AB029. Next generation sequencing analysis in hereditary muscle diseases.

Still many cases with probable hereditary myopathy are genetically undiagnosed for two major reasons: (I) muscle genes are often big in size and thus it is difficult to at least routinely sequence such genes even though mutations in those genes have been known to cause muscle diseases; and (II) most cases are sporadic without parental consanguinity, which makes us difficult to do linkage study to identify new causative genes. However, the advent of next-generation sequencers is changing the diagnostic and research scenes in myology just as in many other fields. We have set up target resequencing panels that basically cover all known causative genes for hereditary muscle diseases (as of early 2014). We started providing genetic analysis in September 2014 using this system to the cases whose pathological analysis was done at NCNP. So far we have reached diagnosis in 27% of those cases. To identify new causative genes, we applied whole exome sequencing (WES) analysis. In the last 3 years, we have performed more than 750 exome analyses but we found causative mutations in only 11% of cases. This low rate appears to be at least partly due to the fact that Japanese variation database is not well established, in addition to the fact that currently available WES analysis kits do not fully, albeit mostly, cover all exonic regions. In my talk, I will demonstrate some of our analysis data, including the identification of ORAI1 as a causative gene for tubular aggregate myopathy, and discuss current status and yet-to-be-solved issues of next-generation sequencing in myology field.