Desmoplakin missense and non-missense mutations in arrhythmogenic right ventricular cardiomyopathy: Genotype-phenotype correlation

Castelletti, Silvia; Vischer, Annina S.; Syrris, Petros; Crotti, Lia; Spazzolini, Carla; Ghidoni, Alice; Parati, Gianfranco; Jenkins, Sharon; Kotta, Maria Christina; McKenna, William J.; Schwartz, Peter J.; Pantazis, Antonis

doi:10.1016/j.ijcard.2017.05.018

Cited by 79 publications

(88 citation statements)

References 49 publications

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“…DSP is a key desmosomal protein associated with the predominantly left ventricular forms of AC. To date, there are only a limited number of genotype–phenotype studies in AC, or in particular in DSP mutation carriers …”

Section: Discussionmentioning

confidence: 99%

“…Personal history of cutaneous features was collected, and detailed clinical examination of the skin and hair phenotype was carried out by a dermatologist (T.M.). Cardiac phenotyping was performed in 30 family members according to the protocol described (three of the 33 carriers resided abroad and were therefore unavailable to participate in cardiac phenotyping) . Arrhythmic characterization included arrhythmia recorded during 24‐h ambulatory electrocardiogram (ECG) monitoring and/or exercise testing, cardiac arrest and implantable cardioverter defibrillator (ICD) appropriate discharges.…”

Section: Methodsmentioning

confidence: 99%

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Loss‐of‐function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype

et al. 2019

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Loss‐of‐function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype

et al. 2019

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“…The presence of recurrent myocarditis as well as a positive family history of myocarditis or cardiomyopathy should alert clinicians to look for cardiomyopathy genes. Phenotype/genotype studies suggest that DSP mutations are associated with a severe ARVC phenotype, with a higher risk of ventricular arrhythmias and sudden cardiac death and a high level of LV involvement, particularly in patients with truncating DSP mutations. The same studies would also indicate a higher incidence of myocarditis in DSP mutation carriers affected by the left dominant type of ARVC.…”

Section: Discussionmentioning

confidence: 99%

Monozygotic twins with myocarditis and a novel likely pathogenic desmoplakin gene variant

et al. 2020

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Myocarditis most often affects otherwise healthy athletes and is one of the leading causes of sudden death in children and young adults. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder with increased risk for paroxysmal ventricular arrhythmias and sudden cardiac death. The clinical picture of myocarditis and ARVC may overlap during the early stages of cardiomyopathy, which may lead to misdiagnosis. In the literature, we found several cases that presented with episodes of myocarditis and ended up with a diagnosis of arrhythmogenic cardiomyopathy, mostly of the left predominant type. The aim of this case presentation is to shed light upon a possible link between myocarditis, a desmoplakin (DSP) gene variant, and ARVC by describing a case of male monozygotic twins who presented with symptoms and signs of myocarditis at 17 and 18 years of age, respectively. One of them also had a recurrent episode of myocarditis. The twins and their family were extensively examined including electrocardiograms (ECG), biochemistry, multimodal cardiac imaging, myocardial biopsy, genetic analysis, repeated cardiac magnetic resonance (CMR) and echocardiography over time. Both twins presented with chest pain, ECG with slight ST-T elevation, and increased troponin T levels. CMR demonstrated an affected left ventricle with comprehensive inflammatory, subepicardial changes consistent with myocarditis. The right ventricle did not appear to have any abnormalities. Genotype analysis revealed a nonsense heterozygous variant in the desmoplakin (DSP) gene [NM_004415.2:c.2521_2522del (p.Gln841Aspfs*9)] that is considered likely pathogenic and presumably ARVC related. There was no previous family history of heart disease. There might be a common pathophysiology of ARVC, associated with desmosomal dysfunction, and myocarditis. In our case, both twins have an affected left ventricle without any right ventricular involvement, and they are carriers of a novel DSP variant that is likely associated with ARVC. The extensive inflammation of the LV that was apparent in the CMR may or may not be the primary event of ARVC. Nevertheless, our data suggest that irrespective of a possible link here to ARVC, genetic testing for arrhythmogenic cardiomyopathy might be advisable for patients with recurrent myocarditis associated with a family history of myocarditis.

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“…In fact, pure RV forms are rare, and some alterations of the LV can be demonstrated even when RV involvement predominates. Among mutations in the desmosomal genes associated with ACM, those in DSP, especially non-missense, are most often associated to LV involvement [17]. A number of non-desmosomal genes, including TMEM43, PLN, SCN5A, and DES, have also been associated with ACM, DCM, or overlap syndromes frequently complicated by malignant ventricular arrhythmias.…”

Section: Depicting the Genetic Background Of Inherited Hfmentioning

confidence: 99%

Novel Basic Science Insights to Improve the Management of Heart Failure: Review of the Working Group on Cellular and Molecular Biology of the Heart of the Italian Society of Cardiology

Ameri

Schiattarella

Crotti

et al. 2020

IJMS

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Despite important advances in diagnosis and treatment, heart failure (HF) remains a syndrome with substantial morbidity and dismal prognosis. Although implementation and optimization of existing technologies and drugs may lead to better management of HF, new or alternative strategies are desirable. In this regard, basic science is expected to give fundamental inputs, by expanding the knowledge of the pathways underlying HF development and progression, identifying approaches that may improve HF detection and prognostic stratification, and finding Int.

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Desmoplakin missense and non-missense mutations in arrhythmogenic right ventricular cardiomyopathy: Genotype-phenotype correlation

Cited by 79 publications

References 49 publications

Loss‐of‐function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype

Loss‐of‐function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype

Monozygotic twins with myocarditis and a novel likely pathogenic desmoplakin gene variant

Novel Basic Science Insights to Improve the Management of Heart Failure: Review of the Working Group on Cellular and Molecular Biology of the Heart of the Italian Society of Cardiology

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