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Background: Laminopathies are caused by rare alterations in LMNA, leading to a wide clinical spectrum. Though muscular dystrophy begins at early ages, disease progression is different in each patient. We investigated variability in laminopathy phenotypes by performing a targeted genetic analysis of patients diagnosed with LMNA-related muscular dystrophy to identify rare variants in alternative genes, thereby explaining phenotypic differences.Methods: We analyzed 105 genes associated with muscular diseases by targeted sequencing in 26 pediatric patients of different countries, diagnosed with any LMNA-related muscular dystrophy. Family members were also clinically assessed and genetically analyzed.Results: All patients carried a pathogenic rare variant in LMNA. Clinical diagnoses included Emery-Dreifuss muscular dystrophy (EDMD, 13 patients), LMNA-related congenital muscular dystrophy (L-CMD, 11 patients), and limb-girdle muscular dystrophy 1B (LGMD1B, 2 patients). In 9 patients, 10 additional rare genetic variants were identified in 8 genes other than LMNA. Genotype-phenotype correlation showed additional deleterious rare variants in five of the nine patients (3 L-CMD and 2 EDMD) with severe phenotypes.Conclusion: Analysis f known genes related to muscular diseases in close correlation with personalized clinical assessments may help identify additional rare variants of LMNA potentially associated with early onset or most severe disease progression.

Atrial fibrillation is the most common sustained arrhythmia and remains as one of main challenges in current clinical practice. The disease may be induced secondary to other diseases such as hypertension, valvular heart disease, and heart failure, conferring an increased risk of stroke and sudden death. Epidemiological studies have provided evidence that genetic factors play an important role and up to 30% of clinically diagnosed patients may have a family history of atrial fibrillation. To date, several rare variants have been identified in a wide range of genes associated with ionic channels, calcium handling protein, fibrosis, conduction and inflammation. Important advances in clinical, genetic and molecular basis have been performed over the last decade, improving diagnosis and treatment. However, the genetics of atrial fibrillation is complex and pathophysiological data remains still unraveling. A better understanding of the genetic basis will induce accurate risk stratification and personalized clinical treatment. In this review, we have focused on current genetics basis of atrial fibrillation.

Cardiomyopathies are a heterogeneous group of inherited cardiac diseases characterized by progressive myocardium abnormalities associated with mechanical and/or electrical dysfunction. Massive genetic sequencing technologies allow a comprehensive genetic analysis to unravel the cause of disease. However, most identified genetic variants remain of unknown clinical significance due to incomplete penetrance and variable expressivity. Therefore, genetic interpretation of variants and translation into clinical practice remain a current challenge. We performed retrospective comprehensive clinical assessment and genetic analysis in six families, four diagnosed with arrhythmogenic cardiomyopathy, and two diagnosed with hypertrophic cardiomyopathy (HCM). Genetic testing identified three rare variants (two non-sense and one small indel inducing a frameshift), each present in two families. Although each variant is currently classified as pathogenic and the cause of the diagnosed cardiomyopathy, the onset and/or clinical course differed in each patient. New genetic technology allows comprehensive yet cost-effective genetic analysis, although genetic interpretation, and clinical translation of identified variants should be carefully done in each family in a personalized manner.

Background: Laminopathies are caused by rare alterations in LMNA, leading to a wide clinical spectrum. Though muscular dystrophy begins at early ages, disease progression is different in each patient. We investigated variability in laminopathy phenotypes by performing a targeted genetic analysis of patients diagnosed with LMNA-related muscular dystrophy to identify rare variants in alternative genes, thereby explaining phenotypic differences. Methods: We analyzed 105 genes associated with muscular diseases by targeted sequencing in 26 pediatric patients of different countries, diagnosed with any LMNA-related muscular dystrophy. Family members were also clinically assessed and genetically analyzed. Results: All patients carried a pathogenic rare variant in LMNA. Clinical diagnoses included Emery-Dreifuss muscular dystrophy (EDMD, 13 patients), LMNA-related congenital muscular dystrophy (L-CMD, 11 patients), and limb-girdle muscular dystrophy 1B (LGMD1B, 2 patients). In 9 patients, 10 additional rare genetic variants were identified in 8 genes other than LMNA. Genotype-phenotype correlation showed additional deleterious rare variants in five of the nine patients (3 L-CMD and 2 EDMD) with severe phenotypes. Conclusion: Analysis f known genes related to muscular diseases in close correlation with personalized clinical assessments may help identify additional rare variants of LMNA potentially associated with early onset or most severe disease progression. [ABSTRACT FROM AUTHOR]

