Test Id : CCMGP

Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel. See FMTT / Familial Mutation, Targeted Testing, Varies.

1. Hereditary Cardiomyopathies and Arrhythmias: Patient Information (T725) is strongly recommended, but not required, to be filled out and sent with the specimen. This information aids in providing a more thorough interpretation of test results. Ordering providers are strongly encouraged to complete the form and send it with the specimen.

2. Include physician name and phone number with specimen.

3. Prior Authorization is available for this assay. Submit the required form with the specimen.

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: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions: Send specimen in original tube. Do not aliquot.

• Informed Consent for Genetic Testing
• Comprehensive Cardiomyopathy Multi-Gene Panel Prior Authorization Ordering Instructions
• Hereditary Cardiomyopathies and Arrhythmias: Patient Information
• Informed Consent for Genetic Testing (Spanish)

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. Comprehensive Cardiomyopathy Multi-Gene Panel Prior Authorization Ordering Instructions

3. Hereditary Cardiomyopathies and Arrhythmias: Patient Information (T725) is recommended.

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

1 mL

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

Establishing a diagnosis of a hereditary cardiomyopathy and, in some cases, allowing for appropriate management and surveillance for disease features based on the gene involved

Identifying a pathogenic variant within a gene known to be associated with disease that allows for predictive testing of at-risk family members

This test uses next-generation sequencing to test for variants in the ABCC9, ACTC1, ACTN2, ANKRD1, BRAF, CAV3, CBL, CRYAB, CSRP3, DES, DSC2, DSG2, DSP, DTNA, GLA, HRAS, JUP, KRAS, LAMA4, LAMP2, LDB3, LMNA, MAP2K1, MAP2K2, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEXN, NRAS, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SHOC2, SOS1, TAZ, TCAP, TMEM43, TNNC1, TNNI3, TNNT2, TPM1, TTN (excluding the following genomic regions: Chr2(GRCh37):g. 179523879-179524002 and Chr2(GRCh37):g. 179523712-179523835), TTR, and VCL genes.

This test uses Sanger sequencing to test for variants in certain exons of the following genes:

MYH6 exon 26

MYH7 exon 27

Identification of a pathogenic variant may assist with prognosis, clinical management, familial screening, and genetic counseling.

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 inherited, genetic factors or by nongenetic (acquired) causes such as infection or trauma. 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. Overall, the cardiomyopathies are some of the most common genetic disorders. The inherited forms of cardiomyopathy include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC or AC), and left ventricular noncompaction (LVNC).

The hereditary form of HCM is characterized by left ventricular hypertrophy in the absence of other causes, such as structural abnormalities, systemic hypertension, or physiologic hypertrophy due to rigorous athletic training (athlete's heart). The incidence of HCM in the general population is approximately 1 in 500, and the hereditary form is most often caused by variants in genes encoding the components of the cardiac sarcomere. The clinical presentation of HCM can be variable, even within the same family. HCM can be asymptomatic in some individuals but can also cause life-threatening arrhythmias that increase the risk of sudden cardiac death.

DCM is established by the presence of left ventricular enlargement and systolic dysfunction. DCM may present with heart failure with symptoms of congestion, arrhythmias or conduction system disease, or thromboembolic disease (stroke). The incidence of DCM is likely higher than originally reported due to subclinical phenotypes and underdiagnosis, with recent estimates suggesting that DCM affects approximately 1 in every 250 people. After exclusion of nongenetic causes such as ischemic injury, DCM is traditionally referred to as "idiopathic" dilated cardiomyopathy. Approximately 20% to 50% of individuals with idiopathic DCM may have an identifiable genetic cause for their disease. Families with 2 or more affected individuals are diagnosed with familial dilated cardiomyopathy.

