Beyond Wall Thickness: Clinical Predictors of Genotype Positivity in Hypertrophic Cardiomyopathy
Year: 2026
Type: article
Study design: Observational Study
Abstract: 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 modestly improved the model performance (AUC 0.769, p = 0.016, ΔAUC +0.024; DeLong p = 0.016) but without leading to meaningful patient reclassification. 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 shape a personalized approach to genetic counseling in HCM.
Source: Cardiogenetics
Authors: Filippo Angelini, Veronica Dusi, Amedeo Maria Feneziani, Rossella Manai, Matteo Bianco, Enrica Lonni, Giulia Margherita Brach Del Prever, Pier Paolo Bocchino, Giuseppe Giannino, Daniele Melis, Giulia Gobello, Francesco Ravera, Lucia Elena Laiso, Federico Juvenal, Guglielmo Gallone, Stefano Pidello, Barbara Mabritto, Daniela Giachino, Giuseppe Musumeci, Alessandra Chinaglia, Walter Grosso Marra, Silvia Deaglio, Gaetano Maria De Ferrari, Claudia Raineri
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,689
OpenAlex ID: W7160833614