State of the Art Review on Genetics and Precision Medicine in Arrhythmogenic Cardiomyopathy

Patel, Viraj; Asatryan, Babken; Siripanthong, Bhurint; Munroe, Patricia B.; Tiku-Owens, Anjali; Lopes, Luís Rocha; Khanji, Mohammed Y; Protonotarios, Alexandros; Muser, Daniele; Marchlinski, Francis E.; Brady, Peter A.; Chahal, C. Anwar A.

doi:10.3390/ijms21186615

Cited by 30 publications

(40 citation statements)

References 157 publications

(210 reference statements)

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“…It is crucial to clarify their clinical role whether definitive risk stratification can be based on genetics. Even if a conclusive pathogenic variation associated with ACM is identified, it does not indicate that the patient is going to be affected because of the variable expressivity and incomplete penetrance [4]. This represents an additional challenge to perform a genetic interpretation of rare variants.…”

Section: Genetic Basismentioning

confidence: 99%

“…All other rare variants remain with an ambiguous role and further data is needed to conclude if they play a decisive role in ACM. Table 1 shows information related to the genetic role and ventricular involvement of the ACM causal genes (plakophilin-2 -PKP2-, desmocollin-2 -DSC2-, desmoglein-2 -DSG2-, desmoplakin -DSP-, plakoglobin -JUP-, desmin -DES-, transforming growth factor beta-3 -TGFβ3-, transmembrane protein 43 -TMEM43-, lamin A/C -LMNA-, titin -TTN-, phospholamban -PLN-, αT-catenin -CTNNA3-, voltage-gated sodium channel -SCN5A-, Cadherin 2 -CDH2-, Filamin C -FLNC-, Ryanodine Receptor 2 -RYR2-, RNA-Binding Motif Protein 20 -RBM20-, Tight Junction Protein ZO-1 -TJP1-) [4,11]. Figure 1 presents the intracellular localization of proteins codified by ACM-associated genes and their prevalence in causing the disease.…”

Section: Genetic Basismentioning

confidence: 99%

“…This cell union provide structural resilience that allows heart tissue to resist mechanical stress. Moreover, it has been described that desmosomal proteins have a role in the regulation of transcription of genes involved in adipogenesis and apoptosis, and play a major role in myocardial electrical conduction through regulation of gap junctions and calcium homeostasis [4]. Deleterious alterations are mainly located in genes encoding desmosomal proteins that are responsible for around 60% of all ACM cases [4,17].…”

Section: Desmosomal Genesmentioning

confidence: 99%

“…Moreover, it has been described that desmosomal proteins have a role in the regulation of transcription of genes involved in adipogenesis and apoptosis, and play a major role in myocardial electrical conduction through regulation of gap junctions and calcium homeostasis [4]. Deleterious alterations are mainly located in genes encoding desmosomal proteins that are responsible for around 60% of all ACM cases [4,17]. Concretely, the main gene associated with ACM is PKP2, being responsible for approximately 35-40% of cases [35,38,39].…”

Section: Desmosomal Genesmentioning

confidence: 99%

“…Arrhythmogenic cardiomyopathy (ACM), (Online Mendelian Inheritance in Man -OMIM-107970) is a rare (prevalence 1:2500-5000) inheritable structural heart disease first described by Fontaine et al in 1978 [1]. ACM is characterized by progressive replacement of myocardium by fibro-fatty infiltrates, predominantly of the right ventricle (RV) [2], but biventricular forms have also been reported in nearly 50% of cases [3,4]. Moreover, isolated forms affecting only the left ventricle have been reported in 15% of cases [5,6].…”

Section: Introductionmentioning

confidence: 99%

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Update on Genes Associated with Arrhythmogenic Cardiomyopathy

Vallverdú-Prats¹,

Alcalde²,

Sarquella‐Brugada³

et al. 2021

Cardiomyopathy - Disease of the Heart Muscle

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Arrhythmogenic cardiomyopathy is a rare genetic entity characterized by progressive fibro-fatty replacement of myocardium leading to malignant arrhythmias, syncope, and sudden cardiac death. Mostly it affects the right ventricle, but cases have also been described with biventricular and even isolated left ventricular involvement. The disease affects mainly young males and arrhythmias are usually induced by exercise. Arrhythmogenic cardiomyopathy has a genetic origin and is basically caused by deleterious alterations in genes encoding desmosomal proteins, especially plakophilin-2. To date, more than 400 rare genetic alterations have been identified in 18 genes, mainly with autosomal dominant inheritance, but some recessive forms have also been reported (Naxos disease and Carvajal syndrome). A comprehensive genetic analysis identifies a rare variant as potential cause of the disease in around 60% of patients, suggesting the existence of unknown genes as well as other genome alterations not yet discovered. Genetic interpretation classifies some of these rare variants as ambiguous, playing an uncertain role in arrhythmogenic cardiomyopathy. This makes a proper translation of genetic data into clinical practice difficult. Moreover, incomplete penetrance and variable phenotypic expression makes it difficult to arrive at the correct diagnosis. In the present chapter, we focus on recent advances in the knowledge regarding the genetic basis of arrhythmogenic cardiomyopathy.

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Section: Genetic Basismentioning

confidence: 99%

Section: Genetic Basismentioning

confidence: 99%

Section: Desmosomal Genesmentioning

confidence: 99%

Section: Desmosomal Genesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Update on Genes Associated with Arrhythmogenic Cardiomyopathy

Vallverdú-Prats¹,

Alcalde²,

Sarquella‐Brugada³

et al. 2021

Cardiomyopathy - Disease of the Heart Muscle

View full text Add to dashboard Cite

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Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form‐associated genes provides new insights for molecular diagnosis and clinical management

et al. 2022

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Arrhythmogenic cardiomyopathy with right dominant form (ACR) is a rare heritable cardiac cardiomyopathy disorder associated with sudden cardiac death. Pathogenic variants (PVs) in desmosomal genes have been causally related to ACR in 40% of cases. Other genes encoding nondesmosomal proteins have been described in ACR, but their contribution in this pathology is still debated. A panel of 71 genes associated with inherited cardiopathies was screened in an ACR population of 172 probands and 856 individuals from the general population. PVs and uncertain significance variants (VUS) have been identified in 36% and 18.6% of patients, respectively. Among the cardiopathy‐associated genes, burden tests show a significant enrichment in PV and VUS only for desmosomal genes PKP2 (plakophilin‐2), DSP (desmoplakin), DSC2 (desmocollin‐2), and DSG2 (desmoglein‐2). Importantly, VUS may account for 15% of ACR cases and should then be considered for molecular diagnosis. Among the other genes, no evidence of enrichment was detected, suggesting an extreme caution in the interpretation of these genetic variations without associated functional or segregation data. Genotype–phenotype correlation points to (1) a more severe and earlier onset of the disease in PV and VUS carriers, underlying the importance to carry out presymptomatic diagnosis in relatives and (2) to a more prevalent left ventricular dysfunction in DSP variant carriers.

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