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Test Information Sheet Arrhythmogenic Cardiomyopathy Panel Up to 23 genes The Arrhythmogenic Cardiomyopathy Panel is a comprehensive next-generation sequencing (NGS) panel that includes genes related to cardiomyopathy conditions with prominent arrhythmias. This test can be used to confirm a clinical diagnosis or identify at-risk individuals. Disorders of the heart can include abnormalities of the heart muscle (cardiomyopathies), irregularities of the heart’s electrical system leading to irregular heartbeats (arrhythmias), or both. One condition that features cardiomyopathy with prominent arrhythmia is arrhythmogenic right ventricular cardiomyopathy (dysplasia). Arrhythmogenic right ventricular cardiomyopathy is characterized by the progressive replacement of normal heart muscle with fibrous fatty tissue. This predisposes individuals to irregular heart rhythms, including ventricular tachycardia, and sudden death in some cases. PREVALENCE The prevalence of arrhythmogenic right ventricular cardiomyopathy is estimated to be 1 in 1,000 to 1 in 1,250 individuals (Peters, 2006). INCLUDED DISORDERS This panel includes genes associated with: • Arrhythmogenic right ventricular cardiomyopathy (dysplasia) • Hypertrophic cardiomyopathy and arrhythmias • Dilated cardiomyopathy and arrhythmias • Other conditions that include both cardiomyopathy and arrhythmias as features CLINICAL SENSITIVITY Disease causing mutations can be identified in approximately 50% of arrhythmogenic right ventricular cardiomyopathy cases (Quarta et al, 2011). The Arrhythmogenic Right Ventricular Cardiomyopathy Panel includes all of the genes commonly associated with this disease. methods. Copy number variants, including intragenic deletions and duplications are detected to a resolution of single exon. To request analysis of a specific single exon copy number variant, please contact our Client Services team prior to ordering. Analytical sensitivity of the assay is >99%. INHERITANCE AND PENETRANCE Arrhythmogenic right ventricular cardiomyopathy (ARVC) is typically inherited in autosomal dominant manner, although Emery-Dreifuss muscular dystrophy, caused by mutations in the EMD gene, is inherited in an X-linked manner, and Naxos disease, caused by mutations in the JUP gene, is inherited in an autosomal recessive manner. Compound heterozygosity and digenic inheritance has also been reported (Bauce et al, 2010; Xu et al, 2010). Arrhythmogenic right ventricular cardiomyopathy exhibits reduced penetrance. In one family with a mutation in the DSP gene, the penetrance was 50% (Rampazzo et al, 2002), and in other families with dominant ARVC, the penetrance was estimated at 20-30% (Chowdhury et al, 2005). METHODOLOGY AND ANALYTICAL SENSITIVITY Next-generation sequencing technology is used to test clinically relevant portions of each gene, including coding exons, adjacent intron/exon boundaries, and selected introns/noncoding variants. Pathogenic and likely pathogenic variants are confirmed by orthogonal © Phosphorus 2017 www. phosphorus.com | 1-855-746-7423 | [email protected] 032017 ACTIS 1.0 INDICATIONS FOR TESTING • Confirmation of a clinical diagnosis • Unexplained cardiac arrest • Cardiomyopathy and arrhythmia • Risk assessment for asymptomatic family of members of proband with molecular diagnosis of arrhythmogenic right ventricular cardiomyopathy or other arrhythmogenic cardiomyopathy INCLUDED GENES (20): ACTN2 DES DSC2 DSG2 DSP EMD JUP LDB3 LMNA PKP2 PLN PRKAG2 RBM20 RYR2 SCN5A TGFB3 TMEM43 TNNI3 TNNT2 TTN ADDITIONS TO THE COMPREHENSIVE PANEL Emerging Evidence Genes (3): Emerging evidence genes can also be added on to the Arrhythmogenic Cardiomyopathy panel. These genes do not have a clear association with arrhythmogenic cardiomyopathy, but emerging evidence suggests that they may play a role in disease pathogenicity. ANKRD1 CTNNA3 PDLIM3 REFERENCES 1. Bauce B, Nava A, Beffagna G, et al. Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm. 2010;7(1):22-9. 2. Peters S. Advances in the diagnostic management of arrhythmogenic right ventricular dysplasia-cardiomyopathy. Int J Cardiol. 2006;113(1):4-11. 3. Quarta G, Muir A, Pantazis A, et al. Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. Circulation. 2011;123(23):2701-9. 4. Rampazzo A, Nava A, Malacrida S, et al. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet. 2002;71(5):1200-6. 5. Sen-chowdhry S, Syrris P, Mckenna WJ. Genetics of right ventricular cardiomyopathy. J Cardiovasc Electrophysiol. 2005;16(8):927-35. 6. Xu T, Yang Z, Vatta M, et al. Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2010;55(6):587-97. © Phosphorus 2017 www. phosphorus.com | 1-855-746-7423 | [email protected] 032017 ACTIS 1.0