Genetic basis of dilated cardiomyopathy

Pérez‐Serra, Alexandra; Toro, Rocío; Sarquella-Brugada, Geòrgia; Gonzalo-Calvo, David de; César, Sergi; Carro, Esther; Llorente‐Cortés, Vicenta; Iglesias, Anna; Brugada, Josép; Brugada, Ramón; Campuzano, Òscar

doi:10.1016/j.ijcard.2016.09.068

Cited by 70 publications

(58 citation statements)

References 180 publications

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“…In a recent published data, in which only truncated variants were considered, the estimated prevalence of FLNC was about 3.9% (n = 508 patients) in DCM, and 3% in arrhythmogenic cardiomyopathies (n = 219 patients) and 2.2% in RCM (1/45). These observations lead to consider FLNC gene as a gene especially prevalent in the DCM . In another publication dedicated to hypertrophic cardiomyopathy, the estimated prevalence on 92 patients was 7.6% and comprised one truncating variant and six missense variants .…”

Section: Discussionmentioning

confidence: 99%

FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype‐phenotype correlations

et al. 2019

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Pathogenic variants in FLNC encoding filamin C have been firstly reported to cause myopathies, and were recently linked to isolated cardiac phenotypes. Our aim was to estimate the prevalence of FLNC pathogenic variants in subtypes of cardiomyopathies and to study the relations between phenotype and genotype. DNAs from a cohort of 1150 unrelated index‐patients with isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non‐compactions) have been sequenced on a custom panel of 51 cardiomyopathy disease‐causing genes. An FLNC pathogenic variant was identified in 28 patients corresponding to a prevalence ranging from 1% to 8% depending on the cardiomyopathy subtype. Truncating variants were always identified in patients with dilated cardiomyopathy, while missense or in‐frame indel variants were found in other phenotypes. A personal or family history of sudden cardiac death (SCD) was significantly higher in patients with truncating variants than in patients carrying missense variants (P = .01). This work reported the first observation of a left ventricular non‐compaction associated with a unique probably causal variant in FLNC which highlights the role of FLNC in cardiomyopathies. A correlation between the nature of the variant and the cardiomyopathy subtype was observed as well as with SCD risk.

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Section: Discussionmentioning

confidence: 99%

FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype‐phenotype correlations

et al. 2019

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“…In fact, rare variants (both truncating and non-truncating) have also been described in sarcomeric genes, Z-disk genes, cytoskeletal genes, ion channels genes, nuclear envelope genes, desmosomal genes, transcription factors genes, gamma secretase activity genes, sarcoplasmic reticulum genes (Fig. 4; schematic of cardiomyocyte depicting genes associated with non-syndromic familial DCM, in their approximate subcellular context), and for other cardiac genes causally linked with DCM (Hershberger et al 2013; Pérez-Serra et al 2016). Z-disk gene variants exhibit remarkable cardiac phenotypic variability, which might also be the case for TTNtvZ variants.…”

Section: Animal Models Of Ttn Mutationsmentioning

confidence: 99%

“…High NGS utility has also led to the identification of a vast number of missense variants in DCM-linked genes, such as desmosomal, sarcomeric, cytoskeletal, nuclear envelope, and ion channels, as well as in genes with minor frequency linked to DCM (Pérez-Serra et al 2016). Similar to TTNtv, missense variants were also non-uniformly distributed over the length of TTN and were over-represented in A-band TTN (Begay et al 2015).…”

Section: Ttn Missense Variantsmentioning

confidence: 99%

Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy

et al. 2017

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Heart failure (HF) is a complex clinical syndrome defined by the inability of the heart to pump enough blood to meet the body’s metabolic demands. Major causes of HF are cardiomyopathies (diseases of the myocardium associated with mechanical and/or electrical dysfunction), among which the most common form is dilated cardiomyopathy (DCM). DCM is defined by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness, which leads to progressive HF. Over 60 genes are linked to the etiology of DCM. Titin (TTN) is the largest known protein in biology, spanning half the cardiac sarcomere and, as such, is a basic structural and functional unit of striated muscles. It is essential for heart development as well as mechanical and regulatory functions of the sarcomere. Next-generation sequencing (NGS) in clinical DCM cohorts implicated truncating variants in titin (TTNtv) as major disease alleles, accounting for more than 25% of familial DCM cases, but these variants have also been identified in 2–3% of the general population, where these TTNtv blur diagnostic and clinical utility. Taking into account the published TTNtv and their association to DCM, it becomes clear that TTNtv harm the heart with position-dependent occurrence, being more harmful when present in the A-band TTN, presumably with dominant negative/gain-of-function mechanisms. However, these insights are challenged by the depiction of position-independent toxicity of TTNtv acting via haploinsufficient alleles, which are sufficient to induce cardiac pathology upon stress. In the current review, we provide an overview of TTN and discuss studies investigating various TTN mutations. We also present an overview of different mechanisms postulated or experimentally validated in the pathogenicity of TTNtv. DCM-causing genes are also discussed with respect to non-truncating mutations in the etiology of DCM. One way of understanding pathogenic variants is probably to understand the context in which they may or may not affect protein–protein interactions, changes in cell signaling, and substrate specificity. In this regard, we also provide a brief overview of TTN interactions in situ. Quantitative models in the risk assessment of TTNtv are also discussed. In summary, we highlight the importance of gene–environment interactions in the etiology of DCM and further mechanistic studies used to delineate the pathways which could be targeted in the management of DCM.

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“…This is more common with cytoskeletal and z-disc mutations (Seidman and Seidman, 2001; Chang and Potter, 2005). Genome Wide Association Studies (GWAS) have helped identify many of the sarcomeric mutations associated with the phenotype of DCM (Kamisago et al, 2000; Li et al, 2001; Olson et al, 2001; Mogensen et al, 2004; Murphy et al, 2004; Lakdawala et al, 2010, 2012a; Branishte et al, 2013; Pérez-Serra et al, 2016). Despite the identification of sarcomeric mutations associated with DCM, it is still difficult to predict the exact functional consequences of the mutation at the cellular level based on its molecular structure and function.…”

Section: Introductionmentioning

confidence: 99%

Insights and Challenges of Multi-Scale Modeling of Sarcomere Mechanics in cTn and Tm DCM Mutants—Genotype to Cellular Phenotype

et al. 2017

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Dilated Cardiomyopathy (DCM) is a leading cause of sudden cardiac death characterized by impaired pump function and dilatation of cardiac ventricles. In this review we discuss various in silico approaches to elucidating the mechanisms of genetic mutations leading to DCM. The approaches covered in this review focus on bridging the spatial and temporal gaps that exist between molecular and cellular processes. Mutations in sarcomeric regulatory thin filament proteins such as the troponin complex (cTn) and Tropomyosin (Tm) have been associated with DCM. Despite the experimentally-observed myofilament measures of contractility in the case of these mutations, the mechanisms by which the underlying molecular changes and protein interactions scale up to organ failure by these mutations remains elusive. The review highlights multi-scale modeling approaches and their applicability to study the effects of sarcomeric gene mutations in-silico. We discuss some of the insights that can be gained from computational models of cardiac biomechanics when scaling from molecular states to cellular level.

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Genetic basis of dilated cardiomyopathy

Cited by 70 publications

References 180 publications

FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype‐phenotype correlations

FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype‐phenotype correlations

Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy

Insights and Challenges of Multi-Scale Modeling of Sarcomere Mechanics in cTn and Tm DCM Mutants—Genotype to Cellular Phenotype

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