TNNT2 Genotype-Phenotype in HCM — EECC MCQ

Correct answer: C — TNNT2 mutations can cause HCM with relatively mild LVH but disproportionately high SCD risk — the discrepancy between modest hypertrophy and significant arrhythmic risk means standard risk calculators (which incorporate wall thickness) may underestimate SCD risk in TNNT2 carriers

Genotype-phenotype correlations in HCM are imperfect but clinically relevant: (1) TNNT2: relatively mild LVH (often <20 mm) but disproportionately high SCD risk — the myocardial disarray and fibrosis are extensive relative to the degree of hypertrophy; (2) MYH7: variable hypertrophy, earlier onset, often more malignant course; (3) MYBPC3: later onset (often adulthood), generally more favourable prognosis, but exceptions exist; (4) Multiple sarcomeric mutations: worst prognosis. The 2023 ESC Cardiomyopathy Guidelines acknowledge that the HCM Risk-SCD calculator may underestimate risk in TNNT2 carriers because wall thickness (a key variable) is often only mildly increased. Clinical implication: when the calculator gives a low/intermediate score in a TNNT2 carrier with a family history of SCD, additional risk modifiers (LGE extent, exercise-induced arrhythmias) should be given extra weight.

Reference: ESC (2023): Cardiomyopathies Guidelines