Prediction of genotype positivity in patients with Hypertrophic Cardiomyopathy: validation of the Mayo score in a large Portuguese HCM cohort

Introduction

Hypertrophic cardiomyopathy (HCM) is a primary hereditary myocardial disorder, with an autosomal-dominant inheritance pattern, mainly caused by mutations in sarcomere genes. Genetic testing has a key role in diagnosis, risk stratification, and family cascade screening. The Mayo score has been proposed as an easy-tool to estimate the pre-test probability of a positive HCM genotype. However, it is yet to be determined whether this prediction tool is useful in Portuguese HCM patients.

Aims

To evaluate the predictive value of the Mayo score in a Portuguese HCM cohort.

Methods

Retrospective study of all patients with HCM regularly followed in our center up until November 2025.Genotype positivity was defined as the presence of pathogenic or likely pathogenic (P/LP) variants. We applied thesimplified version of the Mayo Clinic HCM genotype predictor score: age at diagnosis (<45 years), family history of HCM and of sudden cardiac death, known hypertension and maximal left ventricular wall thickness (≥20mm), while excluding reverse-curve morphology (due to inconsistent reporting). The modified score using ECG parameters was also evaluated, incorporating atrial fibrillation, intraventricular conduction disturbance (QRS ≥120ms), a Sokolow–Lyon index ≥3.5 mV, and precordial T-wave inversion. The predictive performance was assessed using logistic regression, ROC curve analysis and genotype-positivity across score categories.

Results

Overall, 258 patients were included (mean age 55 ± 19 years, 16% family history of HCM; 7% family history of sudden cardiac death; 59% hypertension; median maximal left ventricular wall thickness 17 [14-21] mm). A total of 85(33%) patients were genotype positive. P/LP variants were most frequently identified in MYBPC3 (n=35), followed by MYH7 (n=26).

The prevalence of genotype positivity increased progressively with higher scores (central figure). In the simplified (clinical) Mayo score, a score of 2, 3 and 4 was observed in 17, 7 and 3 patients, of whom 13 (76.5%), 7 (100%) and 3 (100%) were genotype-positive, respectively. Similarly, in the modified (clinical-ECG) version, a score of 2, 3 and 4 was documented in 31, 9 and 4 patients, of whom 19 (61.3%), 8 (88.9%) and 4 (100%) were genotype- positive, respectively. The discriminative performance of these two versions of the Mayo score was moderate, having an observed AUC of 0.71 (95% CI 0.64-0.78) and 0.74 (95% CI 0.68-0.81), respectively, with neither outperforming the other (p=0.914).

Conclusions

The Mayo Clinic HCM genotype predictor score is useful for predicting a positive genetic test result in Portuguese HCM Patients. The stepwise increase in the P/LP prevalence across score categories supports the use of this adapted model as a simple and practical tool to optimize genetic testing strategies in routine HCM care.For image description, please refer to the figure legend and surrounding text.