A 28-year-old male athlete presents to the cardiology clinic for pre-participation screening after a family history of sudden cardiac death in a first-degree relative. His 12-lead ECG shows the pattern marked **B** in the diagram: left ventricular hypertrophy by voltage criteria, deep narrow Q waves in the inferior and lateral leads, and giant negative T-wave inversions (10 mm, dagger-shaped) in the precordial leads V3–V5. Transthoracic echocardiography confirms left ventricular wall thickness of 18 mm at the apex with a left ventricular outflow tract gradient of 35 mmHg at rest. Which of the following genetic mutations is MOST COMMONLY responsible for this clinical presentation?

Question

A 28-year-old male athlete presents to the cardiology clinic for pre-participation screening after a family history of sudden cardiac death in a first-degree relative. His 12-lead ECG shows the pattern marked **B** in the diagram: left ventricular hypertrophy by voltage criteria, deep narrow Q waves in the inferior and lateral leads, and giant negative T-wave inversions (>10 mm, dagger-shaped) in the precordial leads V3–V5. Transthoracic echocardiography confirms left ventricular wall thickness of 18 mm at the apex with a left ventricular outflow tract gradient of 35 mmHg at rest. Which of the following genetic mutations is MOST COMMONLY responsible for this clinical presentation?

Accepted Answer

C. MYH7 (beta-myosin heavy chain) or MYBPC3 (myosin-binding protein C). ## Why MYH7 or MYBPC3 is right

The ECG pattern marked **B** — left ventricular hypertrophy, deep septal Q waves, and giant dagger-shaped T-wave inversions — is the classic electrocardiographic signature of hypertrophic cardiomyopathy (HCM), the most common hereditary cardiac disorder (prevalence 1:500). The clinical presentation (apical HCM variant with wall thickness ≥15 mm, LVOT gradient, and family history of SCD) is pathognomonic for HCM caused by sarcomeric protein mutations. MYH7 (encoding beta-myosin heavy chain) and MYBPC3 (myosin-binding protein C) together account for approximately 70% of all identified HCM mutations and are the most frequent genetic causes. These mutations cause myocyte hypertrophy, myocyte disarray, and interstitial fibrosis, leading to the characteristic ECG findings and hemodynamic obstruction seen in this patient. The AHA/ACC HCM Guidelines 2024 and Maron NEJM 2018 establish MYH7 and MYBPC3 as the predominant sarcomeric genes in HCM.

## Why each distractor is wrong

- **PRKAG2**: This gene encodes the AMP-activated protein kinase regulatory subunit and causes a HCM phenocopy associated with Wolff-Parkinson-White (WPW) preexcitation (marked **D** in the diagram), not the classic HCM ECG pattern shown in **B**. PRKAG2 mutations are rare and account for <5% of HCM cases.
- **LMNA**: Mutations in lamin A/C cause dilated cardiomyopathy with conduction system disease and arrhythmias, not the hypertrophic phenotype with apical wall thickening and the specific ECG pattern of **B**.
- **TNNT2 or TNNI3**: While these genes encoding cardiac troponins are indeed HCM-associated mutations, they account for only a small minority of cases (~5% combined) compared to MYH7 and MYBPC3. They are not the most common genetic cause.

**High-Yield:** HCM = MYH7 or MYBPC3 mutations (70% of cases) → sarcomere dysfunction → LVH + deep Q waves + giant dagger T-waves (especially apical variant) → SCD risk in young athletes.

[cite: AHA/ACC HCM Guidelines 2024; Maron NEJM 2018]

Answer

A. TNNT2 (cardiac troponin T) or TNNI3 (cardiac troponin I)

Answer

B. PRKAG2 (AMP-activated protein kinase regulatory subunit)

Answer

D. LMNA (lamin A/C)

Explanation

Why MYH7 or MYBPC3 is right

Why each distractor is wrong

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