Identification of a PKP2 gene deletion in a family with arrhythmogenic right ventricular cardiomyopathy

Mura, Ilena Egle Astrid Li; Bauce, Barbara; Nava, Andrea; Fanciulli, Manuela; Vazza, Giovanni; Mazzotti, Elisa; Rigato, Ilaria; Bortoli, Marzia De; Beffagna, Giorgia; Lorenzon, Alessandra; Calore, Martina; Dazzo, Emanuela; Nobile, Carlo; Mostacciuolo, Maria Luisa; Corrado, Domenico; Basso, Cristina; Daliento, Luciano; Thiene, Gaetano; Rampazzo, Alessandra

doi:10.1038/ejhg.2013.39

Cited by 40 publications

(28 citation statements)

References 41 publications

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“…Recent studies have shown that stop-coding in diseasecausing genes are more pathogenic than missense mutations, since the former are causing alteration of protein length and conformation, leading to haploinsufficiency due to protein instability [67][68][69][70]. Entire PKP2 exons or even whole gene deletions have been recently described in AC families with a frequency of approximately 2 % [71][72][73]. These data are further stressing the question whether haploinsufficiency is enough to determine the disease phenotype.…”

Section: Ac Genes/mutations and Diagnostic Implicationsmentioning

confidence: 73%

Arrhythmogenic Cardiomyopathy

Corrado

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Judge

2017

Circulation Research

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Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias and pathologically by an acquired and progressive dystrophy of the ventricular myocardium with fibro-fatty replacement. Due to an estimated prevalence of 1:2000-1:5000, AC is listed among rare diseases. A familial background consistent with an autosomal-dominant trait of inheritance is present in most of AC patients; recessive variants have also been reported, either or not associated with palmoplantar keratoderma and woolly hair. AC-causing genes mostly encode major components of the cardiac desmosome and up to 50 % of AC probands harbor mutations in one of them. Mutations in non-desmosomal genes have been also described in a minority of AC patients, predisposing to the same or an overlapping disease phenotype. Compound/ digenic heterozygosity was identified in up to 25 % of AC-causing desmosomal gene mutation carriers, in part explaining the phenotypic variability. Abnormal trafficking of intercellular proteins to the intercalated discs of cardiomyocytes and Wnt/beta catenin and Hippo signaling pathways have been implicated in disease pathogenesis. AC is a major cause of sudden death in the young and in athletes. The clinical picture may include a sub-clinical phase; an overt electrical disorder; and right ventricular or biventricular pump failure. Ventricular fibrillation can occur at any stage. Genotype-phenotype correlation studies led to identify biventricular and dominant left ventricular variants, thus supporting the use of the broader term AC. Since there is no "gold standard" to reach the diagnosis of AC, multiple categories of diagnostic information have been combined and the criteria recently updated, to improve diagnostic sensitivity while maintaining specificity. Among diagnostic tools, contrast enhanced cardiac magnetic resonance is playing a major role in detecting left dominant forms of AC, even preceding morpho-functional abnormalities. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, sarcoidosis, dilated cardiomyopathy, right ventricular infarction, congenital heart diseases with right ventricular overload and athlete heart. A positive genetic test in the affected AC proband allows early identification of asymptomatic carriers by cascade genetic screening of family members. Risk stratification remains a major clinical challenge and antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator are the currently available therapeutic tools. Sport disqualification is life-saving, since effort is a major trigger not only of electrical instability but also of disease onset and progression. We review the current knowledge of this rare cardiomyopathy, suggesting a flowchart for primary care clinicians and geneticists.Arrhythmogenic Cardiomyopathy-key points summary

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Section: Ac Genes/mutations and Diagnostic Implicationsmentioning

confidence: 73%

Arrhythmogenic Cardiomyopathy

Corrado

Basso

Judge

2017

Circulation Research

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349

363

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“…Hence, the first study was published in 2011 [48], which identified three PKP2 exon deletions among 149 individuals affected by ARVC. After that, in the last 3 years [58], Mura et al [59] reported cases of CNV in this pathology. Consequently, we strongly recommend that genetic testing in ARVC includes CNV screening when conventional sequencing analysis does not identify any pathogenic genetic variants in ARVC associated genes.…”

Section: Plakophilin-2mentioning

confidence: 96%

“…Genetic series have reported that 30-40 % carry a pathogenic genetic variant in the PKP2 gene, followed by DSP (10-15 %) [55], DSG2 (3-8 %) [56], and DSC2 (1-5 %) [57]. Recently, other genetic alterations such as copy number variations (CNV) in PKP2 gene have been associated with the disease but they are very rare [58,59]. Therefore, after a comprehensive genetic analysis, nearly 40 % of clinically diagnosed cases remain without identified genetic cause.…”

Section: Desmosomal Genesmentioning

confidence: 97%

Clinical interpretation of genetic variants in arrhythmogenic right ventricular cardiomyopathy

et al. 2014

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Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiac entity characterized by right ventricular, or biventricular, fibrofatty replacement of myocardium. Structural alterations may lead to sudden cardiac death, mainly in young males during exercise. Autosomal dominant pattern of inheritance is reported in most parts of pathogenic genetic variations identified. Currently, 13 genes have been associated with the disease but nearly 40 % of clinically diagnosed cases remain without a genetic diagnosis. New genetic technologies allow further genetic analysis, generating a significant amount of genetic data in novel genes, which is often classified as of ambiguous significance. We focus on genetic advances of arrhythmogenic right ventricular cardiomyopathy, helping clinicians to interpret and translate genetic data into clinical practice.

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“…2013; Li Mura et al. 2013), but the overall prevalence of CNVs in cardiomyopathy‐associated genes remains incompletely characterized.…”

Section: Introductionmentioning

confidence: 99%

Next generation sequencing‐based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies

Ceyhan‐Birsoy

Pugh

Bowser

et al. 2015

Molec Gen & Gen Med

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BackgroundDiagnostic testing for genetic cardiomyopathies has undergone dramatic changes in the last decade with next generation sequencing (NGS) expanding the number of genes that can be interrogated simultaneously. Exon resolution copy number analysis is increasingly incorporated into routine diagnostic testing via cytogenomic arrays and more recently via NGS. While NGS is an attractive option for laboratories that have no access to array platforms, its higher false positive rate requires weighing the added cost incurred by orthogonal confirmation against the magnitude of the increase in diagnostic yield. Although copy number variants (CNVs) have been reported in various cardiomyopathy genes, their contribution has not been systematically studied.MethodsWe performed single exon resolution NGS‐based deletion/duplication analysis for up to 46 cardiomyopathy genes in >1400 individuals with cardiomyopathies including HCM, DCM, ARVC, RCM, and LVNC.Results and ConclusionClinically significant deletions and duplications were identified in only 9 of 1425 (0.63%) individuals. The majority of those (6/9) represented intragenic events. We conclude that the added benefit of exon level deletion/duplication analysis is low for currently known cardiomyopathy genes and may not outweigh the increased cost and complexity of incorporating it into routine diagnostic testing for these disorders.

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Identification of a PKP2 gene deletion in a family with arrhythmogenic right ventricular cardiomyopathy

Cited by 40 publications

References 41 publications

Arrhythmogenic Cardiomyopathy

Arrhythmogenic Cardiomyopathy

Clinical interpretation of genetic variants in arrhythmogenic right ventricular cardiomyopathy

Next generation sequencing‐based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies

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