title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
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.
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Andreas
authors.initials: A
authors.lastname: Brodehl
authors.affiliation: Department of Medical Genetics, University of Calgary and Alberta Health Services, Calgary, Alberta, Canada.
authors.forename: Raechel A
authors.initials: RA
authors.lastname: Ferrier
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Hamilton
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.|Department of Paediatrics, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Greenway
authors.affiliation: Department of Paediatrics, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.|Departments of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Brundler
authors.affiliation: Departments of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Weiming
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.|Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: William T
authors.initials: WT
authors.lastname: Gibson
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: McKinnon
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Barbara
authors.initials: B
authors.lastname: McGillivray
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Nanette
authors.initials: N
authors.lastname: Alvarez
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Giuffre
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.|Department of Medical Genetics, University of Calgary and Alberta Health Services, Calgary, Alberta, Canada.
authors.forename: Brenda
authors.initials: B
authors.lastname: Gerull
mesh_terms: D000293:Adolescent; D000328:Adult; D009202:Cardiomyopathies / Q000378:metabolism; D002313:Cardiomyopathy, Restrictive / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D064448:Filamins / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D055815:Young Adult
chemical_list: C578661:FLNC protein, human; D064448:Filamins
keywords: FLNC; exome sequencing; filamin-C; heart failure; restrictive cardiomyopathy