Clinical Predictors of Genotype Positivity in Hypertrophic Cardiomyopathy: Data From a Multicenter Registry

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 counselling and refine expectations, given the typical 30–50% yield of genetic testing in HCM, which varies across cohorts and settings. Methods We analysed 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 counselling in HCM that emphasizes when disease manifests and how it aggregates within families, rather than how patients initially present clinically