The Complex and Diverse Genetic Architecture of Dilated Cardiomyopathy

Hershberger, Ray E.; Cowan, Jason; Kinnamon, Daniel D.

doi:10.1161/circresaha.121.318157

Cited by 61 publications

(78 citation statements)

References 123 publications

(278 reference statements)

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“…Hereditary cardiomyopathies are major causes of heart failure and sudden cardiac death [ 1 , 3 ] . Hereditary dilated cardiomyopathy (DCM) comprises a genetically heterogeneous group of disorders characterized by cardiac dilatation and systolic dysfunction [ 4 ] . Mutations in the LMNA gene, encoding nuclear envelope protein Lamin A/C (LMNA), are important causes of hereditary DCM [ 4 - 7 ] .…”

Section: Introductionmentioning

confidence: 99%

Deletion of the Lmna gene in fibroblasts causes senescence-associated dilated cardiomyopathy by activating the double-stranded DNA damage response and induction of senescence-associated secretory phenotype

Rouhi¹,

Auguste²,

Zhou³

et al. 2022

J Cardiovasc Aging

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Introduction: Mutations in the LMNA gene, encoding Lamin A/C (LMNA), are established causes of dilated cardiomyopathy (DCM). The phenotype is typically characterized by progressive cardiac conduction defects, arrhythmias, heart failure, and premature death. DCM is primarily considered a disease of cardiac myocytes. However, LMNA is also expressed in other cardiac cell types, including fibroblasts. Aim: The purpose of the study was to determine the contribution of the fibroblasts to DCM caused by LMNA deficiency. Methods and Results: The Lmna gene was deleted by crossing the platelet-derived growth factor receptor α-Cre recombinase (Pdgfra-Cre) and floxed Lmna (LmnaF/F) mice. The LMNA protein was nearly absent in ~80% of the cardiac fibroblasts and ~25% of cardiac myocytes in the Pdgfra-Cre:LmnaF/F mice. The Pdgfra-Cre:LmnaF/F mice showed an early phenotype characterized by cardiac conduction defects, arrhythmias, cardiac dysfunction, myocardial fibrosis, apoptosis, and premature death within the first six weeks of life. The Pdgfra-Cre:LmnaWild type/F(LmnaW/F) mice also showed a similar but slowly evolving phenotype that was expressed within one year of age. RNA sequencing of LMNA-deficient and wild-type cardiac fibroblasts identified differential expression of ~410 genes, which predicted activation of the TP53 and TNFA/NFκB and suppression of the cell cycle pathways. In agreement with these findings, levels of phospho-H2AFX, ATM, phospho-TP53, and CDKN1A, markers of the DNA damage response (DDR) pathway, were increased in the Pdgfra-Cre:LmnaF/F mouse hearts. Moreover, expression of senescence-associated beta-galactosidase was induced and levels of the senescence-associated secretory phenotype (SASP) proteins TGFβ1, CTGF (CCN2), and LGLAS3 were increased as well as the transcript levels of additional genes encoding SASP proteins in the Pdgfra-Cre:LmnaF/F mouse hearts. Finally, expression of pH2AFX, a bonafide marker of the double-stranded DNA breaks, was increased in cardiac fibroblasts isolated from the Pdgfra-Cre:LmnaF/F mouse hearts. Conclusion: Deletion of the Lmna gene in fibroblasts partially recapitulates the phenotype of the LMNA-associated DCM, likely through induction of double-stranded DNA breaks, activation of the DDR pathway, and induction of expression of the SASP proteins. The findings indicate that the phenotype in the LMNA-associated DCM is the aggregate consequence of the LMNA deficiency in multiple cardiac cells, including cardiac fibroblasts.

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Section: Introductionmentioning

confidence: 99%

Deletion of the Lmna gene in fibroblasts causes senescence-associated dilated cardiomyopathy by activating the double-stranded DNA damage response and induction of senescence-associated secretory phenotype

Rouhi¹,

Auguste²,

Zhou³

et al. 2022

J Cardiovasc Aging

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“…However, data also suggest polygenic contributions with SNPs. (11) Limited data also suggest that PuPV might be more frequent in CMP-associated genes than the disease prevalence itself, highlighting the critical role of knowledge to interpret incidental findings and further underscoring the role of phenotype modulators. (31) The combination of genetic effect modifiers and environmental factors may explain why some individuals can show markedly more severe phenotype than individuals in the same family carrying the same PuPV, as well as differences in disease severity compared to unrelated individuals.…”

Section: Discussionmentioning

confidence: 99%

“…(10) However, data regarding whether CMP genotype can predict mortality, diagnosis of CMP later in life, or CMP-related outcomes are limited in the general population setting. (11) Thus, we leveraged the UK Biobank (UKBB) using a ‘genotype-first’ approach to test the hypotheses that individuals with PuPV in genes implicated in CMPs have increased mortality, higher risk of being diagnosed with cardiomyopathy and clinically relevant, CMP-related outcomes compared to genotype-negative controls.…”

Section: Introductionmentioning

confidence: 99%

“…Genetic modifiers include biallelic compound heterozygotes, recessive PuPV carriers, as well as digenic inheritance. However, data also suggest polygenic contributions with SNPs (11). Limited data also suggest that PuPV might be more frequent in CMPassociated genes than the disease prevalence itself, highlighting the critical role of knowledge to interpret incidental findings and further underscoring the role of phenotype modulators (31).…”

