Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Variants in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C), are the leading cause of HCM. However, the pathogenicity status of hundreds of MYBPC3 variants found in patients remains unknown, as a consequence of our incomplete understanding of the pathomechanisms triggered by HCM-causing variants. Here, we examined 44 nontruncating MYBPC3 variants that we classified as HCM-linked or nonpathogenic according to cosegregation and population genetics criteria. We found that around half of the HCM-linked variants showed alterations in RNA splicing or protein stability, both of which can lead to cMyBP-C haploinsufficiency. These protein haploinsufficiency drivers associated with HCM pathogenicity with 100% and 94% specificity, respectively. Furthermore, we uncovered that 11% of nontruncating MYBPC3 variants currently classified as of uncertain significance in ClinVar induced one of these molecular phenotypes. Our strategy, which can be applied to other conditions induced by protein loss of function, supports the idea that cMyBP-C haploinsufficiency is a fundamental pathomechanism in HCM.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260873PMC
http://dx.doi.org/10.1016/j.jbc.2021.100854DOI Listing

Publication Analysis

Top Keywords

mybpc3 variants
16
protein haploinsufficiency
8
haploinsufficiency drivers
8
hypertrophic cardiomyopathy
8
hcm pathogenicity
8
nontruncating mybpc3
8
cmybp-c haploinsufficiency
8
variants
7
protein
5
mybpc3
5

Similar Publications

Background: Females with hypertrophic cardiomyopathy present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors behind these differences are unclear. We aimed to investigate sex-related differences in clinical and genetic factors affecting adverse outcomes in the Sarcomeric Human Cardiomyopathy Registry.

View Article and Find Full Text PDF

Congenital heart disease (CHD) is a prevalent condition characterized by defective heart development, causing premature death and stillbirths among infants. Genome-wide association studies (GWASs) have provided insights into the role of genetic variants in CHD pathogenesis through the identification of a comprehensive set of single-nucleotide polymorphisms (SNPs). Notably, 90-95% of these variants reside in the noncoding genome, complicating the understanding of their underlying mechanisms.

View Article and Find Full Text PDF

The impact of common and rare genetic variants on bradyarrhythmia development.

Nat Genet

January 2025

Telemachus and Irene Demoulas Family Foundation Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA.

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively.

View Article and Find Full Text PDF

Early genetic screening and cardiac intervention in patients with cardiomyopathies in a multidisciplinary clinic.

ESC Heart Fail

December 2024

Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.

Article Synopsis
  • The study aims to investigate how early assessment and genetic counseling in a multidisciplinary Cardiomyopathy Clinic can enhance patient outcomes and reduce the severity of heart failure.
  • A total of 421 patients with various types of cardiomyopathy participated, with a significant portion undergoing genetic testing that revealed a notable incidence of pathogenic variants.
  • Follow-up showed increased use of heart failure medications and improved heart function, indicated by a rise in left ventricular ejection fraction (LVEF) and a decrease in left ventricular mass index (LVMI) among patients with dilated cardiomyopathy (DCM).
View Article and Find Full Text PDF

Haplotyping-based preimplantation genetic testing for inherited cardiovascular disease: a multidisciplinary approach.

Mol Genet Genomics

December 2024

Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China.

Given the high morbidity, mortality, and hereditary risk of cardiovascular diseases (CVDs), their prevention and control have garnered widespread attention and remain central to clinical research. This study aims to assess the feasibility and necessity of haplotyping-based preimplantation genetic testing for the prevention of inherited CVD. A total of 15 preimplantation genetic testing for monogenic defect (PGT-M) cycles were performed in 12 CVD families from January 2016 to July 2022.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!