A targeted next-generation gene panel reveals a novel heterozygous nonsense variant in the TP63 gene in patients with arrhythmogenic cardiomyopathy

Poloni, Giulia; Calore, Martina; Rigato, Ilaria; Marras, Elena; Minervini, Giovanni; Mazzotti, Elisa; Lorenzon, Alessandra; Mura, Ilena Egle Astrid Li; Telatin, Andrea; Zara, Ivano; Simionati, Barbara; Marra, Martina Perazzolo; Ponti, Jessica; Occhi, Gianluca; Vitiello, Libero; Daliento, Luciano; Thiene, Gaetano; Basso, Cristina; Corrado, Domenico; Tosatto, Silvio C. E.; Bauce, Barbara; Bortoli, Marzia De

doi:10.1016/j.hrthm.2018.11.015

Cited by 15 publications

(14 citation statements)

References 26 publications

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“…This review first highlighted the great genetic heterogeneity and complexity that characterizes the molecular basis of inherited channelopathies and cardiomyopathies related to SCD. This complexity imposes the need to refer to experts in the field of molecular cardiology, who can use the most advanced sequencing methods, such as NGS, to sequence multiple genes simultaneously, in the effort to reach the maximum genetic yield [ 57 , 61 , 75 , 76 , 88 , 95 , 100 , 101 ]. Another difficult issue is the interpretation of genetic variants in the context of SCD.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in genes coding proteins involved in other types of cell-cell junctions have been recently described, such as CADH2 and CTTNA3 , involved in the formation of adherent junctions, or TJP1 gene, which encodes zonula occludens-1 intercalated disk protein. However, the prevalence of these ACM form remains to be determined [ 100 , 101 ]. Therefore, the hypothesis that has been postulated is that ACM is not exclusively a desmosomal disease, but it more generally involves the intercalary discs.…”

Section: Genetic Basis Of Inherited Cardiomyopathiesmentioning

confidence: 99%

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The Hidden Fragility in the Heart of the Athletes: A Review of Genetic Biomarkers

Barretta

Mirra

Monda

et al. 2020

IJMS

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Sudden cardiac death (SCD) is a devastating event which can also affect people in apparent good health, such as young athletes. It is known that intense and continuous exercise along with a genetic background that predisposes a person to the risk of fatal arrhythmias is a trigger for SCD. Therefore, knowledge of the athlete’s genetic conditions underlying the onset of SCD must be extended, in order to develop new effective prevention and/or therapeutic strategies. Arrhythmic features occur across a broad spectrum of cardiac diseases, sometimes presenting with overlapping phenotypes. The genetic basis of arrhythmogenic disorders has been greatly highlighted in the last 30 years, and has shown marked heterogeneity. The advent of next-generation sequencing has constantly updated our understanding of the genetic basis of arrhythmogenic diseases and is laying the foundation for precision medicine. With the exception of a few clinical cases involving a single athlete showing a highly suspected phenotype for the presence of a heart disease, there are few studies to date that analysed the applicability of genetic testing on cohorts of athletes. This evidence shows that genetic testing can contribute to the diagnosis of up to 13% of athletes; however, the presence of clinical markers is essential. This review aims to provide a reference collection on current knowledge of the genetic basis of sudden cardiac death in athletes and to review updated evidence on the effectiveness of genetic testing in early identification of athletes at risk for SCD.

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Section: Discussionmentioning

confidence: 99%

Section: Genetic Basis Of Inherited Cardiomyopathiesmentioning

confidence: 99%

The Hidden Fragility in the Heart of the Athletes: A Review of Genetic Biomarkers

Barretta

Mirra

Monda

et al. 2020

IJMS

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“…In some cases of EDs, a congenital heart defect was found; however, a case report described a missense mutation in TP63 in a patient with ED and typical cardiac findings of ACM ( Valenzise et al, 2008 ). More recently, a novel heterozygous nonsense variant was reported in a typical nonsyndromic ACM case, suggesting that haploinsufficiency may play a role in the disease process ( Poloni et al, 2019 ). Knockout of Tp63 in mice and zebrafish are viable and indicate its role in development and ectodermal differentiation, but no obvious cardiac abnormalities have been detected in either homozygous or heterozygous animals ( Mills et al, 1999 ; Santos-Pereira et al, 2019 ).…”

Section: Animal Models For Acm Associated With Mutations In Nondesmosmentioning

confidence: 99%

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

Gerull

Brodehl

2020

Front. Physiol.

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Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell–cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.

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“…The tool has been used, for example, in the setup of a target enrichment panel targeting 71 human genes (Poloni et al, 2019), in order to detect uncovered regions.…”

Section: Example Applicationsmentioning

confidence: 99%