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confidence: 99%

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Screening for Pathogenic Variants in Cardiomyopathy Genes Predicts Mortality and Composite Outcomes in UK Biobank

Asatryan

Shah

Dabbagh

et al. 2022

Preprint

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Background: Inherited cardiomyopathies can present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with putative pathogenic variants (PuPV) in cardiomyopathy-associated genes in the general population. Objective: We aimed to determine the risk of mortality and cardiomyopathy-related outcomes associated with PuPV in cardiomyopathy-associated genes in UK Biobank. Methods: Using whole exome sequencing data, variants in dilated, hypertrophic and arrhythmogenic cardiomyopathy-associated genes with at least limited evidence of disease causality according to ClinGen Expert Panel curations, were annotated using REVEL (≥0.65) and ANNOVAR (predicted loss of function) to identify PuPVs. Individuals with PuPV comprised the genotype-positive (G+) and those without PuPV the genotype-negative (G-) cohorts. Group comparisons were made using time-to-event analyses for the primary (all-cause mortality) and secondary outcomes (diagnosis of cardiomyopathy; composite outcome of diagnosis of cardiomyopathy, heart failure, arrhythmia, stroke, and death). Results: Among 200,619 participants, 22,401 (11.2%) were found to host ≥1 PuPV in cardiomyopathy-associated genes (G+). After adjusting for age and sex, G+ individuals had increased all-cause mortality [HR 1.07 (95%CI 1.02-1.13; p=0.011)] and increased rates of diagnosis of cardiomyopathy later in life [HR 2.37 (95%CI 1.98-2.85; p<0.0001)], which further increased in those with PuPV in definitive/strong evidence ClinGen genes [3.25 (95%CI 2.63-4.00; p<0.0001)]. G+ individuals had a higher risk of developing the composite outcome [HR 1.11 (95%CI 1.06-1.15; p<0.0001)]. Conclusions: Adults with PuPV in cardiomyopathy-associated genes have higher all-cause mortality and increased risk of developing cardiomyopathy-associated features and complications, compared to genotype-negative controls.

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“…Recently, Jordan et al [ 101 ] evaluated the potential of a large gene panel for DCM prediction and summarized 12 definitive (strongly associated, included in Table 2 and shown in Figure 2 ) genes to be exclusively associated with the DCM pathophysiology, not hypertrophic cardiomyopathy (HCM) or any other cardiomyopathy. The panel of these 12 genes should be evaluated across different populations to be implemented as a standard genetic test to screen for DCM patients [ 13 , 34 ].…”

Section: Diagnosis Of Dcmmentioning

confidence: 99%

A Comprehensive Outlook on Dilated Cardiomyopathy (DCM): State-Of-The-Art Developments with Special Emphasis on OMICS-Based Approaches

Sarohi

Srivastava

2022

JCDD

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Dilated cardiomyopathy (DCM) remains an enigmatic cardiovascular disease (CVD) condition characterized by contractile dysfunction of the myocardium due to dilation of the ventricles. DCM is one of the major forms of CVD contributing to heart failure. Dilation of the left or both ventricles with systolic dysfunction, not explained by known causes, is a hallmark of DCM. Progression of DCM leads to heart failure. Genetic and various other factors greatly contribute to the development of DCM, but the etiology has still remained elusive in a large number of cases. A significant number of studies have been carried out to identify the genetic causes of DCM. These candidate-gene studies revealed that mutations in the genes of the fibrous, cytoskeletal, and sarcomeric proteins of cardiomyocytes result in the development of DCM. However, a significant proportion of DCM patients are idiopathic in nature. In this review, we holistically described the symptoms, causes (in adults and newborns), genetic basis, and mechanistic progression of DCM. Further, we also summarized the state-of-the-art diagnosis, available biomarkers, treatments, and ongoing clinical trials of potential drug regimens. DCM-mediated heart failure is on the rise worldwide including in India. The discovery of biomarkers with a better prognostic value is the need of the hour for better management of DCM-mediated heart failure patients. With the advent of next-generation omics-based technologies, it is now possible to probe systems-level alterations in DCM patients pertaining to the identification of novel proteomic and lipidomic biomarkers. Here, we also highlight the onset of a systems-level study in Indian DCM patients by applying state-of-the-art mass-spectrometry-based “clinical proteomics” and “clinical lipidomics”.

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The Complex and Diverse Genetic Architecture of Dilated Cardiomyopathy

Cited by 61 publications

References 123 publications

Deletion of the Lmna gene in fibroblasts causes senescence-associated dilated cardiomyopathy by activating the double-stranded DNA damage response and induction of senescence-associated secretory phenotype

Deletion of the Lmna gene in fibroblasts causes senescence-associated dilated cardiomyopathy by activating the double-stranded DNA damage response and induction of senescence-associated secretory phenotype

Screening for Pathogenic Variants in Cardiomyopathy Genes Predicts Mortality and Composite Outcomes in UK Biobank

A Comprehensive Outlook on Dilated Cardiomyopathy (DCM): State-Of-The-Art Developments with Special Emphasis on OMICS-Based Approaches

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