Genetics of Hypertrophic Cardiomyopathy

Introduction

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiovascular diseases, affecting an estimated 1 in 200–500 individuals worldwide. Characterized by unexplained thickening of the heart muscle—most often the interventricular septum—HCM can lead to diastolic dysfunction, outflow tract obstruction, arrhythmias, and sudden cardiac death (SCD).

While the clinical spectrum of HCM ranges from asymptomatic to life-threatening, its foundation lies in genetic mutations affecting cardiac sarcomeric proteins. Since the first discovery of mutations in the β-myosin heavy chain (MYH7) gene in the early 1990s, more than a dozen genes have been implicated, particularly those encoding components of the sarcomere.

This article explores the genetics of HCM, focusing on key mutations, their molecular mechanisms, genotype–phenotype correlations, and implications for diagnosis, prognosis, and therapy.

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Understanding Hypertrophic Cardiomyopathy

HCM is defined by:

• Left ventricular hypertrophy (LVH) in the absence of another cause (e.g., hypertension, aortic stenosis).
• Histological hallmarks: myocyte hypertrophy, myofibrillar disarray, and interstitial fibrosis.
• Clinical consequences: impaired diastolic filling, arrhythmias, ischemia, and SCD.

Importantly, genetic mutations lead to structural and functional changes in sarcomere proteins, resulting in hypercontractility, energy inefficiency, and abnormal myocardial signaling.

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Genetic Basis of HCM

Inheritance Pattern

• HCM is primarily inherited in an autosomal dominant manner.
• A child of an affected individual has a 50% chance of inheriting the mutation.
• Incomplete penetrance and variable expressivity mean not all carriers develop disease, and severity differs widely.

Categories of Genes Involved

1. Sarcomeric Genes (most common)
   • MYH7 (β-myosin heavy chain)
   • MYBPC3 (myosin-binding protein C)
   • TNNT2 (cardiac troponin T)
   • TNNI3 (cardiac troponin I)
   • ACTC1 (cardiac actin)
   • TPM1 (α-tropomyosin)
2. Non-sarcomeric Genes (rare)
   • PRKAG2 (AMPK γ2 subunit)
   • LAMP2 (Danon disease)
   • GLA (Fabry disease)
3. Modifier Genes
   • Influence phenotype severity (e.g., fibrosis, arrhythmias).

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Key Sarcomeric Mutations

1. MYH7 (β-Myosin Heavy Chain)

• Accounts for 25–40% of HCM cases.
• Encodes a motor protein essential for force generation in cardiomyocytes.
• Mutations often cause missense substitutions.

Mechanism:

• Increases ATPase activity → hypercontractility.
• Impaired relaxation → diastolic dysfunction.
• Triggers maladaptive hypertrophy and fibrosis.

Clinical Features:

• Earlier onset of symptoms.
• Higher risk of SCD.
• Severe hypertrophy (≥30 mm).

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2. MYBPC3 (Myosin-Binding Protein C)

• Mutated in 30–40% of HCM patients.
• Encodes a regulatory protein that stabilizes thick filaments and modulates cross-bridge cycling.
• Most mutations are truncating (frameshift, nonsense, splice site).

Mechanism:

• Haploinsufficiency → reduced protein levels.
• Disrupts sarcomere assembly and contractile regulation.

Clinical Features:

• Later onset compared to MYH7 mutations.
• Progressive hypertrophy and heart failure.
• Variable penetrance (some carriers remain asymptomatic).

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3. TNNT2 (Cardiac Troponin T)

• Found in 5–10% of cases.
• Troponin T anchors troponin complex to tropomyosin, regulating calcium-mediated contraction.

Mechanism:

• Alters calcium sensitivity of the contractile apparatus.
• Reduces maximal force generation.
• Triggers compensatory hypertrophy.

Clinical Features:

• Mild hypertrophy but disproportionately high risk of SCD.
• Often associated with lethal arrhythmias in young individuals.

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4. TNNI3 (Cardiac Troponin I)

• Encodes inhibitory subunit of troponin complex.
• Mutations affect calcium sensitivity and relaxation.

Clinical Features:

• Phenotypic diversity: restrictive cardiomyopathy, mild hypertrophy, or severe HCM.
• Associated with arrhythmias and diastolic dysfunction.

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5. ACTC1 (Cardiac Actin)

• Rare (~1–2% of cases).
• Encodes α-cardiac actin, essential for thin filament structure.
• Mutations impair actin-myosin interaction.

Clinical Features:

• Variable penetrance.
• Some patients develop apical HCM.

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6. TPM1 (α-Tropomyosin)

• Found in ~2–3% of HCM patients.
• Mutations alter tropomyosin positioning on actin filaments.