Arrhythmogenic right ventricular dysplasia (ARVD or AC) is characterized by breakdown of the myocardium and replacement of the muscle tissue with fibrofatty tissue, resulting in an increased risk of arrhythmia and sudden death. Age of onset and severity are variable, but symptoms typically develop in adulthood. The incidence of ARVC is approximately 1 in 1000 to 1 in 2500.

LVNC is characterized by left ventricular hypertrophy and prominent trabeculations of the ventricular wall, giving a spongy appearance to the muscle wall. It is thought to be caused by the arrest of normal myocardial morphogenesis. Clinical presentation is highly variable, ranging from no symptoms to congestive heart failure and life-threatening arrhythmias. An increased risk of thromboembolic events is also present with LVNC. Approximately 67% of LVNC is considered familial.

Restrictive cardiomyopathy (RCM) is the rarest form of cardiomyopathy and is associated with abnormally rigid ventricular walls. Systolic function can be normal or near normal, but diastolic dysfunction is present. There are several nongenetic causes of RCM, but this condition can be familial as well, with the TNNI3 gene accounting for the majority of inherited cases. The age at presentation for familial RCM ranges from childhood to adulthood, and there is an increased risk of sudden death associated with this condition.

Noonan syndrome (NS) is an autosomal dominant disorder of variable expressivity characterized by short stature, congenital heart defects, and characteristic facial dysmorphology. HCM is present in approximately 20% to 30% of individuals affected with NS. There are a number of disorders with significant phenotypic overlap with NS, including Costello syndrome, cardiofaciocutaneous (CFC) syndrome, and multiple lentigines syndrome (formerly called LEOPARD syndrome). NS and related disorders (also called the RASopathies) are caused by variants in genes involved in the RAS-MAPK signaling pathway. In some cases, variants in these genes may cause cardiomyopathy in the absence of other syndromic features.

Cardiomyopathy may also be caused by an underlying systemic disease such as a mitochondrial disorder, a muscular dystrophy, or a metabolic storage disorder. In these cases, cardiomyopathy may be the first feature to come to attention clinically. The hereditary forms of cardiomyopathy are most frequently associated with an autosomal dominant form of inheritance; however, X-linked and autosomal recessive forms of disease are also present. In some cases, compound heterozygous or homozygous variants may be present in genes typically associated with autosomal dominant inheritance, often leading to a more severe phenotype. Digenic variants (2 different heterozygous variants at separate genetic loci) in autosomal dominant genes have also been reported to occur in patients with severe disease (particularly HCM and ARVC).

The inherited cardiomyopathies display both allelic and locus heterogeneity, whereby a single gene may cause different forms of cardiomyopathy (allelic heterogeneity) and variants in different genes can cause the same form of cardiomyopathy (locus heterogeneity).This comprehensive cardiomyopathy panel includes sequence analysis of 55 genes and may be considered for individuals with HCM, DCM, ARVC, or LVNC, whom have had uninformative test results from a more targeted, disease-specific test. This test may also be helpful when the clinical diagnosis is not clear, or when there is more than 1 form of cardiomyopathy in the family history. It is important to note that the number of variants of uncertain significance detected by this panel may be higher than for the disease-specific panels, making clinical correlation more difficult.

Genes included in this gene panel

Abbreviations: Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), left ventricular noncompaction cardiomyopathy (LVNC), restrictive cardiomyopathy (RCM), limb-girdle muscular dystrophy (LGMD), Emory muscular dystrophy (EMD), congenital heart defect (CHD), sudden infant death syndrome (SIDS), long QT syndrome (LQTS), sick sinus syndrome (SSS), autosomal dominant (AD), autosomal recessive (AR)

An interpretive report will be provided.

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

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 predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Clinical Correlations:

Some individuals who have involvement of 1 or more of the genes on the panel may have a variant that is not identified by the methods performed (eg, promoter variants, deep intronic variants). The absence of a variant, therefore, does not eliminate the possibility of a hereditary cardiomyopathy or a related disorder.

