Test Id : ARVGG

This test is intended for genetic screening for and diagnosis of arrhythmogenic cardiomyopathy.

Specimen preferred to arrive within 96 hours of collection.

Prior Authorization is available, but not required, for this test. If proceeding with the prior authorization process, submit the required form with the specimen.

Specimen Type: Whole blood

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood

2. Send whole blood specimen in original tube. Do not aliquot.

Specimen Stability Information: Ambient (preferred)/Refrigerated

• Informed Consent for Genetic Testing
• Hereditary Cardiomyopathies and Arrhythmias: Patient Information
• Informed Consent for Genetic Testing (Spanish)
• Targeted Genes and Methodology Details for Arrhythmogenic Cardiomyopathy Gene Panel
• Arrhythmogenic Cardiomyopathy Gene Panel (ARVGG) Prior Authorization Ordering Instructions

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing (Spanish) (T826)

2. Hereditary Cardiomyopathies and Arrhythmias: Patient Information

3. Arrhythmogenic Cardiomyopathy Gene Panel (ARVGG) Prior Authorization Ordering Instructions

4. If not ordering electronically, complete, print, and send a Cardiovascular Test Request (T724) with the specimen.

1 mL

Providing a genetic evaluation for patients with a personal or family history suggestive of a hereditary form of arrhythmogenic cardiomyopathy

Establishing a diagnosis of a hereditary form of arrhythmogenic cardiomyopathy

This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 18 genes associated with hereditary forms of arrhythmogenic cardiomyopathy: CDH2, DES, DSC2, DSG2, DSP, EMD, FLNC, JUP, LMNA, NKX2-5, PKP2, PLN, PPA2, PRKAG2, RBM20, RYR2, TMEM43, and TTN. See Targeted Genes and Methodology Details for Arrhythmogenic Cardiomyopathy Gene Panel and Method Description for additional details.

Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, familial screening, and genetic counseling for hereditary forms of arrhythmogenic cardiomyopathy.

Prior Authorization is available for this assay.

The cardiomyopathies are a group of disorders characterized by disease of the heart muscle. Cardiomyopathy can be caused by either inherited, genetic factors or by nongenetic (acquired) causes such as infection or inflammation.(1)

When the presence or severity of the cardiomyopathy observed in a patient cannot be explained by acquired causes, genetic testing for the inherited forms of cardiomyopathy may be considered.

Arrhythmogenic cardiomyopathy (ACM) is characterized by the presence of arrhythmogenic cardiac muscle in the absence of ischemic, hypertensive, or valvular cardiac disease. Arrhythmogenic right ventricular cardiomyopathy (ARVC), the most well-defined form of ACM, is characterized by breakdown of the myocardium and replacement of right ventricular muscle tissue with fibrofatty tissue, resulting in an increased risk of arrhythmia and sudden death. In some cases, there may also be left ventricular involvement. The prevalence of ARVC (genetic and acquired) is estimated to be 1 in 2000 to 1 in 5000 in the general population.(2)

The clinical presentation of ACM can be variable, even within the same family. Overt symptoms such as palpitations, ventricular arrythmias, structural heart changes, and sudden cardiac arrest typically manifest in adulthood, but more subtle symptoms may be present in childhood.(2) Additionally, ACM may be apparently asymptomatic in some individuals, but can cause sudden, life-threatening arrhythmias, increasing the risk of sudden cardiac death.(1)

Hereditary forms of ACM primarily follow an autosomal dominant pattern of inheritance. Rarely, ACM may be present as a feature of an autosomal recessive condition (eg, Naxos syndrome, Carvajal syndrome, or myofibrillar myopathy).(1) Cardiomyopathy in combination with cardiac arrhythmia is also common in the X-linked condition Emery-Dreifuss muscular dystrophy.(3)

An interpretive report will be provided.