Brugada syndrome (BrS) is classified as an inherited cardiac channelopathy attributed to dysfunctional ion channels and/or associated proteins in cardiomyocytes rather than to structural heart alterations. However, hearts of some BrS patients exhibit slight histologic abnormalities, suggesting that BrS could be a phenotypic variant of arrhythmogenic cardiomyopathy. We performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) criteria. Our comprehensive analysis of structural findings did not reveal enough definitive evidence for reclassification of BrS as a cardiomyopathy. The collection and comprehensive analysis of new cases with a definitive BrS diagnosis are needed to clarify whether some of these structural features may have key roles in the pathophysiological pathways associated with malignant arrhythmogenic episodes. [ABSTRACT FROM AUTHOR]

Brugada syndrome (BrS) is an inherited arrhythmogenic disease associated with sudden cardiac death. The main gene is SCN5A. Additional variants in 42 other genes have been reported as deleterious, although these variants have not yet received comprehensive pathogenic analysis. Our aim was to clarify the role of all currently reported variants in minor genes associated with BrS. We performed a comprehensive analysis according to the American College of Medical Genetics and Genomics guidelines of published clinical and basic data on all genes (other than SCN5A) related to BrS. Our results identified 133 rare variants potentially associated with BrS. After applying current recommendations, only six variants (4.51%) show a conclusive pathogenic role. All definitively pathogenic variants were located in four genes encoding sodium channels or related proteins: SLMAP, SEMA3A, SCNN1A, and SCN2B. In total, 33.83% of variants in 19 additional genes were potentially pathogenic. Beyond SCN5A, we conclude definitive pathogenic variants associated with BrS in four minor genes. The current list of genes associated with BrS, therefore, should include SCN5A, SLMAP, SEMA3A, SCNN1A, and SCN2B. Comprehensive genetic interpretation and careful clinical translation should be done for all variants currently classified as potentially deleterious for BrS. [ABSTRACT FROM AUTHOR]

Cardiomyopathies are a heterogeneous group of inherited cardiac diseases characterized by progressive myocardium abnormalities associated with mechanical and/or electrical dysfunction. Massive genetic sequencing technologies allow a comprehensive genetic analysis to unravel the cause of disease. However, most identified genetic variants remain of unknown clinical significance due to incomplete penetrance and variable expressivity. Therefore, genetic interpretation of variants and translation into clinical practice remain a current challenge. We performed retrospective comprehensive clinical assessment and genetic analysis in six families, four diagnosed with arrhythmogenic cardiomyopathy, and two diagnosed with hypertrophic cardiomyopathy (HCM). Genetic testing identified three rare variants (two non-sense and one small indel inducing a frameshift), each present in two families. Although each variant is currently classified as pathogenic and the cause of the diagnosed cardiomyopathy, the onset and/or clinical course differed in each patient. New genetic technology allows comprehensive yet cost-effective genetic analysis, although genetic interpretation, and clinical translation of identified variants should be carefully done in each family in a personalized manner. [ABSTRACT FROM AUTHOR]

• Copy Number Variants cause arrhythmogenic diseases leading to sudden cardiac death. • Copy Number Variants explain up to 13% of arrhythmogenic cases. • Genetic interpretation of Copy Number Variants is the main current challenge. • Clinical translation of Copy Number Variants should be done with caution. Over the last ten years, analysis of copy number variants has increasingly been applied to the study of arrhythmogenic pathologies associated with sudden death, mainly due to significant advances in the field of massive genetic sequencing. Nevertheless, few published reports have focused on the prevalence of copy number variants associated with sudden cardiac death. As a result, the frequency of these genetic alterations in arrhythmogenic diseases as well as their genetic interpretation and clinical translation has not been established. This review summarizes the current available data concerning copy number variants in sudden cardiac death-related diseases. [ABSTRACT FROM AUTHOR]