FLNC is a novel gene for Dilated Cardiomyopathy in Two Families. R. L. Begay1, A. Martin2, S. L. Graw1, D. B. Slavov1, C. A. Tharp1, M. Sweet1, F. Brun3, K. L. Jones1, K. Gowan1, D. Miani3, G. Sinagra3, L. Mestroni1, D. M. Garrity2, M. R. G. Taylor1 1) Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver, Aurora, CO., United States; 2) Colorado State University, Ft. Collins, CO., United States; 3) University of Trieste Hospital, Trieste, and S. Maria della Misericordia Hospital, Udine, Italy.

   Background - Dilated cardiomyopathy (DCM) is an important and frequently genetic form of heart failure. More than 30 DCM genes have been reported, the majority of which encode proteins involved in cytoskeletal and sarcomeric function. Currently, 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 used whole exome sequencing (WES) in a multigenerational DCM family from Northern Italy in whom prior DCM genetic testing had been negative. Pathogenic variants were sought by a combination of bioinformatic filtering and cosegregation analysis of affected relatives. Thirteen gene candidates were identified including one novel variant in FLNC (filamin-C gene), previously linked to a skeletal muscle disease phenotype. WES in a second, smaller family from the same region of Northern Italy identified the identical FLNC variant present on the same 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 produced a heart failure phenotype in zebrafish. Conclusion - Using WES, we have identified FLNC as a novel DCM gene leading to heart failure. The zebrafish FLNC model support a haploinsufficiency model leading to the DCM phenotype.

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