Novel filamin C (FLNC) variant causes a severe form of familial mixed hypertrophic‐restrictive cardiomyopathy

Abstract

Variants of filamin C (FLNC) have been identified as rare genetic substrate for hypertrophic cardiomyopathy (HCM). Data on the clinical course of FLNC‐related HCM are conflicting with some studies suggesting mild phenotypes whereas other studies have reported more severe outcomes. In this study, we present a novel FLNC variant (Ile1937Asn) that was identified in a large family of French‐Canadian descent with excellent segregation data. FLNC‐Ile1937Asn is a novel missense variant characterized by full penetrance and poor clinical outcomes. End stage heart failure requiring transplantation occurred in 43% and sudden cardiac death in 29% of affected family members. Other particular features of FLNC‐Ile1937Asn include an early disease onset (mean age of 19 years) and the development of a marked atrial myopathy (severe biatrial dilatation with remodeling and multiple complex atrial arrhythmias) that was present in all gene carriers. The FLNC‐Ile1937Asn variant is a novel, pathogenic mutation resulting in a severe form of HCM with full disease penetrance. The variant is associated with a high proportion of end‐stage heart failure, heart transplantation, and disease‐related mortality. Close follow‐up and appropriate risk stratification of affected individuals at specialized heart centers is recommended.

Advanced searching for hypertrophic cardiomyopathy heritability in real practice tomorrow

“…Over the past year, the first familial HCM caused by a splicing mutation in FLNC was reported ( 60 ). Later, strong evidence for the involvement of FLNC in HCM was confirmed: a novel missense variant Ile1937Asn with complete penetrance and poor outcomes has been identified in a large 3-generation French-Canadian family with excellent segregation data ( 61 ). Interestingly, most missense variants and the aforementioned splice variant are located in the ROD2 domain of FLNC gene, which is also participating in cell signaling, and can be considered as a mutational hotspot region for HCM-related FLNC variants.…”