Journal
HUMAN MUTATION
Volume 37, Issue 3, Pages 269-279Publisher
WILEY
DOI: 10.1002/humu.22942
Keywords
restrictive cardiomyopathy; filamin-C; heart failure; exome sequencing; FLNC
Categories
Funding
- FORGE (Finding of Rare Disease Genes) Canada through Genome Canada
- Canadian Institutes of Health Research
- Ontario Genomics Institute [OGI-049]
- Alberta Innovates Health Solutions [201200822]
- Canadian Institutes of Health Research [FRN: 123351]
- Libin Cardiovascular Institute of Alberta
- Alberta Innovates [201200822] Funding Source: researchfish
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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. (C) 2015 Wiley Periodicals, Inc.
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