Clinical exome approach in families with hereditary neuromuscular diseases

Neuromuscular diseases (NMDs) represent a wide cluster of heterogeneous rare disorders that affect peripheral nervous system, causing defects in the development or functioning of muscles and damages in neuromuscular junctions or in associated nerves. The NMDs are characterized by high clinical and genetically heterogeneity, occurrence of mutations in largest genes, lack of genetic diagnosis for about 40% of the patients. To identify disease causing genes involved in NMDs, we performed, the whole exome sequencing (WES) in two “families of four” affected by congenital muscular dystrophy and congenital myopathy respectively, and the Gene Panel test in third family with motor neuropathy. We identified few candidates genes that are been technically validated by Sanger sequencing in the two family analysed by WES.. In the family with a congenital muscular dystrophy we found a known pathogenic in-frame deletion of the ISPD gene (Isoprenoid Synthase Domain-Containing Protein), previously sequenced with negative result. In the second family with congenital myopathy we identified a mutation in RYR1 gene (Ryanodine Receptor 1), previously screened only for mutations in the hot spot regions. Finally in the third family with motor neuropathy we identified a variation in ATP7A gene (ATPase, Cu++transporting, alpha polypeptide) that define a novel phenotype not previously described and expanding the clinical spectrum associated to ATP7A mutations. In conclusion this study provides evidence that next-generation sequencing can have high success rates in a clinical setting. WES has identified known gene mutations and corrected non exhaustive diagnostic procedures, also showing to be a powerful tool for hereditary motor neuropathies diagnosis and new phenotype discovery.