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Invitae Arrhythmogenic Cardiomyopathy Panel
Test description
The Invitae Arrhythmogenic Cardiomyopathy Panel provides a comprehensive analysis of the genes associated with inherited cardiomyopathy conditions that have a prominent arrhythmia phenotype or that may present with arrhythmia prior to the development of cardiomyopathy. Given the clinical overlap between different arrhythmogenic cardiomyopathy conditions, comprehensive testing enables a more efficient evaluation of multiple conditions based on a single indication for testing.
Individuals with clinical symptoms of arrhythmogenic cardiomyopathy may benefit from diagnostic genetic testing to establish or confirm diagnosis, clarify risks, or inform management. Asymptomatic individuals within a family with a known pathogenic variant may also benefit by avoiding activities and medications that can trigger symptoms.
Genes tested
Primary panel
ACTN2 DES DSC2 DSG2 DSP EMD FLNC JUP LMNA PKP2 PLN PRKAG2 RBM20 RYR2 SCN5A TMEM43 TNNI3 TNNT2 TTN
Add-on Preliminary-evidence Genes for Arrhythmogenic Cardiomyopathy
ANKRD1 CTNNA3 LDB3 PDLIM3 TGFB3
Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.
Order test
Primary panel (19 genes)
Customized gene selection (0 included, 0 excluded)
ACTN2 DES DSC2 DSG2 DSP EMD FLNC JUP LMNA PKP2 PLN PRKAG2 RBM20 RYR2 SCN5A TMEM43 TNNI3 TNNT2 TTN
Add-on Preliminary-evidence Genes for Arrhythmogenic Cardiomyopathy (5 genes)
Customized gene selection (0 included, 0 excluded)
Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.
ANKRD1 CTNNA3 LDB3 PDLIM3 TGFB3
Alternative tests to consider
ARVC can also be ordered as part of broader panels to test for cardiomyopathy and arrhythmia disorders. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. Any of these broader panels can be ordered at no additional charge.
Clinical information
Disorders tested
- arrhythmogenic right ventricular cardiomyopathy (ARVC)
- a subset of the genes associated with dilated cardiomyopathy (DCM)
- a subset of the genes associated with hypertrophic cardiomyopathy (HCM)
- genes on this panel are also associated with other disorders
Clinical description
Arrhythmogenic right ventricular cardiomyopathy (ARVC)
Arrhythmogenic right ventricular cardiomyopathy is characterized by progressive fibrofatty replacement of the myocardium. This fibrofatty replacement typically affects the right ventricle and may progressively affect the left ventricle. However, it can also present primarily in the left ventricle and resemble dilated cardiomyopathy. Ventricular tachycardia and risk of sudden cardiac arrest or death may occur with minimal or absence of cardiomyopathy.
Arrhythmia and cardiomyopathy
Arrhythmia may present with or without cardiomyopathy, a disease of the heart muscle. Some individuals who have a genetic predisposition for a primary arrhythmia condition will only develop arrhythmia. Other individuals who have a genetic predisposition for a primary arrhythmia condition develop chronic arrhythmia which can lead to cardiomyopathy. Finally, some individuals who have a genetic predisposition for a primary cardiomyopathy condition present with arrhythmia before cardiomyopathy is apparent.
Clinical sensitivity
Analysis of the genes on this panel is expected to identify a pathogenic variant in approximately 50% of ARVC cases, with four desmosomal genes (PKP2, DSC2, DSG2, DSP) causing the majority of these cases.
Inheritance
ARVC is most commonly inherited as an autosomal dominant disorder. Several studies have found compound heterozygosity or digenic inheritance in a significant proportion of individuals with ARVC.
ARVC due to Naxos disease or Carvajal syndrome is autosomal recessive. Emery-Dreifuss muscular dystrophy is an X-linked disorder.
Penetrance
ARVC exhibits reduced penetrance, meaning not everyone who inherits a predisposition to develop ARVC will go on to manifest symptoms. The age of onset is variable, with symptoms commonly presenting in late childhood through early adulthood. Strenuous exercise has been associated with disease progression. Naxos disease and Carvajal syndrome have higher penetrance, with most individuals developing signs and symptoms during their lifetime and often at young ages.
Prevalence/Incidence
The prevalence of ARVC affects an estimated 1 in 2,000 to 1 in 5,000 individuals. The prevalence is increased in Italy and Greece, where it can be as high as 1 in 125 to 1 in 250.
