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Invitae Cardiomyopathy Comprehensive Panel
Test description
This test provides a comprehensive analysis of the genes associated with inherited cardiomyopathy conditions. Given the clinical overlap between different cardiomyopathy conditions, comprehensive testing enables a more efficient evaluation of multiple conditions based on a single indication.
Individuals with clinical symptoms of an inherited 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.
Please note that TTN has multiple transcripts. Testing and variant nomenclature for TTN is based on the transcript NM_001267550.2, which includes exons of TTN that are not expressed in the heart. The analysis and interpretation is performed using the clinically-relevant transcript, NM_133378.4, which includes the exons of TTN expressed in the heart.
Genes tested
Primary panel
ABCC9 ACTC1 ACTN2 AGL BAG3 CACNA1C CAV3 CRYAB CSRP3 DES DMD DOLK DSC2 DSG2 DSP EMD EYA4 FHL1 FKRP FKTN FLNC GAA GLA HCN4 JUP LAMP2 LMNA MYBPC3 MYH7 MYL2 MYL3 PKP2 PLN PRKAG2 RAF1 RBM20 RYR2 SCN5A SGCD SLC22A5 TAZ TCAP TMEM43 TNNC1 TNNI3 TNNT2 TPM1 TTN TTR VCL
Add-on Preliminary-evidence Genes for Cardiomyopathy
ANKRD1 CALR3 CHRM2 CTF1 CTNNA3 DTNA FHL2 GATA4 GATA6 GATAD1 ILK JPH2 LAMA4 LDB3 LRRC10 MED12 MYH6 MYLK2 MYOM1 MYOZ2 MYPN NEBL NEXN NKX2-5 NPPA PDLIM3 PLEKHM2 PRDM16 TGFB3 TMPO TXNRD2
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 a gene which does not currently have a definitive clinical association, but which may prove to be clinically significant in the future. This gene can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.
Add-on RASopathy Genes
A2ML1 BRAF CBL HRAS KRAS MAP2K1 MAP2K2 NF1 NRAS PTPN11 RASA1 RIT1 RRAS SHOC2 SOS1 SOS2 SPRED1
Structural heart defects or hypertrophic cardiomyopathy are also a common feature of RASopathy conditions. Clinicians can also choose to include genes associated with RASopathy conditions when placing their order at no additional charge.
Add-on Autosomal Recessive Syndromic Pediatric Cardiomyopathy Genes
ACADVL ALMS1 CPT2 DNAJC19 ELAC2 MTO1 SDHA TMEM70
Genes associated with early-onset cardiomyopathy as part of an autosomal recessive disorder may be included at no additional charge. Clinicians may wish to include these genes for patients who present in infancy or early childhood with clinical features of a multi-system disorder.
Order test
Primary panel (50 genes)
Customized gene selection (0 included, 0 excluded)
ABCC9 ACTC1 ACTN2 AGL BAG3 CACNA1C CAV3 CRYAB CSRP3 DES DMD DOLK DSC2 DSG2 DSP EMD EYA4 FHL1 FKRP FKTN FLNC GAA GLA HCN4 JUP LAMP2 LMNA MYBPC3 MYH7 MYL2 MYL3 PKP2 PLN PRKAG2 RAF1 RBM20 RYR2 SCN5A SGCD SLC22A5 TAZ TCAP TMEM43 TNNC1 TNNI3 TNNT2 TPM1 TTN TTR VCL
Add-on Preliminary-evidence Genes for Cardiomyopathy (31 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 a gene which does not currently have a definitive clinical association, but which may prove to be clinically significant in the future. This gene can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.
ANKRD1 CALR3 CHRM2 CTF1 CTNNA3 DTNA FHL2 GATA4 GATA6 GATAD1 ILK JPH2 LAMA4 LDB3 LRRC10 MED12 MYH6 MYLK2 MYOM1 MYOZ2 MYPN NEBL NEXN NKX2-5 NPPA PDLIM3 PLEKHM2 PRDM16 TGFB3 TMPO TXNRD2
Add-on RASopathy Genes (17 genes)
Customized gene selection (0 included, 0 excluded)
Structural heart defects or hypertrophic cardiomyopathy are also a common feature of RASopathy conditions. Clinicians can also choose to include genes associated with RASopathy conditions when placing their order at no additional charge.