All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(4) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Clinical Correlations:

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

If testing was performed because of a clinically significant family history, it is often useful to first test an affected family member. Detection of a reportable variant in an affected family member would allow for more informative testing of at-risk individuals.

To discuss the availability of additional testing options or for assistance in the interpretation of these results, contact the Mayo Clinic Laboratories genetic counselors at 800-533-1710.

Technical Limitations:

Next-generation sequencing may not detect all types of genomic variants. In rare cases, false-negative or false-positive results may occur. The depth of coverage may be variable for some target regions; assay performance below the minimum acceptable criteria or for failed regions will be noted. Given these limitations, negative results do not rule out the diagnosis of a genetic disorder. If a specific clinical disorder is suspected, evaluation by alternative methods can be considered.

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. Confirmation of select reportable variants will be performed by alternate methodologies based on internal laboratory criteria.

This test is validated to detect 95% of deletions up to 75 base pairs (bp) and insertions up to 47 bp. Deletions-insertions (delins) of 40 or more bp, including mobile element insertions, may be less reliably detected than smaller delins.

Deletion/Duplication Analysis:

This analysis targets single and multi-exon deletions/duplications; however, in some instances single exon resolution cannot be achieved due to isolated reduction in sequence coverage or inherent genomic complexity. Balanced structural rearrangements (such as translocations and inversions) may not be detected.

This test is not designed to detect low levels of mosaicism or to differentiate between somatic and germline variants. If there is a possibility that any detected variant is somatic, additional testing may be necessary to clarify the significance of results.

Genes may be added or removed based on updated clinical relevance. Refer to the Targeted Genes and Methodology Details for Arrhythmogenic Cardiomyopathy Gene Panel for the most up to date list of genes included in this test. For detailed information regarding gene specific performance and technical limitations, see Method Description or contact a laboratory genetic counselor.

If the patient has had an allogeneic hematopoietic stem cell transplant or a recent blood transfusion, results may be inaccurate due to the presence of donor DNA. Call Mayo Clinic Laboratories for instructions for testing patients who have received a bone marrow transplant.

Reclassification of Variants:

At this time, it is not standard practice for the laboratory to systematically review previously classified variants on a regular basis. The laboratory encourages healthcare providers to contact the laboratory at any time to learn how the classification of a particular variant may have changed over time.

Variant Evaluation:

Evaluation and categorization of variants are performed using published American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations as a guideline.(4) Other gene-specific guidelines may also be considered. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Variants classified as benign or likely benign are not reported.

Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and periodic updates to these tools may cause predictions to change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Rarely, incidental or secondary findings may implicate another predisposition or presence of active disease. Incidental findings may include, but are not limited to, results related to the sex chromosomes. These findings will be carefully reviewed to determine whether they will be reported.

1. Towbin JA, McKenna WJ, Abrams DJ, et al: 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. 2019 Nov;16(11):e301-e372. doi: 10.1016/j.hrthm.2019.05.007

2. Corrado D, Link MS, Calkins H: Arrhythmogenic right ventricular cardiomyopathy. N Engl J Med. 2017 Jan;376(1):61-72. doi: 10.1056/NEJMra1509267

3. Bonne G, Leturcq F, Ben Yaou R: Emery-Dreifuss Muscular Dystrophy. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2004. Updated August 15, 2019. Accessed July 14, 2022. Available at www.ncbi.nlm.nih.gov/books/NBK1436/

4. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424

Next-generation sequencing (NGS) and/or Sanger sequencing is performed to test for the presence of variants in coding regions and intron/exon boundaries of the genes analyzed, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletions-insertions (delins) less than 40 base pairs (bp), above 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction-based quantitative method is performed to test for the presence of deletions and duplications in the genes analyzed.

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• Prospective clients should contact their account representative. For assistance, contact Customer Service.

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

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Insurance preauthorization is available for this testing; forms are available.

Patient financial assistance may be available to those who qualify. Patients who receive a bill from Mayo Clinic Laboratories will receive information on eligibility and how to apply.