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A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients.


ABSTRACT: The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity of variants is reclassified frequently, which may result in a changed clinical risk prediction. Here, we present the collection, reclassification, and clinical outcome correlation for the largest series of ARVC patients carrying multiple desmosomal pathogenic variants to date (n = 331). After reclassification, only 29% of patients remained carriers of two (likely) pathogenic variants. They reached the composite endpoint (ventricular arrhythmias, heart failure, and death) significantly earlier than patients with one or no remaining reclassified variant (hazard ratios of 1.9 and 1.8, respectively). Periodic reclassification of variants contributes to more accurate risk stratification and subsequent clinical management strategy. Graphical Abstract.

SUBMITTER: Nagyova E 

PROVIDER: S-EPMC10721666 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients.

Nagyova Emilia E   Hoorntje Edgar T ET   Te Rijdt Wouter P WP   Bosman Laurens P LP   Syrris Petros P   Protonotarios Alexandros A   Elliott Perry M PM   Tsatsopoulou Adalena A   Mestroni Luisa L   Taylor Matthew R G MRG   Sinagra Gianfranco G   Merlo Marco M   Wada Yuko Y   Horie Minoru M   Mogensen Jens J   Christensen Alex H AH   Gerull Brenda B   Song Lei L   Yao Yan Y   Fan Siyang S   Saguner Ardan M AM   Duru Firat F   Koskenvuo Juha W JW   Cruz Marino Tania T   Tichnell Crystal C   Judge Daniel P DP   Dooijes Dennis D   Lekanne Deprez Ronald H RH   Basso Cristina C   Pilichou Kalliopi K   Bauce Barbara B   Wilde Arthur A M AAM   Charron Philippe P   Fressart Véronique V   van der Heijden Jeroen F JF   van den Berg Maarten P MP   Asselbergs Folkert W FW   James Cynthia A CA   Jongbloed Jan D H JDH   Harakalova Magdalena M   van Tintelen J Peter JP  

Journal of cardiovascular translational research 20230707 6


The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity of variants is reclassified frequently, which may result in a changed clinical risk prediction. Here, we present the collection, reclassification, and clinical outcome correlation for the largest series of ARVC patients carrying multiple desmosomal pathogenic vari  ...[more]

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