A 22-year-old college athlete presents with near-syncope during sprinting. His paternal uncle died suddenly at age 35. On examination, a harsh systolic ejection murmur is heard at the left sternal border that increases with Valsalva and standing, but decreases with squatting and hand-grip. Echocardiography demonstrates the structure marked **A** (asymmetric septal hypertrophy with septal thickness 24 mm versus posterior wall 11 mm), systolic anterior motion of the anterior mitral leaflet, and a resting left ventricular outflow tract gradient of 80 mmHg. Which of the following genetic mutations is MOST COMMONLY responsible for this morphologic phenotype of hypertrophic cardiomyopathy?

Question

Accepted Answer

C. Mutation in MYH7 (β-myosin heavy chain) or MYBPC3 (myosin-binding protein C). ## Why MYH7 or MYBPC3 is correct

The structure marked **A** — asymmetric septal hypertrophy — is the hallmark morphologic phenotype of hypertrophic cardiomyopathy (HCM). HCM is an autosomal dominant sarcomeric protein disease, and mutations in MYH7 (β-myosin heavy chain) and MYBPC3 (myosin-binding protein C) account for approximately 70–80% of all HCM cases and are the most common genetic causes. The clinical presentation in this young athlete — dynamic LVOT obstruction with a characteristic murmur that increases with Valsalva and standing — combined with the echocardiographic finding of marked asymmetric septal hypertrophy is pathognomonic for HCM and directly correlates with sarcomeric protein mutations, predominantly MYH7 and MYBPC3 (AHA/ACC HCM Guideline 2020; Maron BJ Review).

## Why each distractor is wrong

- **TNNT2 or TNNI3 mutations**: While these cardiac troponin genes are associated with HCM, they account for only 5–10% of cases and are less common than MYH7/MYBPC3. They do not represent the most common genetic basis for asymmetric septal hypertrophy.
- **TPM1 or ACTC1 mutations**: These tropomyosin and actin mutations are rare causes of HCM, accounting for <5% of cases. They are not the primary genetic drivers of the asymmetric septal hypertrophy phenotype seen in this patient.
- **MYL2 or MYL3 mutations**: Myosin light chain mutations are uncommon causes of HCM and are associated with a minority of cases. They do not represent the most frequent genetic etiology for the morphologic phenotype demonstrated in this patient.

**High-Yield:** MYH7 and MYBPC3 mutations account for ~70–80% of HCM cases; asymmetric septal hypertrophy is the most common morphologic phenotype and is strongly associated with these two genes.

[cite: AHA/ACC HCM Guideline 2020; Maron BJ Review]

Answer

A. Mutation in TPM1 (tropomyosin) or ACTC1 (actin)

Answer

B. Mutation in TNNT2 (cardiac troponin T) or TNNI3 (cardiac troponin I)

Answer

D. Mutation in MYL2 (myosin light chain 2) or MYL3 (myosin light chain 3)

Explanation

Why MYH7 or MYBPC3 is correct

Why each distractor is wrong

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