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Test Catalog

Test ID: CCMGP    
Comprehensive Cardiomyopathy Multi-Gene Panel, Blood

Useful For Suggests clinical disorders or settings where the test may be helpful

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

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test includes next-generation sequencing and supplemental Sanger sequencing to evaluate the genes on this panel.

 

Prior Authorization is available for this assay; see Special Instructions.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

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 1,000 to 1 in 2,500.

 

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 the Comprehensive Cardiomyopathy Multi-Gene Panel

Gene

Protein

Inheritance

Disease Association

ABCC9

ATP-binding cassette, subfamily C, member 9

AD

DCM, Cantu syndrome

ACTC1

Actin, alpha, cardiac muscle

AD

CHD, DCM, HCM, LVNC

ACTN2

Actinin, alpha-2

AD

DCM, HCM

ANKRD1

Ankyrin repeat domain-containing protein 1

AD

HCM, DCM

BRAF

V-RAF murine sarcoma viral oncogene homolog B1

AD

Noonan/CFC/Costello syndrome

CAV3

Caveolin 3

AD, AR

HCM, LQTS, LGMD, Tateyama-type distal myopathy, rippling muscle disease

CBL

CAS-BR-M murine ecotropic retroviral transforming sequence homolog

AD

Noonan syndrome-like disorder

CRYAB

Crystallin, alpha-B

AD, AR

DCM, myofibrillar myopathy

CSRP3

Cysteine-and glycine-rich protein 3

AD

HCM, DCM

DES

Desmin

AD, AR

DCM, ARVC, myofibrillar myopathy, RCM with AV block, neurogenic scapuloperoneal syndrome Kaeser type, LGMD

DSC2

Desmocollin

AD, AR

ARVC, ARVC + skin and hair findings

DSG2

Desmoglein

AD

ARVC

DSP

Desmoplakin

AD, AR

ARVC, DCM, Carvajal syndrome

DTNA

Dystrobrevin, alpha

AD

LVNC, CHD

GLA

Galactosidase, alpha

X-linked

Fabry disease

HRAS

V-HA-RAS Harvey rat sarcoma viral oncogene homolog

AD

Costello syndrome

JUP

Junction plakoglobin

AD, AR

ARVC, Naxos disease

KRAS

V-KI-RAS2 Kirsten rat sarcoma viral oncogene homolog

AD

Noonan/CFC/Costello syndrome

LAMA4

Laminin, alpha-4

AD

DCM

LAMP2

Lysosome-associated member protein 2

X-linked

Danon disease

LDB3

LIM domain-binding 3

AD

DCM, LVNC, myofibrillar myopathy

LMNA

Lamin A/C

AD, AR

DCM, EMD, LGMD, congenital muscular dystrophy (see OMIM for full listing)

MAP2K1

Mitogen-activated protein kinase kinase 1

AD

Noonan/CFC

MAP2K2

Mitogen-activated protein kinase kinase 2

AD

Noonan/CFC

MYBPC3

Myosin-binding protein-C, cardiac

AD

HCM, DCM

MYH6

Myosin, heavy chain 6, cardiac muscle, alpha

 

HCM, DCM

MYH7

Myosin, heavy chain 7, cardiac muscle, beta

AD

HCM, DCM, LVNC, myopathy

MYL2

Myosin, light cahin 2, regulatory, cardiac, slow

AD

HCM

MYL3

Myosin, light chain 3, alkali, ventricular, skeletal, slow

AD, AR

HCM

MYLK2

Myosin light chain kinase 2

AD

HCM

MYOZ2

Myozenin 2

AD

HCM

MYPN

Myopalladin

AD

HCM, DCM

NEXN

Nexilin

AD

HCM, DCM

NRAS

Neuroblastoma RAS viral oncogene homolog

AD

Noonan syndrome

PKP2

Plakophilin 2

AD

ARVC

PLN

Phospholamban

AD

HCM, DCM

PRKAG2

Protein kinase, AMP-activated, noncatalytic, gamma2

AD

HCM, Wolff-Parkinson-White syndrome

PTPN11

Proetin-tyrosine phosphatase, nonreceptor-type, 11

AD

Noonan/CFC/multiple lentigines syndrome

RAF1

V-RAF-1 murine leukemia viral oncogene homolog 1

AD

Noonan/multiple lentigines syndrome

RBM20

RNA-binding motif protein 20

AD

DCM

RYR2

Ryanodine receptor 2

AD

ARVC, CPVT, LQTS

SCN5A

Sodium channel, voltage gated, type V, alpha subunit

AD

Brugada syndrome, DCM, Heart block, LQTS, SSS, SIDS

SGCD

Sarcoglycan, delta

AD, AR

DCM, LGMD

SHOC2

Suppressor of clear, C. elegans, homolog of

AD

Noonan syndrome-like with loose anagen hair

SOS1

Son of sevenless, dropsophil, homolog 1

AD

Noonan syndrome

TAZ

Tafazzin

X-linked

Barth syndrome, LVNC, DCM

TCAP

Titin-cap (telethonin)

AD, AR

HCM, DCM, LGMD

TMEM43

Transmembrane protein 43

AD

ARVC, EMD

TNNC1

Troponin C, slow

AD

HCM, DCM

TNNI3

Troponin I, cardiac

AD, AR

DCM, HCM, RCM

TNNT2

Troponin T2, cardiac

AD

HCM, DCM, RCM, LVNC

TPM1

Tropomyosin 1

AD

HCM, DCM, LVNC

TTN

Titin

AD, AR

HCM, DCM, ARVC, myopathy

TTR

Transthyretin

AD

Transthyretin-related amyloidosis

VCL

Vinculin

AD

HCM, DCM

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)

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided. 

Interpretation Provides information to assist in interpretation of the test results

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline. 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.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

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 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.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Hershberger RE, Morales A: Dilated Cardiomyopathy Overview. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle. 1993-2018. Updated 2015Sep 24. Accessed June 2018. Available at www.ncbi.nlm.nih.gov/books/NBK1309/

2. Cirino AL, Ho C: Hypertrophic Cardiomyopathy Overview. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle. 1993-2018. Updated 2014 Jan 16. Accessed June 2018. Available at www.ncbi.nlm.nih.gov/books/NBK1768/

3. McNally E, MacLeod H, Dellefave-Castillo L: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle. 1993-2018. Updated 2017 May 25. Accessed June 2018. Available at www.ncbi.nlm.nih.gov/books/NBK1131/

4. Allanson JE, Roberts AE: Noonan Syndrome. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle1993--2018. Updated 2016 Feb 25. Accessed June 2018. Available at www.ncbi.nlm.nih.gov/books/NBK1124/

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

6. 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

7. 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

8. 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

Special Instructions Library of PDFs including pertinent information and forms related to the test