Thompson & Thompson Genetics in Medicine, 8th Edition

Case 25. Hypertrophic Cardiomyopathy (Cardiac Sarcomere Gene Mutations, MIM 192600)

Autosomal Dominant


• Locus heterogeneity

• Age-related penetrance

• Variable expressivity

Major Phenotypic Features

• Age at onset: Adolescence and early adulthood (age 12 to 21 years)

• Left ventricular hypertrophy

• Myocardial crypts or scarring

• Elongated mitral leaflets

• Diastolic dysfunction

• Heart failure

• Sudden death

History and Physical Findings

A 30-year-old healthy man presents to clinic with dyspnea, palpitation, and chest pain. His father has congestive heart failure, and his brother had sudden cardiac death at 18 years of age while practicing football. The cardiologist explained to the patient the possibility of hypertrophic cardiomyopathy running in his family. Cardiac examination showed double apical impulse and laterally displaced, split second heart sound, fourth heart sound present, jugular venous pulse, and double carotid arterial pulse. Echocardiogram showed asymmetrical septal hypertrophy with no structural anomalies, diagnostic of hypertrophic cardiomyopathy. Consistent with his clinical history, physical features, and family history, DNA testing identified an Arg403Gln mutation in MYH7.


Disease Etiology and Incidence

Hypertrophic cardiomyopathy (HCM, MIM 192600), the most common monogenic cardiovascular disease, is an autosomal dominant disorder caused by mutations in approximately 20 genes encoding proteins of the cardiac sarcomere. Of those patients with positive genetic tests, approximately 70% are found to have mutations in the two most common genes, MYH7 and MYBPC3, whereas other genes, including those encoding troponin T, troponin I, Tropomyosin 1, and alpha-actin each account for a small proportion of patients (1% to 5%).


Over 1500 mutations have been reported in genes encoding thick and thin myofilament proteins of the sarcomere or contiguous Z disk. Mutations in several additional sarcomere (or calcium-handling) genes have been proposed, but with less evidence supporting pathogenicity.

Approximately 60% of adult and pediatric patients with a family history of HCM will have a sarcomere mutation identified. In contrast, only approximately 30% of patients without a family history will have positive results, often due to sporadic or de novo mutations (65% of the probands) that may, however be passed on to the next generation. Approximately 3% to 4% of males with HCM will have unrecognized Fabry disease, a lysosomal storage disorder caused by mutations in the α galactosidase A gene.

Phenotype and Natural History

HCM is characterized by left ventricular hypertrophy (LVH) (Fig. C-25) in the absence of predisposing cardiac conditions (e.g., aortic stenosis) or cardiovascular conditions (e.g., long-standing hypertension). The clinical manifestations of HCM range from asymptomatic to progressive heart failure to sudden cardiac death and vary from individual to individual even within the same family. Common symptoms include shortness of breath (particularly with exertion), chest pain, palpitations, orthostasis, presyncope, and syncope. Most often the LVH of HCM becomes apparent during adolescence or young adulthood, although it may also develop late in life, in infancy, or in childhood.


FIGURE C-25 Hypertrophic cardiomyopathy with asymmetric septal hypertrophy. A, The septal muscle bulges into the left ventricular outflow tract, and the left atrium is enlarged. The anterior mitral leaflet has been reflected away from the septum to reveal a fibrous endocardial plaque (arrow) (see text). B, Histological appearance demonstrating myocyte disarray, extreme hypertrophy, and exaggerated myocyte branching, as well as the characteristic interstitial fibrosis (collagen is blue in this Masson trichrome stain). C, Echocardiographic appearance of hypertrophic cardiomyopathy. Parasternal long-axis view from a patient with hypertrophic cardiomyopathy demonstrating asymmetrical septal hypertrophy. The interventricular septum (IVS) measures 2.1 cm (normal 0.6 to 1.0 cm), the posterior wall measures 0.99 cm. Ao, Aorta; LA, left atrium; LV, left ventricle; MV, mitral valve; PW, posterior wall; RV, right ventricle. See Sources & Acknowledgments.


