3390/cardiogenetics16010002 - 21 Feb 2026

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Abstract

Background: PRKAG2 cardiac syndrome is a rare autosomal dominant glycogen-storage cardiomyopathy that mimics sarcomeric hypertrophic cardiomyopathy (HCM) but features ventricular pre-excitation, progressive conduction disease and concentric hypertrophy due to intracellular glycogen accumulation. The c.905G>A (p.Arg302Gln) variant is one of the most frequently reported pathogenic substitutions. Case summary: We describe a three-generation family carrying the heterozygous PRKAG2 p.Arg302Gln variant. The proband, a 41-year-old man, presented with paroxysmal atrial fibrillation, short PR interval and abnormal intraventricular conduction associated with concentric left ventricular hypertrophy and preserved ejection fraction. Holter monitoring disclosed episodes of high-grade atrioventricular block, prompting implantation of a primary-prevention dual-chamber ICD. Two gene-positive brothers exhibited milder hypertrophy but shared sinus bradycardia, ventricular pre-excitation and supraventricular arrhythmias; one underwent catheter ablation of a posteroseptal accessory pathway. The affected mother displayed a hypertrophic phenotype complicated by sick sinus syndrome and permanent atypical atrial flutter requiring pacemaker implantation. No relevant extracardiac involvement was detected in any family member. Review and novelty: Using this family as a starting point, we provide a concise narrative review of PRKAG2 syndrome with emphasis on the Arg302Gln genotype, molecular mechanisms and emerging treatment strategies. We highlight key multimodality imaging and tissue-characterization features that help distinguish diffuse, concentric glycogen-storage hypertrophy from the often-asymmetric pattern of sarcomeric HCM. Integration of our findings with published Arg302Gln cohorts illustrates the broad phenotypic variability in conduction disease, pre-excitation and atrial arrhythmias. Conclusions: PRKAG2 p.Arg302Gln-related cardiomyopathy should be suspected in patients with otherwise unexplained left ventricular hypertrophy associated with short PR interval, pre-excitation or early brady–tachy arrhythmias. Early recognition of red-flag features, systematic genetic testing, family screening and tailored arrhythmia/device management are crucial, while emerging gene- and pathway-targeted therapies may offer future disease-modifying potential. Full article

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

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15 pages, 4138 KB

Open AccessCase Report

Digenic Contribution of Heterozygous ALPK3 and TRIM63 Variants to End-Stage Hypertrophic Cardiomyopathy in a Young Adult

by Olga S. Chumakova, Natalia V. Milovanova, Elena A. Mershina, Sergey I. Kutsev and Ekaterina Y. Zakharova

Cardiogenetics 2026, 16(1), 1; https://doi.org/10.3390/cardiogenetics16010001 - 1 Jan 2026

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Abstract

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disorder, is usually caused by pathogenic variants in sarcomeric genes and is inherited in an autosomal dominant manner. Around 5% of cases are caused by variants in non-sarcomeric genes, which may involve alternative modes of inheritance. This study presents the first reported case of HCM associated with digenic contribution of heterozygous variants in two non-sarcomeric genes: ALPK3 and TRIM63. The patient was incidentally diagnosed with non-obstructive HCM in childhood and developed extreme myocardial hypertrophy with moderate heart failure at the age of 18. Rapid progressive left ventricular dysfunction promptly resulted in death at the age of 26. Genetic testing with an extended HCM panel identified no sarcomeric variants but revealed two truncating variants in the ALPK3 and TRIM63 genes. Whole-genome sequencing excluded any other causes of the disease. Heterozygous ALPK3 variants are typically associated with late-onset HCM, whereas TRIM63 variants are only considered pathogenic in a recessive state. This case, therefore, suggests a synergistic contribution of both variants to the development of a severe phenotype. The potential mechanisms of interaction between the protein products of ALPK3 and TRIM63 within the M-band of the sarcomere are discussed. Full article

(This article belongs to the Section Molecular Genetics)

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