2. Academic Validation
  3. Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy

Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy

  • Hum Mutat. 2016 Mar;37(3):269-79. doi: 10.1002/humu.22942.
Andreas Brodehl 1,  Raechel A Ferrier 2,  Sara J Hamilton 3,  Steven C Greenway 1 4,  Marie-Anne Brundler 4 5,  Weiming Yu 5,  William T Gibson 3 6,  Margaret L McKinnon 3,  Barbara McGillivray 3,  Nanette Alvarez 1,  Michael Giuffre 1,  Jeremy Schwartzentruber 7,  FORGE Canada Consortium,  Brenda Gerull 1 2
Affiliations

Affiliations

  • 1 Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
  • 2 Department of Medical Genetics, University of Calgary and Alberta Health Services, Calgary, Alberta, Canada.
  • 3 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
  • 4 Department of Paediatrics, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
  • 5 Departments of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
  • 6 Child and Family Research Institute, Vancouver, British Columbia, Canada.
  • 7 McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada.
PMID: 26666891 DOI: 10.1002/humu.22942
Abstract

Individuals affected by restrictive cardiomyopathy (RCM) often develop heart failure at young ages resulting in early heart transplantation. Familial forms are mainly caused by mutations in sarcomere proteins and demonstrate a common genetic etiology with other inherited cardiomyopathies. Using next-generation Sequencing, we identified two novel missense variants (p.S1624L; p.I2160F) in filamin-C (FLNC), an actin-cross-linking protein mainly expressed in heart and skeletal muscle, segregating in two families with autosomal-dominant RCM. Affected individuals presented with heart failure due to severe diastolic dysfunction requiring heart transplantation in some cases. Histopathology of heart tissue from patients of both families showed cytoplasmic inclusions suggesting protein aggregates, which were filamin-C specific for the p.S1624L by immunohistochemistry. Cytoplasmic aggregates were also observed in transfected myoblast cell lines expressing this mutant filamin-C indicating further evidence for its pathogenicity. Thus, FLNC is a disease gene for autosomal-dominant RCM and broadens the phenotype spectrum of filaminopathies.

Keywords

FLNC; exome sequencing; filamin-C; heart failure; restrictive cardiomyopathy.

Figures