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Genetics of ARVC ARVC is an autosomal dominant genetic disorder. If a parent has a disease-causing mutation, the risk to each child of inheriting the mutation is 50%.  Not all mutation carriers are symptomatic.  Mutations in at least seven genes together account for ARVC in 40%-50% patients. Five genes that code for desmosome proteins— plakoglobin (JUP), desmoplakin (DSP) plakophilin-2 (PKP2), the desmoglein-2 (DSG2) and desmocollin-2 (DSC2)—as well as two other non-desmosomal genes (RYR2 and TMEM43) have been associated with ARVC (Table 1).

Table 1 Gene Symbol Desmocollin 2 DSC2 Desmoplakin DSP Desmoglein 2 DSG2 Plakophilin 2 PKP2 Ryanodine receptor 2 RYR2 Plakoglobin JUP Transmembrane protein 43 TMEM43

Genetic testing for ARVC and its utility:
Diagnostic genetic testing can be considered for patients who clinically manifest with symptoms of ARVC and for patients who are asymptomatic but are within a family with a known mutation. Testing should be performed first on the family member who is symptomatic, i.e. has clinical manifestations of ARVC.  Preferably, the youngest of most severely affected family member should be tested first.  The three possible outcomes of genetic testing are: positive, negative, and variant of unknown clinical significance (VOUS).  Identification of a mutation in the family can lead to genetic identification of at risk family members who are clinically asymptomatic and who may have normal ECGs and echocardiograms.  Family members who test positive for the familial mutation should have regular cardiac evaluations.  Alternatively, a negative genetic test result for the familial mutation would obviate the need for repeated follow-up examinations. Genetic testing can be used for prenatal diagnosis.  All patients who undergo genetic testing should receive pre-test and post-test genetic counseling to understand the implications of testing


Resources for Patients

• GeneDx cardiology page: www.genedx.com/cardiology
• Gene Reviews, a database of genetic diseases: www.geneclinics.org
• National Society of Genetic Counselors, to help you find a counselor near you: www.nsgc.org
• Sudden Arrhythmia Death Syndrome (SADS), a patient support organization: www.sads.org
• Cardiac Arrhythmias Research and Education Foundation (C.A.R.E.), a patient support organization: www.longqt.org
• The Canadian Sudden Arrhythmia Death Syndromes (SADS) Foundation, a patient support organization in Canada:  www.sads.ca
• Sudden Cardiac Arrest Association, a patient support organization:  www.suddencardiacarrest.org 
• Genetic Heart Disease Program: www.geneticheartdisease.org

REFERENCES 

1. McNally E, MacLeod H and Dellafave L. Arrhythmogenic Right ventricular dysplasia/cardiomyopathy, autosomal dominant. GeneReviews, NCBI, NIH, first published 2005, revised 2008.
2. Thiene G, Corrado D and Basso C. Arrythmogenic right ventricular cardiomyopathy/dysplasia. Orphanet Journal of Rare Diseases 2007: 2(45); 1-16.      PMID: 18001465
3. McKenna M, Thiene G and Nava A. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council of Cardiomyopathies of the International Society and Federation of Cardiology. Br Heart J 1994: 71; 215-218. PMID: 8142187
4. Awad MM, Calkins H and Judge DP. Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nature Clinical Practice-Cardiovascular Medicine 2008: 5(5); 258-267. PMID: 18382419
5. Sen-Chowdhry S, Syrris P and McKenna W. Role of Genetic Analysis in the Management of Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Journal of the American College of Cardiology 2007: 50(19); 1813-1821. PMID: 17980246