FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy

Highlights •Deoxyribonucleic acid obtained from 2 large DCM families was studied using whole-exome sequencing and cosegregation analysis resulting in the identification of a novel disease gene, FLNC. The 2 families, from the same Italian region, harbored the same FLNC splice-site mutation ( FLNC c.7251+1G>A). •A third U.S. family was then identified with a novel FLNC splice-site mutation ( FLNC c.5669-1delG) that leads to haploinsufficiency as shown by the FLNC Western blot analysis of the heart muscle. •The FLNC ortholog flncb morpholino was injected into zebrafish embryos, and when flncb was knocked down caused a cardiac dysfunction phenotype. •On electron microscopy, the flncb morpholino knockdown zebrafish heart showed defects with in the Z-discs and sarcomere disorganization.