Gene mutations in apical hypertrophic cardiomyopathy

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Apical hypertrophy is an uncommon variant of hypertrophic cardiomyopathy (HCM).
• This HCM variant is often associated with giant negative T waves and a benign clinical course.
• The genetic basis differentiating typical HCM from apical hypertrophy remains unclear.

Purpose of the Study:

• To investigate the genetic causes of apical hypertrophy.
• To determine if mutations in sarcomere protein genes are associated with apical hypertrophy.
• To understand the genetic relationship between apical hypertrophy and typical HCM.

Main Methods:

• Analyzed DNA from 15 probands with apical hypertrophy.
• Performed DNA sequence analyses of 9 sarcomere protein genes and 3 other relevant genes (GLA, PRKAG2, LAMP2).
• Conducted clinical evaluations to assess familial inheritance and disease manifestations.

Main Results:

• Identified six sarcomere gene mutations in 7 out of 15 samples.
• No mutations were found in GLA, PRKAG2, or LAMP2 genes.
• Found familial apical HCM in 4 probands, with disease-causing mutations identified in 3.
• A cardiac actin Glu101Lys mutation was shared by two families, consistently causing apical hypertrophy in affected members.
• An essential light chain Met149Val mutation caused apical or midventricular HCM in some family members, while others had typical HCM.

Conclusions:

• Sarcomere protein gene mutations contribute to apical hypertrophy, influenced by genetic etiology, modifier genes, and hemodynamic factors.
• Specific sarcomere gene defects, such as cardiac actin Glu101Lys, are consistently linked to apical HCM.
• The genetic landscape of HCM is complex, with distinct mutations leading to varied morphological presentations.