FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy.

OBJECTIVE: To identify novel dilated cardiomyopathy (DCM) causing genes, and to elucidate the pathological mechanism leading to DCM by utilizing zebrafish as a model organism. BACKGROUND: DCM, a major cause of heart failure, is frequently familial and caused by a genetic defect. However, only 50% of DCM cases can be attributed to a known DCM gene variant, motivating the ongoing search for novel disease genes. METHODS: We performed whole exome sequencing (WES) in two multigenerational Italian families and one US family with arrhythmogenic DCM without skeletal muscle defects, in whom prior genetic testing had been unrevealing. Pathogenic variants were sought by a combination of bioinformatic filtering and cosegregation testing among affected individuals within the families. We performed function assays and generated a zebrafish morpholino knockdown model. RESULTS: A novel filamin C gene splicing variant (FLNC c.7251+1 G>A) was identified by WES in all affected family members in the two Italian families. A separate novel splicing mutation (FLNC c.5669-1delG) was identified in the US family. Western blot analysis of cardiac heart tissue from an affected individual showed decreased FLNC protein, supporting a haploinsufficiency model of pathogenesis. To further analyze this model, a morpholino knockdown of the ortholog filamin Cb in zebrafish was created which resulted in abnormal cardiac function and ultrastructure. CONCLUSIONS: Using WES, we identified two novel FLNC splicing variants as the likely cause of DCM in three families. We provided protein expression and in vivo zebrafish data supporting haploinsufficiency as the pathogenic mechanism leading to DCM.

Transcatheter aortic valve implantation via right carotid artery route for severe aortic regurgitation management in a patient with chronic operated type A aortic dissection.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) technique is now widely accepted as an alternative for the treatment of very high-risk patients in cases of aortic stenosis. However, use of this technique in cases of pure native aortic regurgitation (AR) remains discussed. CASE REPORT: We report the case of a 68-year-old patient with severe AR referred to our hospital 10 years after a supracoronary ascending aorta replacement surgery for acute type A aortic dissection. Because of respiratory contraindication to redo sternotomy, we treated this patient with the implantation of a CoreValve prosthesis inserted via right carotid access. We discuss the TAVI strategy in the case of severe AR and the possibility to use alternative vascular access. CONCLUSION: In very high-risk patients, TAVI can be discussed and considered as an alternative treatment for severe AR, with right carotid access proven as feasible.