Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form‐associated genes provides new insights for molecular diagnosis and clinical management

Goudal, Adeline; Karakachoff, Matilde; Livet, Pierre; Baron, Estelle; Bonnaud, Stéphanie; Kyndt, Florence; Arnaud, M.; Minois, Damien; Bourcereau, Emmanuelle; Thollet, Aurélie; Deleuze, Jean‐François; Génin, Emmanuelle; Wiart, François; Pasquié, Jean‐Luc; Galand, Vincent; Sacher, Frédéric; Dina, Christian; Redon, Richard; Bézieau, Stéphane; Schott, Jean‐Jacques; Probst, Vincent; Barc, Julien

doi:10.1002/humu.24436

Cited by 3 publications

(2 citation statements)

References 37 publications

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“…In addition, SCD has also been associated with oligogenic models of cardiac disease, in which potentially pathogenic rare variants may contribute synergistically to the risk of sudden death (24). Consistent with this hypothesis, an overrepresentation of rare variants in cardiac genes has been identified in cohorts of young decedents compared to control population (25,26). All these phenotypical phenomena are likely due to a combination of genetic, environmental, and lifestyle factors.…”

Section: Inherited Arrhythmogenic Syndromesmentioning

confidence: 78%

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death

et al. 2023

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In the forensic medicine field, molecular autopsy is the post-mortem genetic analysis performed to attempt to unravel the cause of decease in cases remaining unexplained after a comprehensive forensic autopsy. This negative autopsy, classified as negative or non-conclusive, usually occurs in young population. In these cases, in which the cause of death is unascertained after a thorough autopsy, an underlying inherited arrhythmogenic syndrome is the main suspected cause of death. Next-generation sequencing allows a rapid and cost-effectives genetic analysis, identifying a rare variant classified as potentially pathogenic in up to 25% of sudden death cases in young population. The first symptom of an inherited arrhythmogenic disease may be a malignant arrhythmia, and even sudden death. Early identification of a pathogenic genetic alteration associated with an inherited arrhythmogenic syndrome may help to adopt preventive personalized measures to reduce risk of malignant arrhythmias and sudden death in the victim’s relatives, at risk despite being asymptomatic. The current main challenge is a proper genetic interpretation of variants identified and useful clinical translation. The implications of this personalized translational medicine are multifaceted, requiring the dedication of a specialized team, including forensic scientists, pathologists, cardiologists, pediatric cardiologists, and geneticists.

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Section: Inherited Arrhythmogenic Syndromesmentioning

confidence: 78%

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death

et al. 2023

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“…Furthermore, SCD has been associated with oligogenic models of heart disease, where rare potentially pathogenic variants may synergistically contribute to the risk of SD, and an over-representation of rare variants in cardiac genes has been identified in young deceased individuals [58,59].…”

Section: Molecular Autopsy (Ma)mentioning

confidence: 99%

Sudden Cardiac Death in the Young: State-of-the-Art Review in Molecular Autopsy

Salzillo,

Sansone,

Napolitano

2024

CIMB

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Sudden cardiac death (SCD) is defined as unexpected death due to a cardiac cause that occurs rapidly. Despite the identification of prevention strategies, SCD remains a serious public health problem worldwide, accounting for 15–20% of all deaths, and is therefore a challenge for modern medicine, especially when it affects young people. Sudden cardiac death in young people affects the population aged ≤ 35 years, including athletes and non-athletes, and it is due to various hereditary and non-hereditary causes. After an autopsy, if the cause remains unknown, it is called sudden unexplained death, often attributable to genetic causes. In these cases, molecular autopsy—post-mortem genetic testing—is essential to facilitate diagnostic and therapeutic pathways and/or the monitoring of family members of the cases. This review aims to elaborate on cardiac disorders marked by genetic mutations, necessitating the post-mortem genetic investigation of the deceased for an accurate diagnosis in order to facilitate informed genetic counseling and to implement preventive strategies for family members of the cases.

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Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form‐associated genes provides new insights for molecular diagnosis and clinical management

et al. 2022

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Arrhythmogenic cardiomyopathy with right dominant form (ACR) is a rare heritable cardiac cardiomyopathy disorder associated with sudden cardiac death. Pathogenic variants (PVs) in desmosomal genes have been causally related to ACR in 40% of cases. Other genes encoding nondesmosomal proteins have been described in ACR, but their contribution in this pathology is still debated. A panel of 71 genes associated with inherited cardiopathies was screened in an ACR population of 172 probands and 856 individuals from the general population. PVs and uncertain significance variants (VUS) have been identified in 36% and 18.6% of patients, respectively. Among the cardiopathy‐associated genes, burden tests show a significant enrichment in PV and VUS only for desmosomal genes PKP2 (plakophilin‐2), DSP (desmoplakin), DSC2 (desmocollin‐2), and DSG2 (desmoglein‐2). Importantly, VUS may account for 15% of ACR cases and should then be considered for molecular diagnosis. Among the other genes, no evidence of enrichment was detected, suggesting an extreme caution in the interpretation of these genetic variations without associated functional or segregation data. Genotype–phenotype correlation points to (1) a more severe and earlier onset of the disease in PV and VUS carriers, underlying the importance to carry out presymptomatic diagnosis in relatives and (2) to a more prevalent left ventricular dysfunction in DSP variant carriers.

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Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form‐associated genes provides new insights for molecular diagnosis and clinical management

Cited by 3 publications

References 37 publications

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death

Sudden Cardiac Death in the Young: State-of-the-Art Review in Molecular Autopsy

Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form‐associated genes provides new insights for molecular diagnosis and clinical management

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