Phenotypic Expression, Natural History, and Risk Stratification of Cardiomyopathy Caused by Filamin C Truncating Variants

Circulation. 2021 Nov 16;144(20):1600-1611. doi: 10.1161/CIRCULATIONAHA.121.053521. Epub 2021 Sep 30.


Background: Filamin C truncating variants (FLNCtv) cause a form of arrhythmogenic cardiomyopathy: the mode of presentation, natural history, and risk stratification of FLNCtv remain incompletely explored. We aimed to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of FLNCtv carriers.

Methods: FLNCtv carriers were identified from 10 tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), nonarrhythmic death/HT/LVAD, and sudden cardiac death/major ventricular arrhythmias. Previously established cohorts of 46 patients with LMNA and 60 with DSP-related arrhythmogenic cardiomyopathies were used for prognostic comparison.

Results: Eighty-five patients carrying FLNCtv were included (42±15 years, 53% men, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area - right ventricular end-systolic area)/right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) experienced nonarrhythmic death/HT/LVAD, and 23 (27%) experienced sudden cardiac death/major ventricular arrhythmias. The sudden cardiac death/major ventricular arrhythmias incidence of FLNCtv carriers did not significantly differ from LMNA carriers and DSP carriers. In FLNCtv carriers, left ventricular ejection fraction was associated with the risk of D/HT/LVAD and nonarrhythmic death/HT/LVAD.

Conclusions: Among patients referred to tertiary referral centers, FLNCtv arrhythmogenic cardiomyopathy is phenotypically heterogeneous and characterized by a high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of left ventricular dysfunction.

Keywords: FLNC protein, human; arrhythmogenic right ventricular dysplasia; death, sudden, cardiac; heart failure; outcome studies; prognosis.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Cardiomyopathies / diagnosis
  • Cardiomyopathies / epidemiology
  • Cardiomyopathies / etiology*
  • Cardiomyopathies / therapy
  • Combined Modality Therapy
  • Disease Management
  • Echocardiography
  • Female
  • Filamins / genetics*
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Outcome Assessment, Health Care
  • Phenotype*
  • Prognosis
  • Registries


  • FLNC protein, human
  • Filamins