Background: Genetic testing in hypertrophic cardiomyopathy (HCM) shows variable genotype positivity, not consistently predicted by clinical features or severity. Identifying clinical predictors of genotype positivity could improve pre-test counseling and refine expectations, given the typical 30-50% yield of genetic testing in HCM, which varies across cohorts and settings. Methods: We analyzed probands with HCM from a contemporary multicenter cohort across four tertiary centers. Family members were excluded. Genotype positivity was defined as at least one pathogenic/likely pathogenic variant (ACMG class 4–5). Multivariable logistic regression identified independent predictors of genotype positivity. Sensitivity analyses evaluated left atrial volume index (LAVI) ≥34 mL/m² and mode of first presentation. Results: Among 274 genotyped probands, 86 (31%) were genotype-positive (median age at diagnosis 54 years, 62% male). Among genotype-positive patients, pathogenic/likely pathogenic variants predominantly involved sarcomeric genes, with MYBPC3 (n = 33; 38.4%) and MYH7 (n = 25; 29.1%) accounting for the majority of genotype-positive cases. A positive genetic test was independently predicted by age at diagnosis <40 years (OR 2.43), family history of SCD/major ventricular arrhythmias (2.27), family history of non-ischemic cardiomyopathy (1.93), and, as a protective factor, hypertension (0.42). Maximal LV wall thickness >20 mm and gender were not independently associated with genotype positivity. The main clinical model demonstrated good discrimination and calibration (AUC ~0.75–0.76). Adding LAVI or first presentation mode provided no meaningful improvement. Conclusions: Genotype positivity in HCM links to early onset and familial clustering; traditional severity markers and initial presentation do not independently indicate genetic causality. These findings support a phenotype-driven, probabilistic approach to genetic counseling in HCM that emphasizes when disease manifests and how it aggregates within families, rather than how patients initially present clinically
Associazione Nazionale Medici Cardiologi Ospedalieri
