Residency · Residency · Medical Genetics Genomics
Hypertrophic Cardiomyopathy: Sarcomere Gene Mutations and Screening
Introduction
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, affecting approximately 1 in 500 individuals. Characterized by unexplained left ventricular hypertrophy (LVH), HCM is a leading cause of sudden cardiac death (SCD) in young athletes and a significant contributor to heart failure and arrhythmia across the lifespan. Approximately 40-60% of HCM cases are caused by pathogenic variants in sarcomere protein genes.
Molecular Genetics
Sarcomere Genes
MYH7 (beta-myosin heavy chain) accounts for approximately 25-30% of genotype-positive HCM. MYBPC3 (myosin-binding protein C) is the most common overall, also representing 25-30%. TNNT2 (cardiac troponin T) accounts for approximately 5% and is notable for association with mild hypertrophy but high SCD risk. TNNI3 (cardiac troponin I) contributes approximately 5%, while TPM1 (alpha-tropomyosin) accounts for approximately 2%. MYL2, MYL3 (myosin light chains) and ACTC1 (cardiac actin) are rare causes.
Inheritance and Penetrance
HCM follows autosomal dominant inheritance with age-dependent, incomplete penetrance. Penetrance increases through adolescence, though some mutation carriers never manifest clinical disease. Variable expressivity means that even within families, severity differs significantly. Compound or double heterozygosity is associated with earlier onset and more severe phenotype.
Phenocopies (Non-Sarcomeric HCM)
Several conditions mimic sarcomeric HCM and require different management. Fabry disease (GLA) is an X-linked lysosomal storage disorder. Danon disease (LAMP2) is X-linked and severe. PRKAG2 syndrome involves glycogen storage with pre-excitation. Noonan syndrome and other RASopathies cause HCM in the pediatric population. Amyloidosis (TTR and AL types) represents an acquired or hereditary phenocopy in older adults. Mitochondrial cardiomyopathy from m.3243A>G and other mtDNA mutations must also be considered.
| Gene | Protein | Frequency in HCM | Key Associations | Inheritance |
|---|---|---|---|---|
| MYBPC3 | Myosin-binding protein C | 25–30% | Most common; often later onset; incomplete penetrance | AD |
| MYH7 | Beta-myosin heavy chain | 25–30% | Often earlier onset; more severe in some families | AD |
| TNNT2 | Cardiac troponin T | ~5% | Mild LVH but high SCD risk | AD |
| TNNI3 | Cardiac troponin I | ~5% | Apical and restrictive forms | AD |
| TPM1 | Alpha-tropomyosin | ~2% | Variable | AD |
| ACTC1 | Cardiac actin | Rare | Apical HCM described | AD |
| HCM Phenocopy | Gene | Inheritance | Distinguishing Clues | Specific Treatment |
|---|---|---|---|---|
| Fabry disease | GLA | X-linked | Cornea verticillata; neuropathic pain; renal disease | ERT or chaperone therapy |
| Danon disease | LAMP2 | X-linked | Severe in males; WPW; skeletal myopathy | Transplant |
| PRKAG2 syndrome | PRKAG2 | AD | Pre-excitation (WPW); glycogen-filled vacuoles | Avoid ICD shock programming errors |
| Noonan/RASopathy | PTPN11, RAF1, others | AD | Dysmorphic facies; short stature; pulmonary stenosis | RAS-MAPK pathway inhibitors (emerging) |
| TTR amyloidosis | TTR | AD | Older adults; neuropathy; carpal tunnel | Tafamidis; gene silencing (patisiran, inotersen) |
Pathophysiology
Sarcomere mutations cause hypercontractility and impaired relaxation. Histologically, myocyte disarray, interstitial fibrosis, and small vessel disease are characteristic. Left ventricular outflow tract obstruction (LVOTO) occurs in approximately 70% of patients at rest or with provocation. Diastolic dysfunction leads to heart failure with preserved ejection fraction. The arrhythmogenic substrate created by fibrosis and disarray underlies the risk of ventricular arrhythmias and SCD.
Clinical Presentation
HCM is often asymptomatic and detected incidentally or through family screening. Symptomatic patients may experience dyspnea on exertion, chest pain, palpitations, or syncope. Sudden cardiac death may be the first presentation, particularly in young athletes. Heart failure symptoms develop as either HFpEF or, in late stages, HFrEF with systolic dysfunction. Atrial fibrillation carries increased stroke risk.
