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Double Sarcomeric Mutations in HCM — EECC MCQ

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HardCardiomyopathyDouble Sarcomeric Mutations in HCMEECC

A 55-year-old man with known HCM develops progressive dyspnoea. Echocardiography shows LVEF 35% (previously 65%), LV cavity dilatation, and thinning of previously hypertrophied segments. Genetic testing confirms a double sarcomeric mutation (MYH7 + MYBPC3). What does the double mutation imply?

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Correct answer: E — Compound or double sarcomeric mutations are associated with earlier disease onset, more severe phenotype, higher risk of SCD, and greater likelihood of progression to the end-stage (burnout) HCM phase with systolic dysfunction

Approximately 5-10% of HCM patients carry compound (homozygous or compound heterozygous) or double (digenic) sarcomeric mutations. The 2023 ESC Cardiomyopathy Guidelines recognise these as high-risk genetic profiles associated with: (1) earlier onset (childhood/adolescence); (2) more severe hypertrophy; (3) higher SCD risk; (4) greater likelihood of end-stage (burnout) progression with LV systolic failure; (5) higher event rates than single mutation carriers. This patient's progression to burnout HCM with double mutation is consistent with this genotype-phenotype correlation. Management includes: aggressive GDMT for HF, ICD assessment (SCD risk is high), and early transplant referral if refractory. Cascade genetic testing of family members should account for the possibility of compound mutations.

Reference: ESC (2023): Guidelines on Cardiomyopathies