The Long-Term Clinical Progression of Genotype-Positive/Phenotype-Negative Patients With Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a genetic myocardial disease. In 20% to 30% of patients, a disease-causing variant can be identified and may also be present in relatives. Individuals carrying a pathogenic variant (G+) without left ventricular hypertrophy (LVH) are classified as genotype-positive/phenotype-negative (G+/P-). Their risk of developing LVH or HCM-related events remains uncertain. The aim of the article is to describe the clinical course of G+/P- individuals during long-term follow-up. G+/P- individuals were recruited from relatives of HCM patients at a tertiary center. All underwent clinical assessment, electrocardiography (ECG), and transthoracic echocardiography (TTE). Phenotype-negative status was defined as maximal left ventricular wall thickness (MLVWT) <13 mm. HCM was diagnosed when MLVWT ≥13 mm was observed without hypertension or other hemodynamic causes. Genetic testing used targeted Sanger sequencing, with variants classified per ACMG/AMP criteria. Thirty-four individuals were classified as G+/P-; the mean age was 31.7 ± 14.8 years, and 27% were men. Variants occurred in MYBPC3 (76%) and MYH7 (24%). Most were asymptomatic (85%), and 71% had a normal ECG. Mean follow-up was 6.6 ± 3.7 years, with complete ECG and TTE data in 88%. MLVWT increased from 9.6 ± 1.6 mm to 10.7 ± 3.3 mm (p = 0.01), while other echocardiographic parameters and ECG findings remained stable. Nine individuals (26%) developed LVH after a mean of 5.1 ± 4.1 years. One patient developed nonsustained ventricular tachycardia and received a primary prevention implantable cardioverter-defibrillator. In conclusion, G+/P- individuals were young and largely asymptomatic, yet 26% progressed to HCM. These results support regular TTE and ECG surveillance to enable early identification of disease progression and guide risk stratification.