Truncating variant in MYOF gene is associated with limb-girdle type muscular dystrophy and cardiomyopathy

Even though genetic studies of individuals with neuromuscular diseases have uncovered the molecular background of many cardiac disorders such as cardiomyopathies and inherited arrhythmic syndromes, the genetic cause of a proportion of cardiomyopathies associated with neuromuscular phenotype still remains unknown. Here, we present a clinical case with a combination of cardiomyopathy and limb-girdle type muscular dystrophy where whole exome sequencing identified myoferlin (MYOF) - a member of the Ferlin protein family and close homolog of DYSF - as the most likely candidate gene. The disease-causative role of the identified variant c.[2576delG; 2575G>C], p.G859fs is supported by functional studies in vitro using primary patient's satellite cells, including both RNA sequencing and morphological studies, as well as recapitulating of muscle phenotype in vivo in zebrafish experiments. We provide the first evidence supporting a role of MYOF in human muscle disease. A muscle biopsy taken from patient’s M. deltoideus was used for morphological examination and SMSC isolation. Control cells were obtained from the hip muscles of healthy donors. The cells were placed in proliferation media (DMEM supplemented with 10% FCS) on cell culture dishes and cultured until 80% confluence. Patient and donor cells were differentiated towards myotubes using low serum condition.