The transmembrane protein 43 (TMEM43/LUMA) gene encodes a ubiquitously expressed and highly conserved nuclear envelope protein that interacts with components of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. Mutations in TMEM43 have been associated with the autosomal dominant arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC-5), Emery-Dreifuss Muscular Dystrophy type 7 (EDMD7) and recently auditory neuropathy spectrum disorder (ANSD). To date, only two heterozygous TMEM43 missense mutations (p.Glu85Lys and p.Ile91Val), causing a EDMD-related myopathy, were reported in four patients from three families. Using deep phenotyping and high-throughput DNA sequencing, we have identified five different potential disease-causing variants (two deleterious missense variants, two small gene deletions and a splice site mutation) in TMEM43 in five unrelated patients. These patients presented with variable clinical features ranging from elevated serum CK levels to an EDMD phenotype. Histopathological analysis of muscle biopsies showed myopathic changes in three out of five patients and the expression of TMEM43 was evaluated by western blot. To investigate the effects of the novel p.W316S TMEM43 mutation identified in one patient, we transiently expressed the wildtype and mutated human TMEM43 gene in zebrafish microinjecting fertilized oocytes with the mRNA encoding hTMEM43 WT and hTMEM43 W316S. In this study we characterized both clinically and morphologically five novel variants in TMEM43 gene and explored the possibility of replicating a myopathic phenotype in zebrafish by inducing the transient expression of human mutated TMEM43.