Phenotypic variations in carriers of predicted protein-truncating genetic variants in MYBPC3: an autopsy-based case...

Area of Science:

• Cardiovascular Genetics
• Molecular Pathology
• Sudden Cardiac Death Etiology

Background:

• Hypertrophic cardiomyopathy (HCM) is frequently linked to pathogenic variants in the MYBPC3 gene.
• Investigating genetic variants in autopsied cases provides insight into disease mechanisms and mortality.
• Predicted protein-truncating variants (PTVs) represent a significant class of genetic alterations with potential clinical impact.

Observation:

• Four pathogenic PTVs in MYBPC3 were identified in male decedents from autopsied HCM cases.
• Two PTVs were located in the cardiac-specific N-terminal M-motif, and two were in the non-cardiac-specific C-terminus.
• PTVs in the cardiac-specific M-motif were associated with earlier age-at-death (38 years) compared to C-terminal PTVs (57 and 67 years).

Findings:

• MYBPC3 PTVs are present in a subset of sudden unexpected cardiac death cases due to HCM.
• The location of PTVs within the MYBPC3 gene correlates with age at death, suggesting differential pathogenicity.
• Cardiac-specific M-motif PTVs appear to confer a more severe phenotype with earlier mortality in male carriers.

Implications:

• Understanding the impact of PTV location in MYBPC3 can refine risk stratification for HCM.
• This research highlights the importance of detailed genetic analysis in sudden cardiac death investigations.
• Further studies are warranted to elucidate the functional consequences of MYBPC3 PTV location on cardiac function and survival.