MUTATIONS IN FILAMIN C CAUSE FAMILIAL RESTRICTIVE CARDIOMYOPATHY

Abstract

Restrictive cardiomyopathy (RCM) is characterized by increased stiffness of the ventricles, impaired diastolic filling with preserved systolic function. Familial RCM is a rare condition and mainly caused by mutations sarcomere proteins and desmin. Filamin C (FLNC) is a muscle specific protein which provides the mechanical link between the extracellular matrix, the plasma membrane and the actin cytoskeleton. Mutations in FLNC are known to cause myofibrillar myopathy (MFM) and most recently suggested to be associated with hypertrophic cardiomyopathy (HCM). Purpose: In families with autosomal dominant RCM we excluded mutations in all known genes for RCM and aimed to identify and validate a novel cause of the disease. Cardiovascular assessment was done in all available family members after the index case was diagnosed with early onset RCM leading to heart transplantation. Genetic studies via next generation sequencing (NGS) have been performed followed by segregation analysis in affected family members. Explanted heart tissue has been evaluated by histology and immunohistochemistry. Functional analysis of mutated FLNC proteins were carried out in cultured cells and analyzed by immunocytochemistry. The index case presented with heart failure at the age of 13 years requiring heart transplantation a year later. Cardiac assessment showed an impaired diastolic filling pattern, enlarged atria, normal systolic LV-function and wall thicknesses suggesting restrictive cardiomyopathy. Subsequently other family members were diagnosed with signs of RCM. Years later her 2 year old daughter also required heart transplantation due to RCM. Genetic studies via Next Generation Sequencing (NGS) found a unique variant in FLNC (p.S1624L) segregating with the disease. Histopathology and immunohistochemistry revealed FLNC specific cytoplasmic aggregates. Further expression of mutant FLNC proteins in C2C12 and H9C2 cells showed perinuclear and cytoplasmic aggregates not observed in wild-type FLNC transfected cells. Finding of a second mutation in a different family with RCM discovered by NGS confirmed the involvement of FLNC in the genetic aetiology of RCM. Mutations in FLNC are a novel cause of familial autosomal dominant RCM. It demonstrates the powerful strategy of NGS to uncover novel genetic causes for familial diseases.