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.

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

1. 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.
2. Ho CY, Day SM, Ashley EA, et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy. Circulation. 2018;138(14):1387-1398.
3. 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.
4. 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.

For the intern

When paged at 3am about a known HCM patient, prioritize acute symptoms. New chest pain or syncope requires immediate ECG, troponin, and evaluation for arrhythmia or ischemia. Sustained palpitations need telemetry review and consideration of atrial fibrillation with stroke risk. Acute dyspnea warrants assessment for heart failure decompensation, but avoid aggressive diuresis in obstructive HCM as preload reduction worsens obstruction. Hypotension in obstructive HCM should never be treated with vasodilators—give fluids and consider phenylephrine if needed. Routine matters like scheduling echocardiography for family screening, discussing genetic testing results, or adjusting beta-blocker doses can wait until morning rounds when the primary team and possibly cardiology can provide continuity.

Common pitfalls

• Treating obstructive HCM like typical heart failure: Aggressive diuresis, ACE inhibitors, and vasodilators worsen LVOT obstruction by reducing preload and afterload. Beta-blockers or calcium channel blockers are first-line.

• Missing phenocopies: Always consider Fabry disease (especially in patients with renal disease or neuropathy), TTR amyloidosis (older adults with carpal tunnel), and Danon disease (young males with pre-excitation). These require completely different treatments like enzyme replacement therapy or tafamidis.

• Assuming negative genetic testing excludes disease: 40-60% of clinical HCM cases remain genotype-negative. Family screening still requires clinical surveillance with serial echocardiography.

• Overlooking TNNT2 mutations: These cause mild hypertrophy but disproportionately high sudden cardiac death risk—don't be falsely reassured by minimal wall thickness.

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