A novel Myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Diseases

Background:

• Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease often caused by sarcomere protein gene mutations.
• Mutations in MYL3, encoding the myosin essential light chain, are rare causes of HCM and have been linked to sudden death, with debated inheritance patterns.
• Previous studies suggest both recessive and dominant inheritance for MYL3 mutations.

Purpose of the Study:

• To investigate the genetic basis of HCM in a large family with a novel MYL3 mutation.
• To determine the inheritance pattern, penetrance, and clinical presentation of this novel MYL3 mutation.
• To understand the molecular mechanism of the identified MYL3 mutation in HCM pathogenesis.

Main Methods:

• Clinical evaluation including echocardiography and ECG of affected family members.
• Genetic analysis including genotyping for a novel MYL3 missense mutation (p.V79I) and cascade screening.
• In silico analysis of the mutation's effect on protein structure and function.

Main Results:

• A novel heterozygous missense mutation, p.V79I, in the MYL3 gene was identified in an HCM-affected patient.
• The mutation was absent in 300 controls and segregated with HCM in the family.
• Cascade screening identified nine mutation carriers, with 40% penetrance by age 47, suggesting low expressivity and late onset. Borderline HCM phenotypes were observed in some carriers.
• The p.V79I mutation alters a conserved residue at the myosin light chain-myosin lever arm interface.

Conclusions:

• MYL3 mutations can cause HCM with variable expressivity and late onset.
• The novel p.V79I mutation in MYL3 is associated with HCM and demonstrates reduced penetrance.
• This finding expands the spectrum of MYL3-associated cardiomyopathies and highlights the importance of genetic testing in HCM.