A2ML1 BRAF CBL HRAS KRAS MAP2K1 MAP2K2 NF1 NRAS PTPN11 RASA1 RIT1 RRAS SHOC2 SOS1 SOS2 SPRED1
Add-on Autosomal Recessive Syndromic Pediatric Cardiomyopathy Genes (8 genes)
Customized gene selection (0 included, 0 excluded)
Genes associated with early-onset cardiomyopathy as part of an autosomal recessive disorder may be included at no additional charge. Clinicians may wish to include these genes for patients who present in infancy or early childhood with clinical features of a multi-system disorder.
ACADVL ALMS1 CPT2 DNAJC19 ELAC2 MTO1 SDHA TMEM70
Alternative tests to consider
The Invitae Arrhythmia and Cardiomyopathy Comprehensive panel has been designed to provide a broad genetic analysis of arrhythmia and cardiomyopathy. Depending on the individual’s clinical and family history, this broader panel may be appropriate. This broader panel can be ordered at no additional charge.
Clinical information
Disorders tested
- arrhythmogenic right ventricular cardiomyopathy (ARVC)
- dilated cardiomyopathy (DCM)
- hypertrophic cardiomyopathy (HCM)
- Fabry disease
- left ventricular noncompaction (LVNC)
- transthyretin amyloidosis
- genes on this panel are also associated with other disorders
Clinical description
Cardiomyopathy is a disease of the heart muscle that causes the heart to thicken, enlarge, or become rigid. These changes to the cardiac muscle cause the heart to weaken and may lead to heart failure. Cardiomyopathy can be acquired, often from another type of disease, or it can be inherited. The most common types of inherited cardiomyopathy include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), left ventricular noncompaction (LVNC) and restrictive cardiomyopathy (RCM).
Cardiomyopathy may also be one feature of a multi-system disorder, such as Noonan syndrome, Fabry disease, Barth syndrome, Danon disease, glycogen storage disease, transthyretin amyloidosis, various types of muscular dystrophy or myopathy, or combined oxidative phosphorylation deficiency. Please note that the genes associated with Noonan syndrome and/or autosomal recessive syndromic pediatric cardiomyopathy can be included when placing an order for this test.
Clinical sensitivity
The clinical sensitivity of this test is dependent on the patient’s underlying genetic condition. This test covers all of the common genetic causes of the hereditary cardiomyopathy conditions HCM, DCM, LVNC, and ARVC. For each condition, the chart below shows the percentage of clinical cases in which a pathogenic variant is expected to be identified in one of the genes on this panel.
| Clinical sensitivity by underlying condition | |||
|---|---|---|---|
| ARVC | DCM | HCM | LVNC |
| 50% | 20%-40% | 40%-60% | 20%-30% |
Inheritance
The majority of inherited cardiomyopathy conditions exhibit an autosomal dominant inheritance pattern. Alternate inheritance patterns are listed below.
Autosomal recessive conditions
- 3-methylglutaconic aciduria, type V
- AGL-related glycogen storage disorder
- Alstrom syndrome
- Carvajal syndrome
- combined oxidative phosphorylation deficiency due to ELAC2, MTO1 or SDHA
- CPT II deficiency
- DOLK-related congenital disorder of glycosylation
- Naxos syndrome
- Pompe disease
- primary carnitine deficiency
- TMEM70-related mitochondrial complex V deficiency
- VLCAD deficiency
X-linked conditions
- Barth syndrome
- Danon disease
- Duchenne muscular dystrophy
- Emery-Dreifuss muscular dystrophy
- Fabry disease
Penetrance
Most genetic forms of cardiomyopathy exhibit reduced penetrance, meaning that not everyone who inherits a predisposition to develop cardiomyopathy will go on to manifest the disorder. Individuals with a genetic predisposition to develop cardiomyopathy have an increased risk for cardiomyopathy at any age and frequently present with symptoms at younger ages compared to individuals with acquired cardiomyopathy. Symptoms are variable, even among affected members of the same family.