Before identification of the genes responsible for HCM, diagnosis of HCM could only be made through integration of examination, electrocardiogram, echocardiogram, and invasive angiographic/hemodynamic studies, disproportionately identifying patients with left ventricular outflow obstruction. Genetic testing for HCM is now available and can provide important insights into family management by definitively identifying at-risk relatives (i.e., those who have inherited the family's pathogenic mutation). Mutations found are considered pathogenic based on the following criteria: (1) cosegregation with the HCM phenotype in family members; (2) previously reported or identified as a cause of HCM; (3) absent from unrelated and ethnic-matched normal controls; (4) important alteration in protein structure and function; and (5) amino acid sequence change in a region of the protein otherwise highly conserved through evolution. However, even with the use of these criteria, a considerable number of variants are classified as VUSs (see Chapter 16), making the test results ambiguous.

Because diagnosis and sudden cardiac death risk are both linked to the presence of LVH and because the penetrance of LVH is age-dependent, clinical evaluation must continue longitudinally. Screening is annual during adolescence and early adulthood when LVH most commonly emerges. Early childhood screening is appropriate if there is a family history of early-onset disease or other concerns. During adulthood, screening is recommended approximately every 5 years or in response to clinical changes because LVH can develop late in life. The first-line screening consists of clinical testing with cardiac imaging and electrocardiography to identify phenotype-positive relatives. Genetic testing can also be used to identify family members at risk for developing disease who do not have LVH.

No treatments to prevent disease development or to reverse established manifestations currently exist. The treatment of manifestations includes medical management of diastolic dysfunction, medical or surgical management of ventricular outflow obstruction, restoration and maintenance of sinus rhythm in those with atrial fibrillation, implantable cardioverter-defibrillator in survivors of cardiac arrest and those at high risk for cardiac arrest, medical treatment for heart failure, and consideration for cardiac transplantation when necessary. The prevention of secondary complications includes consideration of anticoagulation in those with persistent or paroxysmal atrial fibrillation to reduce the risk for thromboembolism; consideration of antibiotic prophylaxis when necessary; and during the pregnancy of a woman with HCM, care by an experienced cardiologist and obstetrician trained in high-risk obstetrics. Patients should avoid competitive endurance training, burst activities (e.g., sprinting), intense isometric exercise (e.g., heavy weight lifting), dehydration, hypovolemia (i.e., use diuretics with caution), and medications that decrease afterload (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers, and other direct vasodilators). But the consensus recommendations from the 36th Bethesda Conference do not exclude individuals carrying pathogenic mutations but without manifestations of the disease from sports.

Inheritance Risk

HCM follows autosomal dominant inheritance with variable expressivity and incomplete, age-related penetrance; each first-degree relative of an affected patient has a 50% chance of carrying the mutation and potentially developing HCM. Alternatively, sporadic cases may be due to de novo mutations in the proband but absent from the parents.

Disease prevention based on genetic testing is currently available in the form of assisted reproduction using preimplantation genetic diagnosis (PGD) or prenatal diagnosis with pregnancy termination in the event of an affected fetus (see Chapter 17).

Questions for Small Group Discussion

1. Name other disorders that show age-related penetrance. What types of mutations are associated with these disorders?

2. Discuss possible reasons for locus heterogeneity in HCM.

3. What are the criteria to classify a variant as benign?

4. When is genetic testing indicated in a proband with suspected HCM?


Cirino AL, Ho C. Familial hypertrophic cardiomyopathy overview. [Available from]

Ho CY. Genetic considerations in hypertrophic cardiomyopathy. Prog Cardio Dis. 2012;54:456–460.

Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol. 2012;60:705–715.

Maron BJ, Zipes DP. 36th Bethesda Conference: eligibility recommendations for competitive athletes with cardiovascular abnormalities. J Am Coll Cardiol. 2005;45:1312–1375.