Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice

Fressart, Véronique; Duthoit, Guillaume; Donal, Erwan; Probst, Vincent; Deharo, Jean‐Claude; Chevalier, Philippe; Klug, Didier; Dubourg, Olivier; Delacrétaz, Etienne; Cosnay, P; Scanu, P; Extramiana, Fabrice; Keller, Dagmar I.; Hidden‐Lucet, Françoise; Simon, Françoise; Bessirard, Vanessa; Roux-Buisson, Nathalie; Hébert, Jean-Louis; Azarine, Arshid; Casset-Senon, Daniele; Rouzet, François; Lecarpentier, Yves; Fontaine, G.; Coirault, Catherine; Frank, Robert; Hainque, Bernard; Charron, Philippe

doi:10.1093/europace/euq104

Cited by 213 publications

(184 citation statements)

References 35 publications

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“…Nevertheless, because carriership of multiple pathogenic mutations in more than one gene has been reported, 5,13,17,18 this mutation-negative family member may carry an yet unidentified ARVC-related mutation.…”

Section: Describe the Burden Of Alternative Diagnostic Methods To Thementioning

confidence: 99%

“…[14][15][16] ARVC patients carrying more than one disease-associated mutation often show a more severe phenotype, characterized by a younger age of onset and worse prognosis, suggesting a gene-dosage effect. 5,13,17,18 It is to be expected that the use of NGS techniques will result in the identification of an increasing number of patients with such complex genotypes.…”

Section: Diagnostic Settingmentioning

confidence: 99%

“…On average, the mutation detection rate for the most common ARVC-related genes are: PKP2 11-51%, DSG2 3-20%, DSC2 1-7%, JUP 0.5-16% and DSP 1-7%. 5,12,13,[17][18][19][20][21] …”

Section: Clinical Sensitivity (Proportion Of Positive Tests If the DImentioning

confidence: 99%

“…However, as carriership of multiple disease-causing or -modifying mutations in one or more genes has been reported, it cannot be excluded that this mutation-negative family member carries a still unidentified ARVCrelated mutation. 5,13,17,18 Index case in that family had not been tested: ARVC is believed to be familial in B30-50% of cases. 1,8,9,20 Therefore, when an index patient has been clinically diagnosed with ARVC, and no genetic test has been performed, the chance for a firstdegree relative to develop ARVC may reach up to 15-25%.…”

Section: Positive Clinical Predictive Valuementioning

confidence: 99%

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Clinical utility gene card for: arrhythmogenic right ventricular cardiomyopathy (ARVC)

et al. 2013

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Section: Describe the Burden Of Alternative Diagnostic Methods To Thementioning

confidence: 99%

Section: Diagnostic Settingmentioning

confidence: 99%

“…On average, the mutation detection rate for the most common ARVC-related genes are: PKP2 11-51%, DSG2 3-20%, DSC2 1-7%, JUP 0.5-16% and DSP 1-7%. 5,12,13,[17][18][19][20][21] …”

Section: Clinical Sensitivity (Proportion Of Positive Tests If the DImentioning

confidence: 99%

Section: Positive Clinical Predictive Valuementioning

confidence: 99%

See 2 more Smart Citations

Clinical utility gene card for: arrhythmogenic right ventricular cardiomyopathy (ARVC)

et al. 2013

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“…[16][17][18][19] In a unique systematic study, applying Multiplex Ligationdependent Probe Amplification (MLPA) on 169 Dutch ARVC patients, large copy number variants involving PKP2 gene were detected in three (1,8%) cases. 19 Very recently, a deletion of the entire coding region of PKP2 gene (excluding exon 1) and a 7.9 Mb deletion of chromosome 12p12.1-p11.1 encompassing PKP2 exons 1-14 were identified in two ARVC cases, by chromosomal oligo-array analysis and/or MLPA.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disease characterized by progressive myocardial loss, with fibro-fatty replacement, and high frequency of ventricular arrhythmias that can lead to sudden cardiac death. ARVC is a genetically determined disorder, usually caused by point mutations in components of the cardiac desmosome. Conventional mutation screening of ARVC genes fails to detect causative mutations in about 50% of index cases, suggesting a further genetic heterogeneity. We performed a genome-wide linkage study and a copy number variations (CNVs) analysis, using high Àdensity SNP arrays, in an ARVC family showing no mutations in any of the desmosomal genes. The CNVs analysis identified a heterozygous deletion of about 122 kb on chromosome 12p11.21, including the entire plakophilin-2 gene and shared by all affected family members. It was not listed on any of available public CNVs databases and was confirmed by quantitative real-time PCR. This is the first SNP array-based genome-wide study leading to the identification of a CNV segregating with the disease phenotype in an ARVC family. This result underscores the importance of performing additional analysis for possible genomic deletions/duplications in ARVC patients without point mutations in known disease genes.

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Autosomal‐dominant biventricular arrhythmogenic cardiomyopathy in a large family with a novel in‐frame DSP nonsense mutation

Singh

Casey

Berg

et al. 2018

American J of Med Genetics Pt A

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A novel autosomal-dominant in-frame deletion resulting in a nonsense mutation in the desmoplakin (DSP) gene was identified in association with biventricular arrhythmogenic cardiomyopathy across three generations of a large Caucasian family. Mutations that disrupt the function and structure of desmosomal proteins, including desmoplakin, have been extensively linked to familial arrhythmogenic right ventricular cardiomyopathy (ARVC). Analysis of data from 51 individuals demonstrated the previously undescribed variant p.Cys81Stop (c.243_251delCTTGATGCG) in DSP segregates with a pathogenic phenotype exhibiting variable penetrance and expressivity. The mutation's pathogenicity was first established due to two sudden cardiac deaths (SCDs), each with a biventricular cardiomyopathy identified on autopsy. Of the individuals who underwent genetic screening, 27 of 51 were heterozygous for the DSP mutation (29 total with two obligate carriers). Six of these were subsequently diagnosed with arrhythmogenic cardiomyopathy. An additional nine family members have a conduction disorder and/or myocardial structural changes characteristic of an evolving condition. Previous reports from both human patients and mouse studies proposed DSP mutations with a premature stop codon impart mild to no clinical symptoms. Loss of expression from the abnormal allele via the nonsense-mediated mRNA decay pathway has been implicated to explain these findings. We identified an autosomal-dominant DSP nonsense mutation in a large family that led to SCD and phenotypic expression of arrhythmogenic cardiomyopathy involving both ventricles. This evidence demonstrates the pathogenic significance of this type of desmosomal mutation and provides insight into potential clinical manifestations.

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Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice

Abstract: This study supports the use of genetic testing as a new diagnostic tool in ARVC/D and also suggests a prognostic impact, as the severity of the disease appears different according to the underlying gene or the presence of multiple mutations.

Cited by 213 publications

References 35 publications

Clinical utility gene card for: arrhythmogenic right ventricular cardiomyopathy (ARVC)

Clinical utility gene card for: arrhythmogenic right ventricular cardiomyopathy (ARVC)

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

Autosomal‐dominant biventricular arrhythmogenic cardiomyopathy in a large family with a novel in‐frame DSP nonsense mutation

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