Diagnosis
Imaging
Echocardiography demonstrates LV wall thickness of 15 mm or greater (or 13 mm or greater with positive family history), asymmetric septal hypertrophy, systolic anterior motion (SAM) of the mitral valve, and LVOT gradient. Cardiac MRI is superior for apical HCM and assessment of fibrosis by late gadolinium enhancement (LGE), with LGE extent correlating with SCD risk.
Electrocardiography
The ECG is abnormal in approximately 90% of HCM patients, showing LVH voltage criteria, repolarization abnormalities, deep Q waves, and T-wave inversions.
Genetic Testing
Genetic testing is recommended for all clinically diagnosed HCM patients per ACMG/AHA guidelines. A pathogenic sarcomere variant is identified in 40-60% of cases, enabling predictive cascade testing of at-risk family members. Multi-gene HCM panels (10-30+ genes) typically include sarcomere genes and phenocopy genes.
Sudden Cardiac Death Risk Stratification
Risk Factors (AHA/ACC Guidelines)
Major risk factors include personal history of cardiac arrest or sustained ventricular arrhythmia, family history of SCD from HCM, unexplained syncope, massive LVH (wall thickness 30 mm or greater), nonsustained VT on ambulatory monitoring, and abnormal blood pressure response to exercise.
ESC HCM Risk-SCD Calculator
The ESC provides a quantitative 5-year risk assessment incorporating age, wall thickness, left atrial size, LVOT gradient, family history of SCD, NSVT, and syncope. ICD implantation is recommended if 5-year risk is 6% or greater and considered if 4-6%.
Role of Genotype in Risk Assessment
Sarcomere-positive status alone does not independently dictate ICD placement. However, TNNT2 mutations may carry higher arrhythmic risk despite mild hypertrophy, and double or compound mutations confer a higher risk profile. Genotype informs prognosis but is integrated with clinical risk factors.
Family Screening Protocol
Genotype-Positive Families
Predictive genetic testing is offered to all first-degree relatives. Genotype-positive, phenotype-negative individuals undergo echocardiography and ECG every 1-2 years during adolescence and young adulthood, then every 3-5 years. Genotype-negative relatives can be released from clinical surveillance.
Genotype-Negative or Genotype-Unknown Families
All first-degree relatives should undergo clinical screening with echocardiography and ECG. Repeat screening is recommended every 1-2 years in children and adolescents and every 3-5 years in adults. Screening should continue through at least age 50-60 due to late-onset penetrance.
Management
Lifestyle
Competitive sports restriction was historically recommended, though 2024 guidelines take a more nuanced approach. Shared decision-making regarding exercise intensity occurs after comprehensive risk assessment. Adequate hydration and avoidance of dehydration-inducing conditions are advised.
Medical Therapy
Beta-blockers are first-line for symptomatic obstruction. Verapamil or diltiazem is an alternative if beta-blockers are not tolerated. Disopyramide is added for refractory obstruction. Mavacamten, a cardiac myosin inhibitor FDA-approved in 2022, reduces LVOT gradient and improves symptoms. Aficamten is a next-generation myosin inhibitor in clinical development. Vasodilators, high-dose diuretics, and digoxin should be avoided in obstructive HCM.
Interventional Therapies
Septal myectomy is the surgical gold standard for drug-refractory obstruction. Alcohol septal ablation is a percutaneous alternative. ICD implantation provides primary or secondary SCD prevention.
Clinical Pearls
MYBPC3 and MYH7 together account for approximately 50-60% of genotype-positive HCM and should always be included in genetic testing panels. A negative genetic test does not exclude HCM, as 40-60% of clinical HCM is currently genotype-negative. Phenocopies including Fabry disease, amyloidosis, and RASopathies must be excluded because they require fundamentally different management approaches. Mavacamten represents the first disease-specific therapy targeting the underlying sarcomere dysfunction in HCM, marking a paradigm shift from purely symptomatic treatment.
References
- Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy. Circulation. 2020;142(25):e558-e631.
- Ho CY, Day SM, Ashley EA, et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy. Circulation. 2018;138(14):1387-1398.
- Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM). Lancet. 2020;396(10253):759-769.
- Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J. 2014;35(39):2733-2779.