Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Basis of Heart Disease

Background:

• Filamin C (FLNC) is crucial for sarcomere attachment to the cell membrane.
• FLNC mutations are associated with myofibrillar myopathies and cardiac issues.
• FLNC has been part of genetic screening for cardiomyopathies and sudden death since 2012.

Purpose of the Study:

• To establish the link between FLNC truncating mutations and high-risk dilated and arrhythmogenic cardiomyopathies.
• To characterize the clinical and genetic profile of affected families.

Main Methods:

• Next-generation sequencing of FLNC in 2,877 patients with inherited cardiovascular diseases.
• Clinical and genetic evaluation of 28 families with identified FLNC mutations.
• Immunohistochemistry to analyze filamin C localization in cardiac tissue.

Main Results:

• Twenty-three truncating FLNC mutations were found in 28 probands with dilated, arrhythmogenic, or restrictive cardiomyopathies.
• The phenotype included left ventricular dilation, systolic dysfunction, fibrosis, arrhythmias, and frequent sudden cardiac death (40% of cases).
• High penetrance (>97% in carriers >40 years) and dominant inheritance were observed; no skeletal myopathy or abnormal filamin C aggregates were noted.

Conclusions:

• Truncating FLNC mutations cause an overlapping phenotype of dilated and arrhythmogenic cardiomyopathies with high premature sudden death rates.
• Prompt cardiac defibrillator implantation is advised for patients with truncating FLNC mutations.