The age of onset and penetrance of syndromic causes of cardiomyopathy is dependent on the disorder. For example, Barth syndrome and Duchenne or Becker muscular dystrophy commonly present in males in childhood, while cardiomyopathy due to Fabry disease or transthyretin amyloidosis often does not present until mid to late adulthood.
Prevalence/Incidence
The prevalence of genetic forms of cardiomyopathy is dependent on the underlying condition.
| Condition | Estimated prevalence | Additional information |
|---|---|---|
| HCM | ~1 in 500 | Recently, the prevalence has been suggested to be as high as 1 in 200 individuals. |
| DCM | ~1 in 2,500 to 1 in 3,000 | |
| ARVC | ~1 in 2,000 to ~1:5,000 | 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 test may be considered for individuals with:
- unexplained cardiomyopathy
- cardiomyopathy that may be consistent with multiple genetic cardiomyopathy conditions
References
- Semsarian C, et al. New perspectives on the prevalence of hypertrophic cardiomyopathy. 2015 J Am Coll Cardiol. Mar 31;65(12):1249-1254. PMID: 25814232
- January CT, et al. AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. 2014 J Am Coll Cardiol. Dec; 2:64(21):e1-76. PMID: 24685669
- 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
- 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
- Pugh TJ, et al. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. 2014 Genet Med Aug; 16(8):601-608. PMID: 24503780
- 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
- McNally EM, et al. Genetic mutations and mechanisms in dilated cardiomyopathy. 2013 J Clin Invest. Jan;123(1):19-26. PMID: 23281406
- NCBI GeneReviews. Hypertrophic Cardiomyopathy Overview. PMID: 20301725
- Hoedemaekers YM, et al. The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. 2010 Circ Cardiovasc Genet Jun;3(3):232-239 PMID: 20530761
- Hershberger, RE, Morales, A. Dilated Cardiomyopathy Overview. 2007 Jul 27. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301486
- 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
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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
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 |
|---|---|---|---|
| A2ML1 | NM_144670.4 | ||
| ABCC9 | NM_005691.3 | ||
| ACADVL | NM_000018.3 | ||
| ACTC1 | NM_005159.4 | ||
| ACTN2 | NM_001103.3 | ||
| AGL | NM_000642.2 | ||
| ALMS1 | NM_015120.4 | ||
| ANKRD1* | NM_014391.2 | ||
| BAG3 | NM_004281.3 | ||
| BRAF | NM_004333.4 | ||
| CACNA1C | NM_000719.6; NM_001129840.1 | ||
| CALR3 | NM_145046.4 | ||
| CAV3 | NM_033337.2 | ||
| CBL | NM_005188.3 | ||
| CHRM2 | NM_000739.2 | ||
| CPT2 | NM_000098.2 | ||
| CRYAB | NM_001885.2 | ||
| CSRP3 | NM_003476.4 | ||
| CTF1* | NM_001330.3 | ||
| CTNNA3 | NM_013266.3 | ||
| DES | NM_001927.3 | ||
| DMD | NM_004006.2 | ||
| DNAJC19 | NM_145261.3 | ||
| DOLK | NM_014908.3 | ||
| DSC2 | NM_024422.4 | ||
| DSG2 | NM_001943.3 | ||
| DSP | NM_004415.2 | ||
| DTNA | NM_032978.6 | ||
| ELAC2 | NM_018127.6 | ||
| EMD | NM_000117.2 | ||
| EYA4 | NM_004100.4 | ||
| FHL1 | NM_001449.4 | ||
| FHL2 | NM_201555.1 | ||
| FKRP | NM_024301.4 | ||
| FKTN | NM_001079802.1 | ||
| FLNC | NM_001458.4 | ||
| GAA | NM_000152.3 | ||
| GATA4 | NM_002052.3 | ||
