Test ID: PMCMP    
Postmortem Cardiomyopathy Panel

Providing a comprehensive postmortem genetic evaluation in the setting of sudden unexplained death or with a personal or family history suggestive of hereditary cardiomyopathy

Identification of a pathogenic variant in the decedent, which may assist with risk assessment and predictive testing of at-risk family members

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

The following genomic regions are excluded due to lack of coverage by next-generation sequencing:

TTN gene: Chr2(GRCh37):g.179523879-179524002 and Chr2(GRCh37):g.179523712-179523835

MYH6 gene: Chr14(GRCh37):g.23859675-23859246

MYH7 gene: Chr14(GRCh37):g.23889034-23889463

Sudden cardiac death (SCD) is estimated to occur at an incidence of between 50 to 100 per 100,000 individuals in North America and Europe each year, claiming between 250,000 and 450,000 lives in the United States annually. In younger individuals (ages 15-35), the incidence of SCD is between 1 to 2 per 100,000 young individuals. Sudden cardiac death, particularly in young individuals, may suggest an inherited form of heart disease. In some cases of sudden cardiac death, autopsy may identify a structural abnormality such as a form of cardiomyopathy. Postmortem diagnosis of a hereditary cardiomyopathy may assist in confirmation of the cause and manner of death, as well as risk assessment in living family members.

The cardiomyopathies are a group of disorders characterized by disease of the heart muscle. Cardiomyopathies are often caused by inherited, genetic, factors. When the identified structural or functional abnormality observed in a patient cannot be explained by acquired causes, genetic testing is commonly employed to identify a genetic underpinning. Overall, the cardiomyopathies are some of the most common genetic disorders. The inherited forms of cardiomyopathy include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic cardiomyopathy (ARVC or AC), and left ventricular noncompaction (LVNC).

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 (so-called "athlete's heart"). The incidence of HCM in the general population is approximately 1 in 500, and 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 who harbor pathogenic HCM-associated variants, but can cause life-threatening arrhythmias that increase the risk of sudden cardiac death in other individuals.

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 cardiomyopathy (also referred to as arrhythmogenic right ventricular cardiomyopathy/dyplasia) (ARVD or AC) is characterized by 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 AC 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 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 Noonan syndrome. There are a number of disorders with significant phenotypic overlap with Noonan syndrome, including Costello syndrome, cardiofaciocutaneous (CFC) syndrome, and multiple lentigines syndrome (formerly called LEOPARD syndrome). Noonan syndrome 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 disease such as a mitochondrial disorder, a muscular dystrophy, or a metabolic storage disorder. In these cases, heart disease 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, AC, 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 Postmortem Cardiomyopathy Panel

Abbreviations: Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic cardiomyopathy (AC), 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. 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.

Sample Quality:

This test is intended for use when EDTA whole blood is not available and formalin-fixed, paraffin-embedded (FFPE) tissue or blood spots are the only available samples. DNA extracted from FFPE tissue can be degraded, which results in a higher failure rate (approximately 5%) for next-generation sequencing when compared to DNA extracted from whole blood. Due to the quality of DNA extracted from FFPE, the acceptable coverage threshold is lower than that of the equivalent blood assays. Coverage of at least 40X is expected for all regions assessed but may be adjusted on a case-by-case basis at the discretion of the laboratory director. Sanger sequencing may be used in regions that do not achieve this rate of coverage at the discretion of laboratory director. Genomic regions that are not sufficiently covered for analysis and interpretation will be indicated on the laboratory report. Sanger sequencing on DNA extracted from FFPE may also result in quality limitations when compared to testing on DNA extracted from blood.

In addition, FFPE samples older than 10 years have increased failure rates when compared to more recent blocks and are not recommended for testing.

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 used (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 variants 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.

For blood spot sample type: If the patient has had an allogeneic blood or marrow transplant or a recent (ie, <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.

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

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2. Semsarian C, Ingles J: Molecular autopsy in victims of inherited arrhythmias. J Arrhythm 2016;32(5):359-365

3. Stattin EL, Westin IM, Cederquist K, et al: Genetic screening in sudden cardiac death in the young can save future lives. Int J Legal Med 2016;130(1):59-66

4. Hershberger RE, Morales A: Dilated Cardiomyopathy Overview. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle. 1993-2017. Updated 2013 May 9. Accessed 8/29/2017. Available at www.ncbi.nlm.nih.gov/books/NBK1309/

5. Cirino AL, Ho C: Hypertrophic Cardiomyopathy Overview. 2008 Aug 5. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle. 1993-2017. Updated 2014 Jan 16. Accessed 8/29/2017. Available at www.ncbi.nlm.nih.gov/books/NBK1768/

6. 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. 1993-2017. Updated 2014 Jan 9. Accessed 8/29/2017. Available at www.ncbi.nlm.nih.gov/books/NBK1131/

7. Allanson JE, Roberts AE: Noonan Syndrome. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle. 1993-2017. Updated 2011 Aug 4. Accessed 8/29/2017. Available  at www.ncbi.nlm.nih.gov/books/NBK1124/

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

9. 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

10. 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

11. 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
• Hereditary Cardiomyopathies and Arrhythmias: Patient Information
• Informed Consent for Genetic Testing for Deceased Individuals