Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Epidemiology

Background:

• Phenotypic heterogeneity and incomplete penetrance are hallmarks of hypertrophic cardiomyopathy (HCM).
• Understanding genotype-phenotype correlations is crucial for managing HCM.
• The role of founder mutations and co-existing risk factors in HCM requires further elucidation.

Purpose of the Study:

• To investigate genotype-phenotype correlations in hypertrophic cardiomyopathy (HCM).
• To determine the contribution of an MYL2 founder mutation and additional risk factors to left ventricular hypertrophic remodeling.
• To assess the penetrance of the MYL2 c.64G > A mutation in HCM families.

Main Methods:

• Analysis of 14 HCM families with 38 carriers of the MYL2 c.64G > A mutation.
• Investigation of phenotypic outcomes in relation to the primary mutation and co-existing risk factors (hypertension, obesity, other sarcomeric mutations).
• Statistical analysis to determine the impact of risk factors on disease penetrance.

Main Results:

• The MYL2 c.64G > A mutation alone demonstrated benign manifestation and low penetrance.
• Co-presence of risk factors (hypertension, obesity, other sarcomeric mutations) substantially increased disease penetrance.
• HCM developed in 89% of MYL2 mutation carriers with additional risk factors (P = 0.0005), with hypertension being the most prominent (71% of affected carriers).

Conclusions:

• The MYL2 mutation c.64G > A is insufficient to cause clinical HCM in most individuals.
• Additional risk factors, particularly hypertension, are critical for the development of HCM in MYL2 mutation carriers.
• Early diagnosis and monitoring of risk factors are essential for managing MYL2 mutation carriers; hypertension should not exclude individuals from genetic studies.