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The field of cardiovascular genetics has tremendously benefited from the recent application of massive parallel sequencing technology also referred to as next generation sequencing (NGS). However, along with the discovery of additional genes associated with human cardiac diseases, the analysis of large dataset of genetic information uncovered a much more complex and variegated landscape, which often departs from the comfort zone of the monogenic Mendelian diseases image that clinical molecular geneticists have been well acquainted with for many decades. It is now clear that, in addition to highly penetrant genetic variants, which in isolation are able to recapitulate the full clinical presentation when expressed in animal models, we are now aware that a small but significant fraction of subjects presenting with cardiac muscle diseases such as cardiomyopathies or primary arrhythmias such as long QT syndrome (LQTS), may harbor at least two deleterious variants in the same gene (compound heterozygous) or in different gene (double heterozygous). Although the clinical presentation in subjects with more than one deleterious variant appears to be more severe and with an earlier disease onset, it somehow changes the viewpoint of clinical molecular geneticists whose aim is to identify all possible genetic contributors to a human condition. In this light, the employment in clinical diagnostics of the NGS technology, allowing the simultaneous interrogation of a DNA target spanning from large panel of genes up to the entire genome, will definitely aid at uncovering all such contributors, which will have to be tested functionally to confirm their role in human cardiac conditions. The uncovering of all clinically relevant deleterious changes associated with a cardiovascular disease would probably increase our understanding of the clinical variability commonly occurring among affected family relatives, and potentially provide with unexpected therapeutic targets for the treatment of symptoms related to the presence of “accessory” deleterious genetic variants other than the key molecular culprit. The objective of this Research Topic is to explore the current challenges presenting to the cardiovascular genetics providers, such as clinical geneticists, genetic counselors, clinical molecular geneticists and molecular pathologists involved in the diagnosis, counseling, testing and interpretation of genetic tests results for the comprehensive management of patients affected by cardiovascular genetic disorders.

genetic variants --- Cardiovascular Diseases --- Genetic Testing --- channelopathy --- variant interpretation --- NGS --- Sudden cardiac death --- cardiomyopathy --- Cardiovascular genetics

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The field of cardiovascular genetics has tremendously benefited from the recent application of massive parallel sequencing technology also referred to as next generation sequencing (NGS). However, along with the discovery of additional genes associated with human cardiac diseases, the analysis of large dataset of genetic information uncovered a much more complex and variegated landscape, which often departs from the comfort zone of the monogenic Mendelian diseases image that clinical molecular geneticists have been well acquainted with for many decades. It is now clear that, in addition to highly penetrant genetic variants, which in isolation are able to recapitulate the full clinical presentation when expressed in animal models, we are now aware that a small but significant fraction of subjects presenting with cardiac muscle diseases such as cardiomyopathies or primary arrhythmias such as long QT syndrome (LQTS), may harbor at least two deleterious variants in the same gene (compound heterozygous) or in different gene (double heterozygous). Although the clinical presentation in subjects with more than one deleterious variant appears to be more severe and with an earlier disease onset, it somehow changes the viewpoint of clinical molecular geneticists whose aim is to identify all possible genetic contributors to a human condition. In this light, the employment in clinical diagnostics of the NGS technology, allowing the simultaneous interrogation of a DNA target spanning from large panel of genes up to the entire genome, will definitely aid at uncovering all such contributors, which will have to be tested functionally to confirm their role in human cardiac conditions. The uncovering of all clinically relevant deleterious changes associated with a cardiovascular disease would probably increase our understanding of the clinical variability commonly occurring among affected family relatives, and potentially provide with unexpected therapeutic targets for the treatment of symptoms related to the presence of “accessory” deleterious genetic variants other than the key molecular culprit. The objective of this Research Topic is to explore the current challenges presenting to the cardiovascular genetics providers, such as clinical geneticists, genetic counselors, clinical molecular geneticists and molecular pathologists involved in the diagnosis, counseling, testing and interpretation of genetic tests results for the comprehensive management of patients affected by cardiovascular genetic disorders.

genetic variants --- Cardiovascular Diseases --- Genetic Testing --- channelopathy --- variant interpretation --- NGS --- Sudden cardiac death --- cardiomyopathy --- Cardiovascular genetics --- genetic variants --- Cardiovascular Diseases --- Genetic Testing --- channelopathy --- variant interpretation --- NGS --- Sudden cardiac death --- cardiomyopathy --- Cardiovascular genetics

