Atlas of the clinical genetics of human dilated cardiomyopathy

Haas, Jan; Frese, Karen; Peil, Barbara; Kloos, Wanda; Keller, Andreas; Nietsch, Rouven; Zhu, Feng; Müller, Sabine; Kayvanpour, Elham; Vogel, Britta; Sedaghat‐Hamedani, Farbod; Lim, Wei Keat; Zhao, Xiaohong; Fradkin, Dmitriy; Köhler, Doreen; Fischer, Simon; Franke, Jennifer; Marquart, Sabine; Barb, Ioana; Li, Daniel Tian; Amr, Ali; Ehlermann, Philipp; Mereles, Derliz; Weis, Tanja; Hassel, Sarah; Kremer, Andreas; King, Vanessa M.; Wirsz, Emil; Isnard, Richard; Komajda, Michel; Serio, Alessandra; Grasso, Maurizia; Syrris, Petros; Wicks, Eleanor; Plagnol, Vincent; Lopes, Luís Rocha; Gadgaard, Tenna; Eiskjær, Hans; Jørgensen, Mads Emil; García-Giustiniani, Diego; Ortíz-Genga, Martín; Crespo-Leiro, María G.; Deprez, Rondal H Lekanne Dit; Christiaans, Imke; Rijsingen, Ingrid A van; Wilde, A.; Waldenström, Anders; Bolognesi, Martino; Bellazzi, Riccardo; Mörner, Stellan; Bermejo, Justo Lorenzo; Monserrat, Lorenzo; Villard, Eric; Mogensen, Jens; Pinto, Yigal M.; Charron, Philippe; Elliott, Perry; Arbustini, Eloisa; Katus, Hugo A.; Meder, Benjamin

doi:10.1093/eurheartj/ehu301

Cited by 482 publications

(436 citation statements)

References 25 publications

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“…In DCM, a family history of SCD/SVT/VF is associated with an increased risk of life‐threatening arrhythmias, a concept well established in other forms of arrhythmogenic cardiomyopathies such as ARVC33, 34 and hypertrophic cardiomyopathy 32, 35. Even though none of our AR‐DCM patients fulfilled new task force criteria of ARVC24 with LV involvement, the potential overlap with desmosomal diseases (ARVC, arrhythmogenic cardiomyopathy, left‐dominant arrhythmogenic cardiomyopathy), considered to be distinct disorders,10 warrants further investigations 36…”

Section: Discussionmentioning

confidence: 86%

Arrhythmogenic Phenotype in Dilated Cardiomyopathy: Natural History and Predictors of Life‐Threatening Arrhythmias

Spezzacatene

Sinagra

Merlo

et al. 2015

JAHA

111

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BackgroundPatients with dilated cardiomyopathy (DCM) may present with ventricular arrhythmias early in the disease course, unrelated to the severity of left ventricular dysfunction. These patients may be classified as having an arrhythmogenic DCM (AR‐DCM). We investigated the phenotype and natural history of patients with AR‐DCM.Methods and ResultsTwo hundred eighty‐five patients with a recent diagnosis of DCM (median duration of the disease 1 month, range 0 to 7 months) and who had Holter monitoring at baseline were comprehensively evaluated and followed for 107 months (range 29 to 170 months). AR‐DCM was defined by the presence of ≥1 of the following: unexplained syncope, rapid nonsustained ventricular tachycardia (≥5 beats, ≥150 bpm), ≥1000 premature ventricular contractions/24 hours, and ≥50 ventricular couplets/24 hours, in the absence of overt heart failure. The primary end points were sudden cardiac death (SCD), sustained ventricular tachycardia (SVT), or ventricular fibrillation (VF). The secondary end points were death from congestive heart failure or heart transplantation. Of the 285 patients, 109 (38.2%) met criteria for AR‐DCM phenotype. AR‐DCM subjects had a higher incidence of SCD/SVT/VF compared with non–AR‐DCM patients (30.3% vs 17.6%, P=0.022), with no difference in the secondary end points. A family history of SCD/SVT/VF and the AR‐DCM phenotype were statistically significant and cumulative predictors of SCD/SVT/VF.ConclusionsOne‐third of DCM patients may have an arrhythmogenic phenotype associated with increased risk of arrhythmias during follow‐up. A family history of ventricular arrhythmias in DCM predicts a poor prognosis and increased risk of SCD.

