Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) |
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| Authors: | Brittney Murray MS Edgar T Hoorntje MD Anneline S J M te Riele MD PhD Crystal Tichnell MGC Jeroen F van der Heijden MD PhD Harikrishna Tandri MD Maarten P van den Berg MD PhD Jan D H Jongbloed PhD Arthur A M Wilde MD PhD Richard N W Hauer MD PhD Hugh Calkins MD Daniel P Judge MD Cynthia A James ScM PhD J Peter van Tintelen MD PhD Dennis Dooijes PhD |
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| Institution: | 1. Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA;2. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands;3. Netherlands Heart Institute, Utrecht, the Netherlands;4. Division of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands;5. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands;6. Department of Cardiology, Academic Medical Centre, Heart Center, University of Amsterdam, Amsterdam, The Netherlands;7. Department of Clinical Genetics, Amsterdam Cardiovascular Sciences, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands;8. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands |
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| Abstract: | 1 Aims Arrhythmogenic 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. 2 Methods One 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. 3 Results Six 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. 4 Conclusion These 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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| Keywords: | ARVC cardiomyopathy genetics sarcomere whole‐exome sequencing |
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