The influence of genotype on the phenotype and prognosis of patients with hypertrophic cardiomyopathy.

INTRODUCTION

Hypertrophic Cardiomyopathy (HCM) is a genetic Heart disease characterized by myocardial hypertrophy, which can lead to Heart failure and fatal arrhythmias. The genetic basis of this condition is complex, and its relationship with phenotype and prognosis is not completely understood. Our aim was to evaluate the influence of genotype on clinical and imaging phenotypes, and on a 2-year prognosis in HCM patients.Methods We included 117 HCM patients diagnosed by cardiac magnetic resonance (CMR) between 2018 and 2024. Only 77 patients in the cohort underwent genetic testing and were included in the genetic analysis. Genetic testing results were classified as negative, variants of uncertain significance (VUS), or pathogenic, and correlated with clinical and imaging data. For prognosis, we analyzed major adverse cardiovascular events (MACE) and hospitalizations over 2 years.

RESULTS

Genetic mutations (pathogenic or VUS) were identified in 55.9% of patients and were associated with greater symptom burden (p = 0.021). Both pathogenic and VUS carriers were more symptomatic than mutation-negative patients (p = 0.049 and p = 0.041), with no significant differences between the two groups. Patients with mutations also showed higher prevalence of LGE (p = 0.013), particularly those with pathogenic variants (p = 0.002). Compared to mutation-negative patients, both pathogenic and VUS carriers had more LGE (p = 0.007 and p = 0.005), while pathogenic variant carriers additionally demonstrated greater LV wall thickness (p = 0.042). During follow-up, pathogenic variant carriers had increased risk of MACE (HR 4.40, p < 0.001) and cardiovascular hospitalizations (HR 3.24, p = 0.033) versus mutation-negative patients. Family history of HCM or sudden cardiac death was associated with higher MACE risk (HR 2.33, p = 0.017; HR 3.23, p = 0.001). Patients with thin filament mutations, particularly TPM1, presented with worse imaging phenotypes and higher incidence of non-sustained ventricular tachycardia (80% vs. 0% in mutation-negative).

CONCLUSION

Genotype influences clinical and imaging phenotypes and short-term outcomes in HCM patients, underscoring the importance of genetic testing in risk stratification. However, small sample size limits conclusions about specific gene variants.