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Dilated cardiomyopathy (DCM) is a particular phenotype of non-ischemic systolic heart failure, frequently recognizing a genetic background and affecting relatively young patients with few comorbidities. Nowadays, long-term survival of DCM patients has been markedly improved due to an early diagnosis and uninterrupted and tailored follow-up under constant optimal medical and non-pharmacological evidence-based treatments. Nevertheless, DCM is still one of the most common causes of heart transplantation in the western world. Clinical management requires an integrated and systematic use of diagnostic tools and a deeper investigation of the basic mechanisms underlying the disease. However, several emerging issues remain debated. Specifically, the genotype–phenotype correlation, the role of advanced imaging techniques and genetic testing, the lack of appropriate risk stratification models, the need for a multiparametric and multidisciplinary approach for device implantation, and a continuous reclassification of the disease during follow-up remain challenging issues in clinical practice. Therefore, the aim of this Special Issue is to shed the light on the most recent advancements in characterization and clinical management of DCM in order to unveil the conundrum of this particular disease.

Medicine --- SCN5A --- cardiac sodium channel --- cardiac channelopathy --- dilated cardiomyopathy --- precision medicine --- arrhythmias --- atrial fibrillation --- cardiomyopathy --- heart failure --- supraventricular arrhythmia --- systolic dysfunction --- tachycardiomyopathy --- ventricular arrhythmia --- left atrial strain --- cardiac resynchronization therapy --- muscular dystrophy --- calcium --- heart --- gene therapy --- phospholamban --- Serca2a --- mdx --- oxidative stress --- membrane stabilization --- left ventricular noncompaction --- congenital heart disease --- congestive heart failure --- non-ischemic cardiomyopathy --- genetics --- desmin --- mitochondrial dysfunction --- myopathy --- whole exome sequencing --- laminopathy --- LMNA --- biomarkers --- troponin T --- NT-proBNP --- malignant ventricular arrhythmia --- arrhythmic risk stratification --- DNA methylation --- alternative splicing --- epigenetics --- nonischemic dilated cardiomyopathy --- cardiac magnetic resonance imaging --- late gadolinium enhancement --- long axis strain --- left ventricle sphericity index --- major adverse cardiovascular events --- sex differences --- left ventricular reverse remodelling --- long-term outcomes --- left ventricle non-compaction cardiomyopathy --- cardiac magnetic resonance --- titin --- RNA binding motif protein 20 (RBM20) --- sarcomere --- diastolic dysfunction --- phosphorylation --- non-sense mRNA decay --- mammalian target of rapamycin (mTOR) complex-1 --- duchenne muscular distrophy --- SCN5A --- cardiac sodium channel --- cardiac channelopathy --- dilated cardiomyopathy --- precision medicine --- arrhythmias --- atrial fibrillation --- cardiomyopathy --- heart failure --- supraventricular arrhythmia --- systolic dysfunction --- tachycardiomyopathy --- ventricular arrhythmia --- left atrial strain --- cardiac resynchronization therapy --- muscular dystrophy --- calcium --- heart --- gene therapy --- phospholamban --- Serca2a --- mdx --- oxidative stress --- membrane stabilization --- left ventricular noncompaction --- congenital heart disease --- congestive heart failure --- non-ischemic cardiomyopathy --- genetics --- desmin --- mitochondrial dysfunction --- myopathy --- whole exome sequencing --- laminopathy --- LMNA --- biomarkers --- troponin T --- NT-proBNP --- malignant ventricular arrhythmia --- arrhythmic risk stratification --- DNA methylation --- alternative splicing --- epigenetics --- nonischemic dilated cardiomyopathy --- cardiac magnetic resonance imaging --- late gadolinium enhancement --- long axis strain --- left ventricle sphericity index --- major adverse cardiovascular events --- sex differences --- left ventricular reverse remodelling --- long-term outcomes --- left ventricle non-compaction cardiomyopathy --- cardiac magnetic resonance --- titin --- RNA binding motif protein 20 (RBM20) --- sarcomere --- diastolic dysfunction --- phosphorylation --- non-sense mRNA decay --- mammalian target of rapamycin (mTOR) complex-1 --- duchenne muscular distrophy