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Lab for Molecular Medicine Tests
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Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) Gene Tests

DILATED CARDIOMYOPATHY (DCM) GENE TESTS

Gene:

  • ARVD/C Panel: DSP, DSG2, DSC2, PKP2

Methodology: Bi-directional DNA sequencing of
69exons and splice sites for the ARVD/C Panel

Clinical Sensitivity:

  • DSP: ~6-16%
  • DSG2: ~10-12%
  • DSC2: ~1-5%
  • PKP2: ~11-43%

Turn-Around-Times:
  • ARVD/C Panel: 6 weeks
  • All single gene test: 3 weeks (per gene)

Sample Requirements: 7cc's blood in an K3EDTA (purple
top) tube

Costs:

  • ARVD/C Panel: $3,000
  • DSP Gene Sequencing: $1,700
  • DSG2 Gene Sequencing: $1,075
  • DSC2 Gene Sequencing: $1,150
  • PKP2 Gene Sequencing: $1,500
  • Familial mutation test: $250

How to order test |
Resources | Clinical Services

Background:
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is a form of heritable heart disease estimated to affect approximately 1/5,000 individuals in the general population (up to 4/10,000 in some areas). In up to 50% of cases the disease is familial. ARVD/C is characterized by progressive loss of myocytes which are replaced by fatty or fibrofatty tissue predominantly in the right ventricle but over time may also involve the left. The clinical spectrum of ARVD/C is broad and individuals typically present with ventricular tachyarrhythmias and sudden death in young individuals and athletes. ARVD/C is suspected in individuals with arrhythmias, syncope, cardiac arrest, chamber dilatation or wall motion abnormalities. A clinical diagnosis or ARVD/C is difficult to confirm thus in addition to personal and family histories, a combination of noninvasive and invasive tests is needed to make a diagnosis. Noninvasive tests can include a 12-lead electrocardiogram, echocardiogram, cardiac MRI, CT, Holter monitoring, and exercise stress testing. Invasion tests can consist of electrophysiological testing, right ventricular angiography and endomyocardial biopsy from the right ventricular wall. Clinical diagnostic criteria for ARVD/C have been established and abnormalities in cardiac structure and rhythm as well as an individual's family history are taken into account. However, it is difficult to make a clinical diagnosis of ARVD/C given that the first sign of the condition is often sudden cardiac death. Thus, genetic testing to identify at-risk individuals is highly advantageous.

ARVD/C is typically inherited in an autosomal dominant pattern with incomplete penetrance and variable expressivity. Ten loci have been linked to the disease, however, genes for only seven of them have been identified: RYR2 (cardiac ryanodine receptor protein), DSP (desmoplakin), DSG2 (Desmoglein 2), DSC2 (Desmocollin 2), PKP2 (desmosomal protein plakophilin-2), plakoglobin (JUP), and the 5' untranslated region (UTR) of transforming growth factor beta-3 gene (TGF-β3). Recessive mutations have been described for three of the above genes: Homozygous JUP mutations are associated with Naxos syndrome (ARVD/C, palmoplantar keratoderma, wooly hair). In addition, homozygous DSP mutations are associated with Carvajal syndrome, (dilated cardiomyopathy, wooly hair and palmoplantar keratoderma) and Naxos-like disease (ARVD/C, wooly hair and an epidermolytic skin disorder). For a review see Tintelen et al, 2007 (Tiutelen 2007). Awad et al. have reported a homozygous PKP2 mutation in one individual with ARVD/C (Awad et al. 2006).

In addition to confirming the diagnosis of ARVD/C in patients with suspected disease, genetic testing allows for early identification and diagnosis of individuals at greatest risk for developing ARVD/C, prior to the expression of typical clinical manifestations (e.g. ventricular tachyarrhythmias) and sudden death. If a mutation is identified in such a preclinical individual, regular and serial outpatient follow up is indicated. If clinically unaffected members of the family with an identified causal mutation for ARVD/C are found not to carry that mutation (genotype negative), they can be definitely diagnosed as unaffected with ARVD/C and reassured that neither they nor their offspring will be at higher risk compared to the general population to develop the disorder. 