Considerations for testing
This panel may be considered for individuals with:
- A clinical diagnosis of ARVC meeting Task Force criteria3
- Arrhythmia with nonspecific cardiomyopathy
References
- Pinamonti B, et al. Arrhythmogenic right ventricular cardiomyopathy: From genetics to diagnostic and therapeutic challenges. 2014 World J Cardiol. Dec 26:6(12):1234-44. PMID: 25548613
- Priori, SG, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of individuals with inherited primary arrhythmia syndromes. 2013. Heart Rhythm, Dec;10(12):e85-108. PMID: 23916535
- Ackerman MJ, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). 2011 Heart Rhythm Aug; 8(8):1308-1339. PMID: 21787999
- Hershberger RE, et al. Genetic evaluation of cardiomyopathy--a Heart Failure Society of America practice guideline. 2009 J Card Fail. Mar; 15(2):83-97. PMID: 19254666
- Saguner AM, et al. Arrhythmogenic ventricular cardiomyopathy: A paradigm shift from right to biventricular disease. 2014 World J Cardiol. Apr 26;6(4):154-174. PMID: 24772256
- Marcus FI, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. 2010 Eur Heart J Apr 31(7):806-814. PMID: 20172912
- Saberniak J, et al. Vigorous physical activity impairs myocardial function in patients with arrhythmogenic right ventricular cardiomyopathy and in mutation positive family members. Eur J Heart Fail. 2014 Dec; 16(12):1337-1344. PMID: 25319773
- McNally, E, et al. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. 2005 Apr 18. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1131/ PMID: 20301310
- NCBI GeneReviews. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy.
Management guidelines
For links to published management guidelines for cardiology conditions, please refer to our Management guidelines page.
Assay
Assay and technical information
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
| Gene | Transcript reference | Sequencing analysis | Deletion/Duplication analysis |
|---|---|---|---|
| ACTN2 | NM_001103.3 | ||
| ANKRD1* | NM_014391.2 | ||
| CTNNA3 | NM_013266.3 | ||
| DES | NM_001927.3 | ||
| DSC2 | NM_024422.4 | ||
| DSG2 | NM_001943.3 | ||
| DSP | NM_004415.2 | ||
| EMD | NM_000117.2 | ||
| FLNC | NM_001458.4 | ||
| JUP | NM_002230.2 | ||
| LDB3 | NM_001080116.1; NM_001171610.1; NM_007078.2 | ||
| LMNA | NM_170707.3 | ||
| PDLIM3 | NM_014476.5 | ||
| PKP2 | NM_004572.3 | ||
| PLN | NM_002667.3 | ||
| PRKAG2 | NM_016203.3 | ||
| RBM20 | NM_001134363.2 | ||
| RYR2 | NM_001035.2 | ||
| SCN5A | NM_198056.2 | ||
| TGFB3 | NM_003239.3 | ||
| TMEM43 | NM_024334.2 | ||
| TNNI3 | NM_000363.4 | ||
| TNNT2 | NM_001001430.2 | ||
| TTN* | NM_001267550.2 |
ANKRD1: Deletion/duplication analysis is not offered for exons 3 or 4.
TTN: Deletion/duplication and sequencing analysis is not offered for exons 153-155 (NM_133378.4). Variants are named relative to the NM_001267550.2 (meta) transcript, but only variants in the coding sequence and intronic boundaries of the clinically relevant NM_133378.4 (N2A) isoform are reported (PMID: 25589632).
References
- Ackerman MJ, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). 2011 Heart Rhythm Aug; 8(8):1308-1339. PMID: 21787999
- Hershberger RE, et al. Genetic evaluation of cardiomyopathy--a Heart Failure Society of America practice guideline. 2009 J Card Fail. Mar; 15(2):83-97. PMID: 19254666
- Marcus FI, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. 2010 Eur Heart J Apr 31(7):806-814. PMID: 20172912
- McNally, E, et al. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. 2005 Apr 18. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1131/ PMID: 20301310
- NCBI GeneReviews. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy.
- Pinamonti B, et al. Arrhythmogenic right ventricular cardiomyopathy: From genetics to diagnostic and therapeutic challenges. 2014 World J Cardiol. Dec 26:6(12):1234-44. PMID: 25548613
- Priori, SG, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of individuals with inherited primary arrhythmia syndromes. 2013. Heart Rhythm, Dec;10(12):e85-108. PMID: 23916535
- Saberniak J, et al. Vigorous physical activity impairs myocardial function in patients with arrhythmogenic right ventricular cardiomyopathy and in mutation positive family members. Eur J Heart Fail. 2014 Dec; 16(12):1337-1344. PMID: 25319773
- Saguner AM, et al. Arrhythmogenic ventricular cardiomyopathy: A paradigm shift from right to biventricular disease. 2014 World J Cardiol. Apr 26;6(4):154-174. PMID: 24772256
