Gender- and age-related differences in distinct phenotypes of hypertrophic cardiomyopathy-associated mutation...

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Epidemiology

Background:

• The MYBPC3-E334K mutation is associated with hypertrophic cardiomyopathy (HCM).
• Conflicting classifications in databases like ClinVar stem from limited segregation data and its presence in general populations.
• Understanding its precise clinical significance and genotype-phenotype correlations is crucial for accurate diagnosis and patient management.

Purpose of the Study:

• To clarify the clinical importance of the MYBPC3-E334K mutation in hypertrophic cardiomyopathy.
• To investigate phenotype-genotype correlations in individuals with and without the MYBPC3-E334K mutation alone.
• To determine the inheritance pattern and penetrance of the MYBPC3-E334K variant.

Main Methods:

• Sequencing of the MYBPC3-E334K variant in 1017 unrelated hypertrophic cardiomyopathy probands.
• Analysis of clinical features, morphology, and electrical phenotypes in families with single-mutation MYBPC3-E334K.
• Family studies and co-segregation analyses to establish inheritance patterns and penetrance.

Main Results:

• MYBPC3-E334K was detected in 0.88% of HCM probands; 3 also had a second sarcomere variant.
• Single-mutation MYBPC3-E334K follows autosomal dominant inheritance with incomplete penetrance (52.6% overall).
• Males showed significantly higher penetrance (100% vs. 25%) and earlier onset of HCM compared to females.

Conclusions:

• MYBPC3-E334K is classified as a likely pathogenic variant for hypertrophic cardiomyopathy.
• The mutation exhibits incomplete penetrance, with a notable sex-based difference in disease manifestation.
• Co-occurring second sarcomere variants did not show clear cumulative effects on disease presentation.