Clinical Features:

• Moderate hypertrophy.
• Arrhythmic risk varies.

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Non-Sarcomeric Genetic Causes of HCM

Although HCM is usually a sarcomere disease, certain storage and metabolic disorders mimic its phenotype.

PRKAG2 Syndrome

• Mutation in γ2 subunit of AMP-activated protein kinase (AMPK).
• Leads to glycogen accumulation in cardiomyocytes.
• Distinct features:
  • Pre-excitation (Wolff–Parkinson–White syndrome).
  • Conduction abnormalities.
  • Concentric hypertrophy.

LAMP2 (Danon Disease)

• X-linked disorder of lysosomal glycogen storage.
• Presents with cardiomyopathy, skeletal myopathy, and cognitive impairment.
• Rapid progression → early death without transplantation.

GLA (Fabry Disease)

• X-linked lysosomal storage disorder due to α-galactosidase A deficiency.
• Accumulation of globotriaosylceramide (Gb3) in myocardium causes hypertrophy.
• Treatable with enzyme replacement therapy.

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Mechanisms Linking Mutations to HCM

1. Hypercontractility
   • Mutations in MYH7 and TNNT2 increase sarcomere tension and calcium sensitivity.
   • Leads to excessive energy consumption and diastolic dysfunction.
2. Haploinsufficiency
   • MYBPC3 truncating mutations reduce protein levels, destabilizing sarcomere function.
3. Altered Calcium Handling
   • Troponin mutations modify calcium sensitivity, impairing relaxation.
4. Energy Deficiency
   • Inefficient ATP utilization → metabolic stress → hypertrophy and fibrosis.
5. Cellular Remodeling
   • Myocyte disarray and interstitial fibrosis provide substrate for arrhythmias.

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Genotype–Phenotype Correlations

• MYH7 mutations: severe hypertrophy, earlier onset, higher SCD risk.
• MYBPC3 mutations: later onset, variable penetrance, progression to HF.
• TNNT2 mutations: mild hypertrophy but high arrhythmic risk.
• Compound or double mutations: more severe phenotype and earlier onset.

Notably, even within families, phenotypic variability exists, highlighting the role of modifier genes, environment, and epigenetics.

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Genetic Testing in HCM

Benefits

• Confirms diagnosis in ambiguous cases.
• Enables cascade screening of relatives.
• Identifies high-risk mutations for prognosis.
• Guides reproductive counseling (preimplantation genetic diagnosis).

Challenges

• Variants of uncertain significance (VUS) complicate interpretation.
• Negative test does not exclude HCM (unknown mutations exist).
• Ethical implications of genetic risk disclosure.

Guidelines

• Testing recommended for all patients with HCM.
• First-degree relatives should undergo genetic or echocardiographic screening.

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Clinical Implications of Genetic Knowledge

1. Risk Stratification for SCD
   • Certain mutations (e.g., TNNT2, MYH7) carry higher risk.
   • May influence decisions about implantable cardioverter-defibrillator (ICD) placement.
2. Therapeutic Strategies
   • Current therapies (β-blockers, calcium channel blockers, septal reduction) treat symptoms, not genetics.
   • Genetic insights are guiding targeted therapies (e.g., myosin inhibitors like mavacamten).
3. Family Screening
   • Identifying mutation carriers allows early monitoring and intervention.

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Emerging Research

• Myosin inhibitors (mavacamten, aficamten): normalize hypercontractility by modulating sarcomere function.
• Gene therapy approaches: correcting MYBPC3 truncating mutations using AAV-mediated delivery.
• RNA-based therapies: antisense oligonucleotides to restore protein expression.
• Precision medicine: tailoring therapy to genetic background.

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Case Studies

Case 1: MYH7 Mutation

• 21-year-old male with family history of SCD.
• Echocardiogram: asymmetric septal hypertrophy (28 mm).
• Genetic test: MYH7 missense mutation.
• Management: β-blockers + ICD for primary prevention.

Case 2: MYBPC3 Mutation

• 45-year-old woman, asymptomatic, diagnosed during family screening.
• Moderate LVH (16 mm).
• Mutation: truncating MYBPC3 variant.
• Long-term follow-up: slow progression, no arrhythmic events.

Case 3: TNNT2 Mutation

• 18-year-old athlete with mild LVH (14 mm).
• No symptoms but strong family history of SCD.
• Genetic testing: TNNT2 mutation.
• ICD implanted despite mild hypertrophy due to high arrhythmic risk.

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Psychosocial and Ethical Considerations

• Anxiety and stigma: Carriers may face psychological stress.
• Insurance discrimination: Genetic results may affect coverage in some countries.
• Reproductive decisions: Couples may opt for genetic counseling or preimplantation genetic testing.
• Informed consent: Essential before testing, especially in children.