Test results should be interpreted in 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 family history of hereditary cardiomyopathy or a related disorder, it is often useful to first test an affected family member. Identification of a pathogenic variant in an affected individual allows for more informative testing of at-risk individuals.

Technical Limitations:

Next-generation sequencing may not detect all types of genetic variants. Additionally, rare alterations (ie, polymorphisms) may be present that could lead to false-negative or false-positive results. If results do not match clinical findings, consider alternative methods for analyzing these genes, such as Sanger sequencing or large deletion/duplication analysis. If the patient has had an allogeneic blood or marrow transplant or a recent (ie, less than 6 weeks from time of sample collection) heterologous blood transfusion, results may be inaccurate due to the presence of donor DNA.

Reclassification of Variants Policy:

At this time, it is not standard practice for the laboratory to systematically review likely pathogenic variants or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time. Consultation with a genetics professional should be considered for interpretation of this result.

A list of benign and likely benign variants detected for this patient is available from the laboratory upon request.

Contact the laboratory if additional information is required regarding the transcript or human genome assembly used for the analysis of this patient's results.

1. 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

2. Hershberger RE, Morales A: Dilated cardiomyopathy overview. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2007. Updated July 29, 2021. Accessed September 21, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK1309/

3. Cirino AL, Ho C: Hypertrophic cardiomyopathy overview. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2008. Updated July 8, 2021. Accessed September 21, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK1768/

4. McNally E, MacLeod H, Dellefave-Castillo L: Arrhythmogenic right ventricular dysplasia/cardiomyopathy. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2005. Updated May 25, 2017. Accessed June 2018. Available at www.ncbi.nlm.nih.gov/books/NBK1131/

5. Allanson JE, Roberts AE: Noonan syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2001. Updated August 8, 2019. Accessed September 21, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK1124/

6. Ichida F: Left ventricular noncompaction. Circ J. 2009;73(1):19-26

7. Callis TE, Jensen BC, Weck KE, Willis MS: Evolving molecular diagnostics for familial cardiomyopathies: at the heart of it all. Expert Rev Mol Diagn. 2010 April:10;3:329-351

8. Ackerman MJ, Priori SG, Willems S, et al: HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm. 2011;8:1308-1339

9. Hoedemaekers YM, Caliskan K, Michels M, et al: The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. Circ Cardiovasc Genet. 2010;3:232-239

• Informed Consent for Genetic Testing
• Comprehensive Cardiomyopathy Multi-Gene Panel Prior Authorization Ordering Instructions
• Hereditary Cardiomyopathies and Arrhythmias: Patient Information
• Informed Consent for Genetic Testing (Spanish)

Next-generation sequencing (NGS) is performed using an Illumina instrument with paired-end reads. The DNA is prepared for NGS using a custom Agilent SureSelect Target Enrichment System. Data is analyzed with a bioinformatics software pipeline. Supplemental and confirmatory Sanger sequencing are performed when necessary.(Unpublished Mayo method)

Genes analyzed: ABCC9, ACTC1, ACTN2, ANKRD1, BRAF, CAV3, CBL, CRYAB, CSRP3, DES, DSC2, DSG2, DSP, DTNA, GLA, HRAS, JUP, KRAS, LAMA4, LAMP2, LDB3, LMNA, MAP2K1, MAP2K2, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEXN, NRAS, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SHOC2, SOS1, TAZ, TCAP, TMEM43, TNNC1, TNNI3, TNNT2, TPM1, TTN (excluding the following genomic regions: Chr2(GRCh37):g. 179523879-179524002 and Chr2(GRCh37):g. 179523712-179523835), TTR, and VCL.

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

81439

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

Sample Reports

Normal and Abnormal sample reports are provided as references for report appearance.

Normal Reports | Abnormal Reports

SI Sample Reports

International System (SI) of Unit reports are provided for a limited number of tests. These reports are intended for international account use and are only available through MayoLINK accounts that have been defined to receive them.

SI Normal Reports | SI Abnormal Reports