Abstract 11923: FLNC Gene Splice Mutation Causes Dilated Cardiomyopathy in Two Families
Background: Dilated cardiomyopathy (DCM) is an important and frequently genetic cause of heart failure. Over 30 DCM genes have been described, the majority of which encode proteins that contribute to cytoskeletal and sarcomeric structures. Only 30-40% of cases can be attributed to a known DCM gene, motivating the ongoing search for novel disease genes.
Methods and Results: We performed whole exome sequencing (WES) in a multigenerational DCM family from Northern Italy in whom prior DCM genetic testing had been unrevealing. Pathogenic variants were sought by a combination of bioinformatic filtering and cosegregation among affected individuals within the family. Thirteen gene candidates were identified including one novel variant in FLNC (filamin-C gene), already linked to a skeletal muscle disease phenotype. We further noted that WES found the identical variant in a second smaller family from the same geographical area; the mutation was present on a common haplotype. The variant is located in the 3’ end of the gene and is predicted to disrupt splicing and produce haploinsufficiency for the FLNC protein. Our patients showed no evidence of skeletal myopathy, previously implicated in FLNC mutations. In-situ hybridization demonstrated cardiac filamin expression in zebrafish and morpholino knockdown of zebrafish FLNC-b led to a heart failure phenotype in the zebrafish model.
Conclusion: Using WES, we have identified a novel gene, associated with DCM called FLNC. Furthermore, we have generated a zebrafish model that recapitulates the human FLNC DCM phenotype.
Author Disclosures: R.L. Begay: None. A. Martin: None. S.L. Graw: None. D.B. Slavov: None. C.A. Tharp: None. M. Sweet: None. F. Brun: None. K.L. Jones: None. K. Gowan: None. D. Miani: None. G. Sinagra: None. L. Mestroni: None. D.M. Garrity: None. M.R. Taylor: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.