Synonyms (OMIM#107970):
  • ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL

DCM Genetic Tests
  • Direct DNA sequencing will be performed to detect mutations in the genes most commonly associated with ARVD/C:

Gene         Protein OMIM#       Locus      
DSP Desmoplakin (ARVD8) 125647 6p24
DSG2 Desmoglein 2 (ARVD10) 125671 18q12.1-q12.2
DSC2 Desmocollin 2 (ARVD11) 125645 18q12.1
PKP2 Plakophilin 2 (ARVD9) 602861 12p11

Epidemiology:
  • Estimated prevalence of 1/5,000
  • Males and females are affected in equal frequency
  • No known racial predilection

Clinical Manifestations (variable, and may not occur in every patient):
  • Shortness of breath, chest pain, exercise intolerance, edema, syncope, fatigue, dizziness
  • Ventricular tachyarrhythmias
  • Syncope or cardiac arrest
  • Cardiac structure and rhythm abnormalities as seen on noninvasive and invasive testing
  • None

Inheritance Patterns:
Autosomal Dominant (majority of cases; DSP, DSG2, DSC2, PKP2 )
  • The presence of a pathogenic mutation in one copy of the above listed genes is sufficient to cause ARVD/C.
  • Children of an affected individual with an identified pathogenic mutation have a 50% (or 1 in 2) chance of inheriting the same mutation.
  • Reduced penetrance and variable expressivity exists.
  • If parents are not mutation carriers, the risk to have a second affected child is low (<3-4%) but above the population risk because of the possibility of germline mosaicism.

Autosomal Recessive (rare; DSP, PKP2, JUP)
  • The presence of a pathogenic mutation in two copies of the DSP, PKP2, or JUP gene is sufficient to cause ARVD/C (PKP2), Naxos syndrome (JUP), Carvajal syndrome (DSP) and Naxos-like disease (DSP).
  • Each child of a carrier couple is at a 25% (or 1 in 4) chance of inheriting this condition.

Test Indications:
  • Individuals with clinical features of ARVD/C
  • Parents, siblings, and possibly children of a patient diagnosed with a mutation in one of the ARVD/C genes.
  • Prenatal testing when a parent or child is diagnosed with ARVD/C and has an identified ARVD/C gene mutation.

Test Outcomes:
  • The detection of one pathogenic mutation in DSP, DSG2, DSC2 or PKP2, confirms a diagnosis of ARVD/C. If a familial mutation is known, a positive test result confirms the presence of the mutation in an asymptomatic family member.
  • A negative test result should be interpreted with caution. Sequencing does not detect large deletions spanning several exons, or mutations in non-coding regions that could affect expression of these genes. In addition, mutations in other genes not looked at by this test could be responsible for the individual's clinical features.
  • Referral to a cardiology center with expertise in the management of ARVD/C is highly recommended.

Turn-Around-Times:
  • ARVD/C Panel (all four genes): 6 weeks
  • Any single gene test: 3 weeks (per gene)

Methodology: Bi-directional sequence analysis is performed on 69 exons and splice sites in the four genes of the ARVD/C panel. Genes may also be ordered individually. These tests do not detect mutations in non-coding regions that could affect gene expression or deletions encompassing a large portion of the gene.

Analytical Sensitivity: This assay has greater than 99.9% accuracy to detect mutations in the sequence analyzed.

Clinical Sensitivity: The overall detection rate of mutations by screening patients with clinical symptoms and/or features of ARVD/C are:
Gene         Detection Rate
DSP ~6-16% (Pilichou, 2006; Bauce, 2005; Yang, 2006)
DSG2 ~10-12% (Awad, 2006; Syrris, 2007; Pilichou, 2006)
DSC2 ~1-5% (Heuser, 2006; Syrris 2006)
PKP2 ~11-43% (Dalal, 2006; Dalal, 2006; Gerull, 2004; Pilichou, 2006)

Cost and CPT Codes:

ARVD/C Panel (DSP, DSG2, DSC2, PKP2):
  • Cost: $3,000
  • CPT codes: 83891(1), 83894(1), 83898(87), 83904(87), 83909(1), 83912(1)

DSP Gene Sequencing
  • Cost: $1,700
  • CPT codes: 83891(1), 83894(1), 83898(28), 83904(28), 83909(1), 83912(1)

