Related Experiment Video
Updated: Feb 12, 2026
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Insights Into Hypertrophic Cardiomyopathy Evaluation Through Follow-up of a Founder Pathogenic Variant
Rebeca Lorca1, Juan Gómez1, María Martín2
1Unidad de Cardiopatías Familiares, Departamento de Cardiología y Genética Molecular, Hospital Universitario Central de Asturias (HUCA), Oviedo, Asturias, Spain.
Insights
The MYBPC3 p.G263* variant in hypertrophic cardiomyopathy (HCM) shows high penetrance, especially after age 55. Cardiac MRI improves variant carrier detection in HCM patients.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease.
- Accurate classification of variant pathogenicity is crucial for HCM diagnosis and management.
- MYBPC3 gene variants are frequently associated with HCM.
Purpose of the Study:
- To re-evaluate the penetrance and clinical presentation of the MYBPC3 p.G263* variant.
- To assess the utility of cardiac magnetic resonance (CMR) in detecting HCM in carriers.
- To understand the age-dependent clinical expression of this specific HCM-associated variant.
Main Methods:
- Next-generation sequencing was used to study 384 HCM probands and 450 controls for sarcomere genes.
- MYBPC3 p.G263* carriers were identified, and family screening was conducted.
- Clinical data were collected retrospectively and prospectively, with a focus on performing CMR in all identified carriers.
Main Results:
- The MYBPC3 p.G263* pathogenic variant was identified in 13 HCM probands but no controls.
- A total of 39 carriers were identified through family screening.
- Penetrance increased with age, reaching 100% in carriers over 55 years; CMR enhanced penetrance detection to 87.2% compared to TTE alone (70%).
Conclusions:
- The MYBPC3 p.G263* variant exhibits late onset, a generally benign course in younger individuals, and high penetrance, consistent with other MYBPC3 truncating variants.
- Cardiac magnetic resonance (CMR) is a valuable tool for evaluating carriers of the MYBPC3 p.G263* variant, potentially offering a more comprehensive assessment than transthoracic echocardiography (TTE) alone.
- Understanding the penetrance and clinical expression of specific variants like MYBPC3 p.G263* is essential for accurate HCM diagnosis and genetic counseling.
Introduction And Objectives:
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. The current challenge relies on the accurate classification of the pathogenicity of the variants. Transthoracic echocardiography (TTE) is recommended at initial evaluation and cardiac magnetic resonance (CMR) imaging should also be considered. We aimed to reappraise the penetrance and clinical expression of the MYBPC3 p.G263* variant.
Methods:
Three hundred and eighty-four HCM probands and a control cohort of 450 individuals were studied for the main sarcomere genes by next-generation sequencing. All MYBPC3 p.G263* carriers were identified and family screening was performed. Clinical information was recorded retrospectively before 2015 and prospectively thereafter. Extra effort was invested in performing CMR in all carriers, despite TTE results.
Results:
Thirteen HCM probands and none of the controls were carriers of the MYBPC3 p.G263* pathogenic variant (according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology). A total of 39 carriers were identified with family screening. Most patients with HCM were asymptomatic at the time of diagnosis and showed late-onset disease. Despite having a relatively benign course in the young, late HCM-related complications could occur. Penetrance was around 70% when evaluated by TTE and was 87.2% with TTE plus CMR. Penetrance was age-dependent, reaching 100% in carriers older than 55 years.
Conclusions:
MYBPC3 p.G263* shares with most truncating pathogenic variants in this gene a late onset, relatively benign clinical course in the young, and high penetrance. Cardiac magnetic resonance could be a useful tool to evaluate carriers despite TTE results.
Related Concept Videos
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
01:30Cardiomyopathy II: Dilated Cardiomyopathy
01:29Cardiomyopathy IV: Restrictive Cardiomyopathy
02:30Histone Variants at the Centromere
01:29Cardiomyopathy V: Interprofessional Care
01:25Cardiomyopathy I: Introduction and Classification