Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Medicine

Background:

• Mutations in the Lamin A/C gene (LMNA) are recognized causes of familial and sporadic dilated cardiomyopathy (DC).
• The spectrum of LMNA-associated cardiac disease often includes conduction system abnormalities, but variants can present differently.

Purpose of the Study:

• To investigate the role of LMNA gene mutations in a cohort of patients with dilated cardiomyopathy.
• To identify specific LMNA mutations associated with severe familial DC and explore the phenotypic variability.

Main Methods:

• Genomic DNA was extracted from 67 consecutive DC patients.
• Coding regions of the LMNA gene were amplified and analyzed using single-strand conformation polymorphism and sequencing.
• Mutations were confirmed using restriction fragment length polymorphism.

Main Results:

• Two pathogenic LMNA mutations, R349L and R190W, were identified in families with severe familial DC.
• The R349L mutation was found in a mother and identical twin daughters, all requiring cardiac transplantation at young ages.
• The R190W mutation was identified in cousins and their sons, with affected individuals experiencing severe cardiac events, including sudden death and transplantation; one carrier showed left ventricular noncompaction.

Conclusions:

• The R349L and R190W LMNA mutations are associated with severe forms of familial dilated cardiomyopathy.
• LMNA gene analysis should be considered in the genetic evaluation of familial DC, particularly in cases without conduction system disease.
• Isolated left ventricular noncompaction may represent a manifestation within the spectrum of laminopathies.