Phenotypic Variability of a Pathogenic PKP2 Mutation in an Italian Family Affected by Arrhythmogenic Cardiomyopathy and Juvenile Sudden Death: Considerations From Molecular Autopsy to Sport Restriction

Leone, Maria Pia; Palumbo, Pietro; Saenen, Johan; Mastroianno, Sandra; Castellana, Stefano; Amico, Cesare; Mazza, Tommaso; Potenza, Domenico; Petracca, Antonio; Castori, Marco; Chessa, Massimo; Stolfo, Giuseppe Di

doi:10.3389/fcvm.2021.635141

Cited by 6 publications

(4 citation statements)

References 34 publications

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“…Given the autosomal dominant inheritance of the ARVC/D-PKP2-related gene, incomplete penetrance and variable expressivity could well explain the parent's normal phenotype (12. Leone MP, et al 2021).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Lethal Non-immune Hydrops Fetalis with Biallelic Inheritance of PKP2 Variants

AlSaif

AlFaraj

Al‐Sannaa

2023

Preprint

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Here we describe a male infant with non-immune hydrops fetalis associated with congenital cardiomyopathy diagnosed prenatally. Whole-exome sequencing detected compound heterozygous c.1688+1G>A and p.(Asn759Ilefs*41) variants in the PKP2 gene inherited independently from his asymptomatic parents. Our present case supports the severe phenotype of biallelic inheritance of PKP2 gene pathogenic variants

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Section: Discussionmentioning

confidence: 99%

Case Report: Lethal Non-immune Hydrops Fetalis with Biallelic Inheritance of PKP2 Variants

AlSaif

AlFaraj

Al‐Sannaa

2023

Preprint

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“…Van Tintelen et al studied ACM cases in a Dutch population, and of the 34 patients that satisfied the index criteria for ACM, 23 were familial of which 16 (70%) were caused by PKP2 mutations [80]. PKP2 mutations also have been associated with SCD, particularly in young athletes, and with left ventricular involvement during late stages of the disease [81]. ) nomenclature (superscripts denote references to primary source-see end of caption).…”

Section: Plakophilin (Pkp)mentioning

confidence: 99%

Understanding Arrhythmogenic Cardiomyopathy: Advances through the Use of Human Pluripotent Stem Cell Models

Chua,

Morrissette-McAlmon,

Tung

et al. 2023

Genes

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Cardiomyopathies (CMPs) represent a significant healthcare burden and are a major cause of heart failure leading to premature death. Several CMPs are now recognized to have a strong genetic basis, including arrhythmogenic cardiomyopathy (ACM), which predisposes patients to arrhythmic episodes. Variants in one of the five genes (PKP2, JUP, DSC2, DSG2, and DSP) encoding proteins of the desmosome are known to cause a subset of ACM, which we classify as desmosome-related ACM (dACM). Phenotypically, this disease may lead to sudden cardiac death in young athletes and, during late stages, is often accompanied by myocardial fibrofatty infiltrates. While the pathogenicity of the desmosome genes has been well established through animal studies and limited supplies of primary human cells, these systems have drawbacks that limit their utility and relevance to understanding human disease. Human induced pluripotent stem cells (hiPSCs) have emerged as a powerful tool for modeling ACM in vitro that can overcome these challenges, as they represent a reproducible and scalable source of cardiomyocytes (CMs) that recapitulate patient phenotypes. In this review, we provide an overview of dACM, summarize findings in other model systems linking desmosome proteins with this disease, and provide an up-to-date summary of the work that has been conducted in hiPSC-cardiomyocyte (hiPSC-CM) models of dACM. In the context of the hiPSC-CM model system, we highlight novel findings that have contributed to our understanding of disease and enumerate the limitations, prospects, and directions for research to consider towards future progress.

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“…Likewise, in one recent case report published by Leone et al, a molecular autopsy was performed on a 13year-old boy who suddenly died after physical exertion following cardiopulmonary resuscitation [34]. A sample of the victim's DNA was tested by using NGS in combination with a postmortem examination.…”

Section: Postmortem Genetic Testing In Cardiac-related Causesmentioning

confidence: 99%

“…Plakophilin, which is encoded by the PKP2 gene, has been linked to ACM. A cascade of genetic and clinical screening was introduced to 19 family members in total; 12 more individuals were determined to be genotype-positive, with six of them meeting two or more of the main task force criteria (TFC) used for the clinical standard of diagnosing ARVC [34].…”

Section: Postmortem Genetic Testing In Cardiac-related Causesmentioning

confidence: 99%

Postmortem Genetic Testing in Sudden Unexpected Death: A Narrative Review

Alzahrani¹,

Alswaimil²,

Alammari³

et al. 2023

Cureus

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Sudden unexpected death (SUD) is one of the challenging situations encountered in forensic medicine. As a rule, a comprehensive forensic assessment is performed to identify the cause of death in such cases; however, the absence of findings suggestive of a cause, i.e., a negative autopsy, warrants further investigation such as a molecular autopsy. In this review, we aim to highlight the genetic causes of SUD, tools used in a molecular autopsy, and the role of screening in surviving relatives. As per several guidelines, the most preferred samples for DNA extraction are whole blood and fresh frozen tissues. Furthermore, Sanger sequencing and next-generation sequencing are the technologies that are used for genetic analysis; the latter overcomes the former's drawbacks in terms of cost-effectiveness, time consumption, and the ability to sequence the whole exome. SUD have diverse etiologies; we can generally classify them into cardiac and non-cardiac causes. Regarding cardiac causes, many conditions having an underlying genetic basis are included, such as channelopathies and cardiomyopathies. Regarding non-cardiac causes of SUD, the main etiologies are epilepsy and metabolic disorders. Nevertheless, it has been proposed that there is a genetic overlap between channelopathies, especially long QT syndromes and epilepsy. Additionally, fatty acid oxidation disorders are major metabolic conditions that are caused by certain genetic mutations that can lead to SUD in infancy. Since many SUD causes have an underlying genetic mutation, it is important to understand the genetic variations not only to recognize the cause of death but also to undertake further preventive measures for surviving relatives. In conclusion, a molecular autopsy has a major role in the forensic examination of cases of SUD.

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Phenotypic Variability of a Pathogenic PKP2 Mutation in an Italian Family Affected by Arrhythmogenic Cardiomyopathy and Juvenile Sudden Death: Considerations From Molecular Autopsy to Sport Restriction

Cited by 6 publications

References 34 publications

Case Report: Lethal Non-immune Hydrops Fetalis with Biallelic Inheritance of PKP2 Variants

Case Report: Lethal Non-immune Hydrops Fetalis with Biallelic Inheritance of PKP2 Variants

Understanding Arrhythmogenic Cardiomyopathy: Advances through the Use of Human Pluripotent Stem Cell Models

Postmortem Genetic Testing in Sudden Unexpected Death: A Narrative Review

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