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Test Catalog

Test ID: HCMGP    
Hypertrophic 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 hypertrophic cardiomyopathy (HCM)

 

Establishing a diagnosis of a hereditary HCM, 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 tested 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), and left ventricular noncompaction (LVNC).

 

The hereditary form of HCM is characterized by left ventricular hypertrophy in the absence of other cardiac or systemic causes that may cause hypertrophy of the heart muscle, such as longstanding, uncontrolled hypertension or aortic stenosis. The pathological hallmark of HCM is "myocyte disarray" where there is a loss of parallel alignment of myocytes in the heart wall. HCM is most often caused by genes encoding the cardiac sarcomere, the functional contractile unit of the heart muscle. The clinical presentation of HCM can be variable, even within the same family. HCM can be asymptomatic in some individuals, but can cause life-threatening arrhythmias, which increase the risk of sudden cardiac death. The incidence of HCM in the general population is approximately 1 in 500. Inheritance is autosomal dominant, but compound heterozygosity (biallelic variants in the same gene) and digenic inheritance (variants in 2 different HCM-associated genes) do occur.

 

The MYBPC3, MYL2, MYL3, MYH7, ACTC, TPM1, TNNI3, TNNT2, and CAV3 genes are involved in formation and regulation of the cardiac sarcomere, and account for the majority of variants in HCM. Left ventricular hypertrophy can also be caused by metabolic or storage disorders such as Fabry disease (GLA gene), Danon disease (LAMP2 gene), and Wolf-Parkinson-White syndrome associated with variants in the PRKAG2 gene. The TTR gene causes familial transthyretin amyloidosis, which is characterized by buildup of amyloid protein that affects the peripheral and autonomic nervous system. Other nonneuropathic changes may also be involved, including cardiomyopathy. See table for details regarding the genes tested by this panel and associated diseases.

 

Genes included in the Hypertrophic Cardiomyopathy Multi-Gene Panel

Gene

Protein

Inheritance

Disease Association

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

CAV3

Caveolin 3

AD, AR

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

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

GLA

Galactosidase, alpha

X-linked

Fabry disease

LAMP2

Lysosome-associated membrane protein 2

X-linked

Danon disease

MYBPC3

Myosin-binding protein-C, cardiac

AD

HCM, DCM

MYH7

Myosin, heavy chain 7, cardiac muscle, beta

AD

HCM, DCM, LVNC, myopathy

MYL2

Myosin, light chain 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

NEXN

Nexilin

AD

HCM, DCM

PLN

Phospholamban

AD

HCM, DCM

PRKAG2

Protein kinase, amp-activated, noncatalytic, gamma2

AD

HCM, Wolff-Parkinson-White syndrome

RAF1

V-RAF-1 murine leukemia viral oncogene homolog 1

AD

Noonan/multiple lentigines syndrome

TCAP

Titin-cap (telethonin)

AD, AR

HCM, DCM, LGMD

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, myopathy

TTR

Transthyretin

AD

Transthyretin-related amyloidosis

VCL

Vinculin

AD

HCM, DCM

Abbreviations: Congenital heart defects (CHD), long QT syndrome (LQTS), limb-girdle muscular dystrophy (LGMD), 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 hypertrophic 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 hypertrophic 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. 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/

2. 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

3. Marian AJ, Roberts R: Molecular genetics of hypertrophic cardiomyopathy. Ann Rev Med 1995;46:213-222

4. van Rijsingen IA, Hermans-van Ast JF, Arens YH, et al: Hypertrophic cardiomyopathy family with double-heterozygous mutations; does disease severity suggest double heterozygosity? Neth Heart J 2009;17:458-463

5. Woo A, Rakowski H, Liew JC, et al: Mutations of the beta myosin heavy chain gene in hypertrophic cardiomyopathy: critical functional sites determine prognosis. Heart 2003;89:1179-1185

6. Maron BJ, McKenna WJ, Danielson GK, et al: American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2003;42(9):1687-1713

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

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