DSG2 Gene Sequencing
  • Cost: $1,075
  • CPT codes: 83891(1), 83894(1), 83898(17), 83904(17), 83909(1), 83912(1)

DSC2 Gene Sequencing
  • Cost: $1,150
  • CPT codes: 83891(1), 83894(1), 83898(18), 83904(18), 83909(1), 83912(1)

PKP2 Gene Sequencing
  • Cost: $1,500
  • CPT codes: 83891(1), 83894(1), 83898(16), 83904(16), 83909(1), 83912(1)

Testing for known familial mutation
  • Cost: $250
  • CPT codes: 83891(1), 83894(1), 83898(1), 83904(1), 83909(1), 83912(1)

References
GeneTests Disease Review for Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant: www.GeneTests.com.

Antoniades L, Tsatsopoulou A, Anastasakis A, Syrris P, Asimaki A, Panagiotakos D, Zambartas C, Stefanadis C, McKenna WJ, Protonotarios N (2006). Arrhythmogenic right ventricular cardiomyopathy caused by deletions in plakophilin-2 and plakoglobin (Naxos disease) in families from Greece and Cyprus: genotype-phenotype relations, diagnostic features and prognosis. Eur Heart J. Sep;27(18):2208-16.

Awad MM, Dalal D, Tichnell C, James C, Tucker A, Abraham T, Spevak PJ, Calkins H, Judge DP (2006). Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2. Hum Mutat. Nov;27(11):1157.

Awad MM, Dalal D, Cho E, Amat-Alarcon N, James C, Tichnell C, Tucker A, Russell SD, Bluemke DA, Dietz HC, Calkins H, Judge DP. (2006). DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am J Hum Genet. Jul;79(1):136-42

Bauce B, Basso C, Rampazzo A, Beffagna G, Daliento L, Frigo G, Malacrida S, Settimo L, Danieli G, Thiene G, Nava A. (2005). Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations. Eur Heart J. Aug;26(16):1666-75.

Dalal D, James C, Devanagondi R, Tichnell C, Tucker A, Prakasa K, Spevak PJ, Bluemke DA, Abraham T, Russell SD, Calkins H, Judge DP (2006). Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol. Oct 3;48(7):1416-24.

Dalal D, Molin LH, Piccini J, Tichnell C, James C, Bomma C, Prakasa K, Towbin JA, Marcus FI, Spevak PJ, Bluemke DA, Abraham T, Russell SD, Calkins H, Judge DP (2006). Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2. Circulation. Apr 4;113(13):1641-9.

Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, MacRae CA, Peters S, Grossmann KS, Drenckhahn J, Michely B, Sasse-Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E, Thierfelder L (2004). Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet. Nov;36(11):1162-4.

Heuser A, Plovie ER, Ellinor PT, Grossmann KS, Shin JT, Wichter T, Basson CT, Lerman BB, Sasse-Klaassen S, Thierfelder L, MacRae CA, Gerull B (2006). Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet. Dec;79(6):1081-8.

Pilichou K, Nava A, Basso C, Beffagna G, Bauce B, Lorenzon A, Frigo G, Vettori A, Valente M, Towbin J, Thiene G, Danieli GA, Rampazzo A (2006). Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation. Mar 7;113(9):1171-9.

Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V, Zimbello R, Simionati B, Basso C, Thiene G, Towbin JA, Danieli GA (2002). Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet. Nov;71(5):1200-6.

Syrris P, Ward D, Evans A, Asimaki A, Gandjbakhch E, Sen-Chowdhry S, McKenna WJ (2006). Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2. Am J Hum Genet. Nov;79(5):978-84.

Syrris P, Ward D, Asimaki A, Evans A, Sen-Chowdhry S, Hughes SE, McKenna WJ (2007). Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease. Eur Heart J. Mar;28(5):581-8.

Yang Z, Bowles NE, Scherer SE, Taylor MD, Kearney DL, Ge S, Nadvoretskiy VV, DeFreitas G, Carabello B, Brandon LI, Godsel LM, Green KJ, Saffitz JE, Li H, Danieli GA, Calkins H, Marcus F, Towbin JA (2006). Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Res. Sep 15;99(6):646-55.



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