Expanding the phenotype of FLNC-associated disease

Source: Journal of the American College of Cardiology

Missense variants in the gene filamin C (FLNC) have a longstanding, well-established association with myofibrillar and distal myopathy.1,2 An important study recently published in the Journal of the American College of Cardiology expanded the clinical presentation associated FLNC by specifically linking protein truncating variants with cardiac phenotypes exclusive of myopathy.3 The group identified 23 unique truncating variants in FLNC among 28 unrelated patients with prior diagnoses of dilated, arrhythmogenic, or restrictive cardiomyopathy in their cohort of 2,877 patients with inherited cardiovascular disease.3 The prevalence of truncating FLNC variants was 3.9% among 508 patients with dilated cardiomyopathy, 3.2% among 219 patients arrhythmogenic cardiomyopathy, and 2.2% among 45 patients with restrictive cardiomyopathy.

Importantly, within these 28 families with truncating FLNC pathogenic variants, 21 experienced loss of a family member by sudden death (n=40 individuals).3 An additional 54 family members of these study patients were identified as pathogenic variant carriers.3 Most (74%) had cardiac manifestation of disease and many were asymptomatic, only to be diagnosed through family screening.3 These data highlight the importance of including FLNC in the genetic testing for patients with dilated, arrhythmogenic, restrictive cardiomyopathy, or family history of sudden cardiac arrest or death.3 Identifying the genetic cause of these conditions and allows for life-saving interventions, not only for affected patients, but also their asymptomatic relatives.

About filamin C-related cardiomyopathy

The FLNC gene encodes the filamin C protein which cross-links actin filaments in cardiac and skeletal muscle cells.4 It also plays a role in maintaining the structure of the sarcomeric cytoskeleton and binds to several proteins in the Z-disk of the sarcomere.4

Spectrum of clinical features associated with filamin C protein truncations1

  • Dilated cardiomyopathy
  • Left-dominant arrhythmogenic cardiomyopathy
  • Sudden cardiac arrest or death
  • Myocardial fibrosis
  • Mild LV hypertrophy
  • Ventricular arrhythmias

Testing for FLNC at Invitae

Invitae is currently one of the few laboratories offering FLNC for cardiomyopathy genetic testing. FLNC sequence and deletion/duplication analysis is included on the Invitae Comprehensive Cardiomyopathy Panel as well as disease specific sub-panels. In addition, Invitae’s flexible testing menu allows clinicians to add FLNC to any cardiology panel based on the patient’s clinical presentation.

1 Vorgerd M, van der Ven PF, Bruchertseifer V. A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy. American Journal of Human Genetics. 2005;77(2):297-304

2 Duff RM, Tay V, Hackman P, et al. Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy. American Journal of Human Genetics. 2011;88(6):729-40.

3 Ortiz-Genga MF, Cuenca S, Dal Ferro M, et al. Truncating FLNC Mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies. Journal of the American College of Cardiology. 2016; 68(22):2440-2451.

4 Van der Flier A, Sonnenberg A. Structural and functional aspects of filamins. Biochim Biophys Acta. 2001;1538(2-3):99-117.