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Section: Discussionmentioning

confidence: 86%

Arrhythmogenic Phenotype in Dilated Cardiomyopathy: Natural History and Predictors of Life‐Threatening Arrhythmias

Spezzacatene

Sinagra

Merlo

et al. 2015

JAHA

111

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“…8,[10][11][12][13][14][15][16][17][18][19][20] Although we made a genetic analysis of several cardiac core transcriptional factor genes in the two mutation carriers with DCM, including GATA4, GATA5, GATA6, TBX5, TBX20, and HAND1, as described previously, [22][23][24][25][26][27][28][29][30][31] and found no mutations, we cannot rule out the possibility that the genetic variants in other genes may also contribute to DCM in these two patients. Genome sequencing analysis may help to explain the possibility for these patients.…”

Section: Discussionmentioning

confidence: 89%

“…8,9) At present, an increasing number of causative mutations in > 50 genes have been causally linked to idiopathic DCM. 8,[10][11][12][13][14][15][16][17][18][19][20] Among these well established DCM-associated genes, most encode contractile sarcomeric proteins as well as cytoskeletal/sarcolemmal and nuclear envelope proteins. 8) Nevertheless, these DCM-causing genes can explain only about one-third of patients and for most genes, the mutational frequency is low, with genetic mutation occurring in < 1% of DCM patients.…”

Section: Ilated Cardiomyopathy (Dcm) Which Is Defined Bymentioning

confidence: 99%

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

Guo

et al. 2017

Int. Heart J.

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SummaryDilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is a leading cause of congestive heart failure and the most common indication for heart transplantation. Recently, NKX2-5 mutations have been involved in the pathogenesis of familial DCM. However, the prevalence and spectrum of NKX2-5 mutations associated with sporadic DCM remain to be evaluated. In this study, the coding regions and flanking introns of the NKX2-5 gene, which encodes a cardiac transcription factor pivotal for cardiac development and structural remodeling, were sequenced in 210 unrelated patients with sporadic adult-onset DCM. A total of 300 unrelated healthy individuals used as controls were also genotyped for NKX2-5. The functional effect of the mutant NKX2-5 was investigated using a dual-luciferase reporter assay system. As a result, two novel heterozygous NKX2-5 mutations, p.R139W and p.E167X, were identified in 2 unrelated patients with sporadic adult-onset DCM, with a mutational prevalence of approximately 0.95%. The mutations were absent in 600 referential chromosomes and the altered amino acids were completely conserved evolutionarily across species. Functional assays revealed that the NKX2-5 mutants were associated with significantly reduced transcriptional activity. Furthermore, the mutations abrogated the synergistic activation between NKX2-5 and GATA4 as well as TBX20, two other cardiac key transcription factors that have been causally linked to adult-onset DCM. This study is the first to associate NKX2-5 loss-of-function mutations with enhanced susceptibility to sporadic DCM, which provides novel insight into the molecular etiology underpinning DCM, and suggests the potential implications for the genetic counseling and personalized treatment of the DCM patients. (Int Heart J 2017; 58: 521-529)

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“…The familial form (due to single‐gene mutations) of DCM has an estimated prevalence of approximately 1:2500, although this might be underestimated 18, 19. DCM is most often autosomal‐dominantly inherited, and it is genetically highly heterogeneous 20, 21. Genes associated with DCM primarily encode for structural proteins in the cardiomyocyte sarcomere, cytoskeleton, and nuclear envelope and also for membrane ion channels and desmosomes 22.…”

Section: Genetic Cardiomyopathies and Their Associated Genesmentioning

confidence: 99%

Genetic determinants of heart failure: facts and numbers

2018

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The relevance of gene mutations leading to heart diseases and hence heart failure has become evident. The risk for and the course of heart failure depends on genomic variants and mutations underlying the so‐called genetic predisposition. Genetic contribution to heart failure is highly heterogenous and complex. For any patient with a likely inherited heart failure syndrome, genetic counselling is recommended and important. In the last few years, novel sequencing technologies (named next‐generation sequencing – NGS) have dramatically improved the availability of molecular testing, the efficiency of genetic analyses, and moreover reduced the cost for genetic testing. Due to this development, genetic testing has become increasingly accessible and NGS‐based sequencing is now applied in clinical routine diagnostics. One of the most common reasons of heart failure are cardiomyopathies such as the dilated or the hypertrophic cardiomyopathy. Nearly 100 disease‐associated genes have been identified for cardiomyopathies. The knowledge of a pathogenic mutation can be used for genetic counselling, risk and prognosis determination, therapy guidance and hence for a more effective treatment. Besides, family cascade screening for a known familial, pathogenic mutation can lead to an early diagnosis in affected individuals. At that timepoint, a preventative intervention could be used to avoid or delay disease onset or delay disease progression. Understanding the cellular basis of genetic heart failure syndromes in more detail may provide new insights into the molecular biology of physiological and impaired cardiac (cell) function. As our understanding of the molecular and genetic pathophysiology of heart failure will increase, this might help to identify novel therapeutic targets and may lead to the development of new and specific treatment options in patients with heart failure.

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Atlas of the clinical genetics of human dilated cardiomyopathy

Cited by 482 publications

References 25 publications

Arrhythmogenic Phenotype in Dilated Cardiomyopathy: Natural History and Predictors of Life‐Threatening Arrhythmias

Arrhythmogenic Phenotype in Dilated Cardiomyopathy: Natural History and Predictors of Life‐Threatening Arrhythmias

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

Genetic determinants of heart failure: facts and numbers

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