Multilevel analyses of SCN5A mutations in arrhythmogenic
          right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease
          pathogenesis

Riele, Anneline S J M Te; Agullo‐Pascual, Esperanza; James, Cynthia A.; Leo‐Macias, Alejandra; Cerrone, Marina; Zhang, Mingliang; Lin, Xianming; Lin, Bin; Rothenberg, Eli; Sobreira, Nara; Amat-Alarcon, Nuria; Marsman, Roos F.; Murray, Brittney; Tichnell, Crystal; Heijden, Jeroen F. van der; Dooijes, Dennis; Veen, Toon A.B. van; Tandri, Harikrishna; Fowler, Steven J.; Hauer, Richard N.W.; Tomaselli, Gordon F.; Berg, Maarten P. van den; Taylor, Matthew R.G.; Brun, Francesca; Sinagra, Gianfranco; Wilde, Arthur A.M.; Mestroni, Luisa; Bezzina, Connie R.; Calkins, Hugh; Tintelen, J. Peter van; Bu, Lei; Delmar, Mario; Judge, Daniel P.

doi:10.1093/cvr/cvw234

Cited by 159 publications

(123 citation statements)

References 30 publications

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“…Recent studies have suggested that mutations in SCN5A may account for a small portion of the ARVC phenotype cohorts 31. This is consistent with multiple studies that have demonstrated that desmosomal proteins are associated with altered kinetics of the sodium current in cardiomyocytes,32 a manifestation that precedes structural abnormalities, as seen in a DSG2 mouse model 33.…”

Section: Introductionsupporting

confidence: 82%

Arrhythmogenic cardiomyopathies (ACs): diagnosis, risk stratification and management

Protonotarios

Elliott

2019

Heart

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Section: Introductionsupporting

confidence: 82%

Arrhythmogenic cardiomyopathies (ACs): diagnosis, risk stratification and management

Protonotarios

Elliott

2019

Heart

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“…PLN has been identified as a causative factor in a significant portion of individuals with ARVC patients 3, 6. Additionally, recent reports have identified SCN5A mutations in a small percentage of ARVC patients 7. Overlap between ARVC and dilated cardiomyopathy has been well described, and pathogenic variants in sarcomere genes have been associated with DCM 8.…”

Section: Introductionmentioning

confidence: 99%

Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC)

Murray

Hoorntje

Riele

et al. 2018

Cardiovasc electrophysiol

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AimsArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by ventricular arrhythmias and sudden death. Currently 60% of patients meeting Task Force Criteria (TFC) have an identifiable mutation in one of the desmosomal genes. As much overlap is described between other cardiomyopathies and ARVC, we examined the prevalence of rare, possibly pathogenic sarcomere variants in the ARVC population.MethodsOne hundred and thirty‐seven (137) individuals meeting 2010 TFC for a diagnosis of ARVC, negative for pathogenic desmosomal variants, TMEM43, SCN5A, and PLN were screened for variants in the sarcomere genes (ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1) through either clinical or research genetic testing.ResultsSix probands (6/137, 4%) were found to carry rare variants in the sarcomere genes. These variants have low prevalence in controls, are predicted damaging by Polyphen‐2, and some of the variants are known pathogenic hypertrophic cardiomyopathy mutations. Sarcomere variant carriers had a phenotype that did not differ significantly from desmosomal mutation carriers. As most of these probands were the only affected individuals in their families, however, segregation data are noninformative.ConclusionThese data show variants in the sarcomere can be identified in individuals with an ARVC phenotype. Although rare and predicted damaging, proven functional and segregational evidence that these variants can cause ARVC is lacking. Therefore, caution is warranted in interpreting these variants when identified on large next‐generation sequencing panels for cardiomyopathies.

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“…Molecular genetic testing revealed a rare SCN5A variant. SCN5A variants have been associated with ARVC in 2% of cases [32]. Renewed clinical evaluation of the proband revealed a high burden of atrial and ventricular premature contractions, and cascade screening revealed multiple affected family members (Supplementary Material, page 13).…”

Section: Discussionmentioning

confidence: 99%

Targeted next generation sequencing in a young population with suspected inherited malignant cardiac arrhythmias

et al. 2018

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Aborted sudden cardiac death in the young often is due to inherited heart disease. However, the clinical phenotype in these patients is not always evident. The aim of this study was to identify pathogenic molecular genetic variants in a population with suspected inherited cardiac arrhythmias. Eligible patients were admitted to Aarhus University Hospital, Denmark during the period 1999–2013 with arrhythmias assumed caused by a hereditary heart disease, and in whom no genotype had been established. We used the Danish national pacemaker and ICD registry to identify this cohort. One third (24/80) of the study population had first-line genetic testing with a targeted next-generation sequencing (NGS) panel, and two-third (56/80) of the study population had second-line genetic testing with NGS where prior Sanger sequencing did not reveal a causative variant. Variants were assessed according to the American College of Medical Genetics and Genomics (ACMG) guidelines. We included 80 patients. Median age (IQR) was 38 (28–43) years, 54 (68%) were males. First-line genetic testing identified a genetic variant in 33% (8/24) of the cases and second-line genetic testing revealed a variant in 20% (11/56) of the cases. Eleven variants were considered pathogenic, three likely pathogenic and 10 were variants of unknown significance (VUS). Seventeen variants were very rare with a minor allele frequency (MAF) ≤0.02% in all population databases used in the study. Molecular genetic testing of patients with suspected inherited cardiac arrhythmias with NGS identifies a molecular-genetic cause in a significant proportion of patients.

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Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis

Cited by 159 publications

References 30 publications

Arrhythmogenic cardiomyopathies (ACs): diagnosis, risk stratification and management

Arrhythmogenic cardiomyopathies (ACs): diagnosis, risk stratification and management

Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC)

Targeted next generation sequencing in a young population with suspected inherited malignant cardiac arrhythmias

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