Abstract Objectives The primary objective of this study is risk stratification of patients with arrhythmic right ventricular cardiomyopathy (ARVC). Background There is a need to identify those who ...need an automatic implantable cardioverter-defibrillator (ICD) to prevent sudden death. Methods This is an analysis of 88 patients with ARVC from 3 centers and who were not treated with an ICD. Results Risk factors for subsequent arrhythmic deaths were pre-enrollment sustained or nonsustained ventricular tachycardia and decreased left ventricular function. Conclusions These factors serve as proposed guidelines for implantation of an ICD in patients with ARVC to prevent sudden death.
Genetic testing identified a missense mutation in the protein kinase, AMP-activated, noncatalytic, gamma-2 (PRKAG2) gene leading to an Arg302Glu substitution.
The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving ...diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)
. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown
. The age-related acquisition of somatic mutations that ...lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer
and coronary heart disease
-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)
. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
The term dilated cardiomyopathy (DCM) defines a heterogeneous group of cardiac disorders, which are characterized by left ventricular or biventricular dilatation and systolic dysfunction in the ...absence of abnormal loading conditions or coronary artery disease sufficient to cause global systolic impairment. In approximately one third of cases, DCM is familial with a genetic pathogenesis and various patterns of inheritance. Although the electrocardiogram (ECG) has been considered traditionally non‐specific in DCM, the recently acquired knowledge of the genotype–phenotype correlations provides novel opportunities to identify patterns and abnormalities that may point toward specific DCM subtypes. A learned ECG interpretation in combination with an appropriate use of other ECG‐based techniques including ambulatory ECG monitoring, exercise tolerance test and imaging modalities, such as echocardiography and cardiovascular magnetic resonance, may allow the early identification of specific genetic or acquired forms of DCM. Furthermore, ECG abnormalities may reflect the severity of the disease and provide a useful tool in risk stratification and management. In the present review, we discuss the current role of the ECG in the diagnosis and management of DCM. We describe various clinical settings where the appropriate use and interpretation of the ECG can provide invaluable clues, contributing to the important role of this basic tool as cardiovascular medicine evolves.
Mutations in the LMNA gene, encoding LMNA (lamin A/C), are responsible for laminopathies. Dilated cardiomyopathy (DCM) is a major cause of mortality and morbidity in laminopathies.
To gain insights ...into the molecular pathogenesis of DCM in laminopathies.
We generated a tet-off bigenic mice expressing either a WT (wild type) or a mutant LMNA (D300N) protein in cardiac myocytes. LMNA
mutation is associated with DCM in progeroid syndromes. Expression of LMNA
led to severe myocardial fibrosis, apoptosis, cardiac dysfunction, and premature death. Administration of doxycycline suppressed LMNA
expression and prevented the phenotype. Whole-heart RNA sequencing in 2-week-old WT and LMNA
mice led to identification of ≈6000 differentially expressed genes. Gene Set Enrichment and Hallmark Pathway analyses predicted activation of E2F (E2F transcription factor), DNA damage response, TP53 (tumor protein 53), NFκB (nuclear factor κB), and TGFβ (transforming growth factor-β) pathways, which were validated by Western blotting, quantitative polymerase chain reaction of selected targets, and immunofluorescence staining. Differentially expressed genes involved cell death, cell cycle regulation, inflammation, and epithelial-mesenchymal differentiation. RNA sequencing of human hearts with DCM associated with defined LMNA pathogenic variants corroborated activation of the DNA damage response/TP53 pathway in the heart. Increased expression of CDKN2A (cyclin-dependent kinase inhibitor 2A)-a downstream target of E2F pathway and an activator of TP53-provided a plausible mechanism for activation of the TP53 pathway. To determine pathogenic role of TP53 pathway in DCM, Tp53 gene was conditionally deleted in cardiac myocytes in mice expressing the LMNA
protein. Deletion of Tp53 partially rescued myocardial fibrosis, apoptosis, proliferation of nonmyocyte cells, left ventricular dilatation and dysfunction, and slightly improved survival.
Cardiac myocyte-specific expression of LMNA
, associated with DCM, led to pathogenic activation of the E2F/DNA damage response/TP53 pathway in the heart and induction of myocardial fibrosis, apoptosis, cardiac dysfunction, and premature death. The findings denote the E2F/DNA damage response/TP53 axis as a responsible mechanism for DCM in laminopathies and as a potential intervention target.
Genetics of dilated cardiomyopathy Chen, Suet Nee; Mestroni, Luisa; Taylor, Matthew R G
Current opinion in cardiology,
05/2021, Letnik:
36, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Dilated cardiomyopathy (DCM), which include genetic and nongenetic forms, is the most common form of cardiomyopathy. DCM is characterized by left ventricular or biventricular dilation with impaired ...contraction. In the United States, DCM is a burden to healthcare that accounts for approximately 10,000 deaths and 46,000 hospitalizations annually. In this review, we will focus on the genetic forms of DCM and on recent advances in the understanding of cytoskeletal, sarcomeric, desmosomal, nuclear membrane, and RNA binding genes that contribute to the complexity and genetic heterogeneity of DCM.
Although mutations in TTN remain the most common identifiable cause of genetic DCM, there is a growing appreciation for arrhythmogenic-prone DCM due to mutations in LMNA, desmosomal genes, and the recently described FLNC gene encoding the structural filamin C protein. Mutations in RBM20 highlight the relevance of RNA splicing regulation in the pathogenesis of DCM. Although expanded genetic testing has improved access to genetic diagnostic studies for many patients, the molecular mechanisms in the pathogenesis of the disease remained largely unknown.
: The identification of the molecular causes and subsequent insight into the molecular mechanisms of DCM is expanding our understanding of DCM pathogenesis and highlights the complexity of DCM and the need to develop multifaceted strategies to treat the various causes of DCM.
Lamin A/C Gene and the Heart Mestroni, Luisa, MD, FACC, FESC; Taylor, Matthew R.G., MD, PhD
Journal of the American College of Cardiology,
10/2008, Letnik:
52, Številka:
15
Journal Article
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