What is the clinical evidence from this study?

Study design: Cohort. Population: Genotype-positive/phenotype-negative Hypertrophic Cardiomyopathy (n=34). Intervention: Long-term clinical surveillance. Primary outcome: Development of left ventricular hypertrophy (progression to HCM).

February 28, 2026

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

Key Result

During a mean follow-up of 6.6 years, 26% of genotype-positive/phenotype-negative relatives of HCM patients progressed to develop left ventricular hypertrophy.

Key Points

This research aims to describe the long-term clinical progression of genotype-positive/phenotype-negative individuals with hypertrophic cardiomyopathy.
G+/P- individuals were recruited from relatives of HCM patients at a tertiary center.
Clinical assessments, ECG, and transthoracic echocardiography were performed.
Genetic testing was conducted using targeted Sanger sequencing.
MLVWT increased from 9.6±1.6 mm to 10.7±3.3 mm (p=0.01).
26% of individuals developed left ventricular hypertrophy after a mean follow-up of 5.1±4.1 years.
One patient developed non-sustained ventricular tachycardia.

Study Design

Type

Cohort (n=34)

Multicenter

Structured PICO

Population

34 genotype-positive/phenotype-negative (G+/P-) relatives of hypertrophic cardiomyopathy patients (carrying a pathogenic variant without left ventricular hypertrophy, defined as MLVWT <13 mm), mean age 31.7 years, 27% men.

Intervention

Long-term clinical, ECG, and transthoracic echocardiography surveillance

Outcome

Development of left ventricular hypertrophy (MLVWT ≥13 mm) and clinical coursesurrogate

A significant proportion (26%) of genotype-positive/phenotype-negative individuals progress to overt hypertrophic cardiomyopathy over long-term follow-up, supporting the need for regular surveillance.

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetic myocardial disease. In 20-30% 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. 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 centre. All underwent clinical assessment, 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-; 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 non-sustained ventricular tachycardia and received a primary prevention ICD. 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.

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