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Hypertrophic Cardiomyopathy: A Clinical, Pathologic and Genetic Diagnosis

Posted April 1, 2007

Nick I. Batalis, MD
CAP Forensic Pathology Resource Committee

Sudden cardiac death (SCD) is a leading cause of death in the United States, accounting for 350,000 to 450,000 deaths each year.1,2 While atherosclerotic disease is the predominant cause of SCD, less common cardiac diseases still account for significant mortality in children, adolescents and younger adults (<40 years–old). In these age groups, deaths due to cardiomyopathies (including arrhythmogenic, dilated, hypertrophic and restrictive) are the leading cause of SCD.1,3 Of the cardiomyopathies, hypertrophic cardiomyopathy (HCM) is the form most notorious for causing SCD, often in young, otherwise healthy, athletes.3 While HCM is a well–known clinicopathologic disease, much has been learned over the past few years about the genetic mutations which lead to clinical disease. This additional information has helped us to further understand the disease and provide better counseling for surviving family members.

HCM is defined as an idiopathic, often asymmetrical, hypertrophy of the left cardiac ventricle and interventricular septum.3,4 Clinical symptoms are nonspecific and may include fatigue, palpitations and syncope, or HCM may tragically present without warning signs as SCD.3,4 HCM can be identified readily at autopsy, grossly by recognizing the pattern of asymmetric, hypertrophic myocardium and microscopically by identifying the classical myofiber disarray.3,4 It is now thought that over 90% of HCM cases are inherited in an autosomal dominant pattern.2,4 To date, HCM has been attributed to over 200 mutations in 10 proteins, though mutations in five cardiac sarcomere proteins, including beta–myosin heavy chain (β–MHC) and myosin binding protein C (MyBP–C), are thought to account for over 75% of cases of HCM.2,4,5

When a diagnosis of HCM is made, current recommendations suggest first–degree relatives initially be screened with echocardiogram and electrocardiogram studies to detect and, if indicated, treat clinically significant disease.3 Alternatively, families may opt for genetic testing, which is more sensitive for identifying individuals with HCM than a clinical evaluation. However, there is no definitive treatment plan for a patient with positive genetic test results for HCM and no clinical, echocardiogram or electrocardiogram, evidence of disease, as some patients with mutations for HCM will never develop severe disease.3 Genetic testing for HCM is not widely performed, but it is available at some commercial and research laboratories; however, the high cost of this labor-intensive testing remains prohibitive.4 One leading laboratory charges $4,150 for a comprehensive panel of eight of the most common mutations causing HCM, although the charge drops to $250 if looking for a single known familial mutation.5 Given the cost of the screening panel, the vast majority of budget conscious hospitals and medical examiner’s offices will not pay for genetic testing that does not aid death certification. In addition, many insurance providers have been reluctant to pay for screening surviving family members. Though the molecular genetic diagnosis of HCM is still in its early stages, as the technology continues to evolve, individual high–risk mutations may be identified, which could dictate prophylactic treatment, surgical and/or medical, or lifestyle modification prior to the clinical disease manifesting itself.

Sudden unexpected deaths in young persons are tragic for families to understand and cope with, but knowing exactly why a family member died can be of great comfort to a family. In the case of HCM and other hereditary cardiac diseases, a definitive diagnosis at autopsy can also provide information that may help detect and prevent similar diseases in surviving family members. It is critical that the pathologist communicate a diagnosis of HCM, made at autopsy or otherwise, to treating clinicians and genetic counselors so that surviving family members can be informed, screened and treated appropriately.4


  1. Ackerman MJ, Tester DJ, Driscoll DJ. Molecular autopsy of sudden unexplained death in the young. Am J Forensic Med Pathol. 2001;22(2):105–111.
  2. Ingles J, Semsarian C. Sudden cardiac death in the young: a clinical genetic approach. Intern Med J. 2007;37(1):32–37.
  3. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, 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.
  4. Murphy RT, Starling RC. Genetics and cardiomyopathy: where are we now? Cleve Clin J Med. 2005;72(6):465–483.
  5. Harvard Medical School Partners Healthcare for Genetics and Genomics Web site. Available at: Accessed March 26, 2007.

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NewsPath® Editor: Megan J. DiFurio, MD, FCAP
This newsletter is produced in cooperation with the College of American Pathologists Public Affairs Committee and may be reproduced in whole or in part as a service to the medical community. Copyright © 2006 by the College of American Pathologists.
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