| GATA6 | NM_005257.5 | ||
| GATAD1 | NM_021167.4 | ||
| GLA | NM_000169.2 | ||
| HCN4 | NM_005477.2 | ||
| HRAS | NM_005343.2 | ||
| ILK | NM_004517.3 | ||
| JPH2 | NM_020433.4 | ||
| JUP | NM_002230.2 | ||
| KRAS | NM_004985.4 | ||
| LAMA4 | NM_002290.4 | ||
| LAMP2 | NM_002294.2 | ||
| LDB3 | NM_001080116.1; NM_001171610.1; NM_007078.2 | ||
| LMNA | NM_170707.3 | ||
| LRRC10 | NM_201550.3 | ||
| MAP2K1 | NM_002755.3 | ||
| MAP2K2 | NM_030662.3 | ||
| MED12 | NM_005120.2 | ||
| MTO1 | NM_012123.3 | ||
| MYBPC3* | NM_000256.3 | ||
| MYH6 | NM_002471.3 | ||
| MYH7 | NM_000257.3 | ||
| MYL2 | NM_000432.3 | ||
| MYL3 | NM_000258.2 | ||
| MYLK2 | NM_033118.3 | ||
| MYOM1 | NM_003803.3 | ||
| MYOZ2 | NM_016599.4 | ||
| MYPN | NM_032578.3 | ||
| NEBL | NM_006393.2 | ||
| NEXN | NM_144573.3 | ||
| NF1 | NM_000267.3 | ||
| NKX2-5 | NM_004387.3 | ||
| NPPA | NM_006172.3 | ||
| NRAS | NM_002524.4 | ||
| PDLIM3 | NM_014476.5 | ||
| PKP2 | NM_004572.3 | ||
| PLEKHM2 | NM_015164.2 | ||
| PLN | NM_002667.3 | ||
| PRDM16 | NM_022114.3 | ||
| PRKAG2 | NM_016203.3 | ||
| PTPN11 | NM_002834.3 | ||
| RAF1 | NM_002880.3 | ||
| RASA1 | NM_002890.2 | ||
| RBM20 | NM_001134363.2 | ||
| RIT1 | NM_006912.5 | ||
| RRAS | NM_006270.4 | ||
| RYR2 | NM_001035.2 | ||
| SCN5A | NM_198056.2 | ||
| SDHA* | NM_004168.3 | ||
| SGCD | NM_000337.5 | ||
| SHOC2 | NM_007373.3 | ||
| SLC22A5 | NM_003060.3 | ||
| SOS1 | NM_005633.3 | ||
| SOS2 | NM_006939.2 | ||
| SPRED1 | NM_152594.2 | ||
| TAZ | NM_000116.4 | ||
| TCAP | NM_003673.3 | ||
| TGFB3 | NM_003239.3 | ||
| TMEM43 | NM_024334.2 | ||
| TMEM70 | NM_017866.5 | ||
| TMPO | NM_003276.2 | ||
| TNNC1 | NM_003280.2 | ||
| TNNI3 | NM_000363.4 | ||
| TNNT2 | NM_001001430.2 | ||
| TPM1 | NM_001018005.1 | ||
| TTN* | NM_001267550.2 | ||
| TTR | NM_000371.3 | ||
| TXNRD2 | NM_006440.4 | ||
| VCL | NM_014000.2 |
ANKRD1: Deletion/duplication analysis is not offered for exons 3 or 4.
CTF1: Deletion/duplication and sequencing analysis are not offered for exon 1.
MYBPC3: Analysis includes the intronic variant NM_000256.3:c.3628-41_3628-17del25.
SDHA: Deletion/duplication analysis is not offered for this gene. Sequencing analysis for exons 6-8, 14 includes only cds +/- 10 bp.
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
- Hershberger, RE, Morales, A. Dilated Cardiomyopathy Overview. 2007 Jul 27. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301486
- Hoedemaekers YM, et al. The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. 2010 Circ Cardiovasc Genet Jun;3(3):232-239 PMID: 20530761
- January CT, et al. AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. 2014 J Am Coll Cardiol. Dec; 2:64(21):e1-76. PMID: 24685669
- McNally EM, et al. Genetic mutations and mechanisms in dilated cardiomyopathy. 2013 J Clin Invest. Jan;123(1):19-26. PMID: 23281406
- 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. Hypertrophic Cardiomyopathy Overview. PMID: 20301725
- 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
- Pugh TJ, et al. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. 2014 Genet Med Aug; 16(8):601-608. PMID: 24503780
- Semsarian C, et al. New perspectives on the prevalence of hypertrophic cardiomyopathy. 2015 J Am Coll Cardiol. Mar 31;65(12):1249-1254. PMID: 25814232
