Key result
Age at diagnosis under 40 is linked to ~2.4-fold higher odds of genotype-positive HCM.
Why the study?
Genetic testing in HCM yields variable positivity rates, and identifying clinical predictors of positive genetic tests could improve pre-test counseling and refine expectations about diagnostic yield.
Do clinical and echocardiographic factors predict genotype positivity in probands with hypertrophic cardiomyopathy?
Cohort (n=274)
Yes
Do clinical and echocardiographic factors predict genotype positivity in probands with hypertrophic cardiomyopathy?
In hypertrophic cardiomyopathy, genotype positivity is independently predicted by younger age at diagnosis, family history of sudden cardiac death or non-ischemic cardiomyopathy, absence of hypertension, and increased left atrial volume index, rather than maximal left ventricular wall thickness or mode of initial presentation.
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.
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Juvenal et al. (2026) conducted a cohort in Hypertrophic cardiomyopathy (n=274). Clinical predictors (including age at diagnosis <40 years, family history, and hypertension) vs. Genotype-negative status or absence of clinical predictors was evaluated on Genotype positivity (presence of ≥1 pathogenic or likely pathogenic variant, ACMG classes 4–5) (OR 2.38, 95% CI 1.26-4.51, p=0.008). Age at diagnosis <40 years (OR 2.38, 95% CI 1.26-4.51) and family history predicted genotype positivity in HCM (31% yield), while hypertension was inversely associated (OR 0.42).
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