Beyond wall thickness: clinical predictors of genotype positivity in hypertrophic cardiomyopathy
F Juvenal, F Angelini, V Dusi, M Bianco, G Brach Del Prever, P P Bocchino, G Gallone, S Pidello, G Giannino, G Musumeci, A Chinaglia, W Grosso Marra, S Deaglio, G M De Ferrari, C RaineriAbstract
Background
Genetic testing in hypertrophic cardiomyopathy (HCM) yields variable positivity rates. Identifying clinical predictors of positive genetic tests could improve pre-test counseling and refine expectations about diagnostic yield.
Methods
We analyzed consecutive genotyped HCM probands from a contemporary multicenter cohort across four Italian tertiary centers. Genotype positivity was defined as the presence of ≥ 1 pathogenic or likely pathogenic variant (ACMG classes 4–5). Multivariable logistic regression identified predictors of genotype positivity. Sensitivity analyses assessed the incremental value of left atrial volume index (LAVI) ≥34 mL/m² and the mode of first clinical presentation.
Results
Among 274 genotyped probands (median age at diagnosis 54 years; 62% male), 86 (31%) were genotype-positive (38% MYBPC3, 29% MYH7). Age at diagnosis <40 years (OR 2.38, 95%CI 1.26-4.51, p = 0.008), family history of sudden cardiac death/major ventricular arrhythmias (OR 2.34, 95%CI 1.16-4.84, p = 0.019) and family history of non-ischemic cardiomyopathy (OR 1.92, 95%CI 1.04-3.54, p = 0.038), were independently associated with genotype positivity whereas arterial hypertension was inversely associated (OR 0.42, 95%CI 0.23-0.77). Maximal left ventricular wall thickness > 20 mm and gender were not predictive of genotype positivity. Inclusion of LAVI improved the model performance (AUC 0.769, p = 0.016, ΔAUC +0.024; DeLong p = 0.016) while mode of first presentation did not.
Conclusions
Genotype positivity in HCM links to earlier onset and family history; traditional severity markers and initial presentation may not independently suggest genetic causality. These findings may help shaping a personalized approach to genetic counseling in HCM.