[Massively parallel sequence analysis for revealing causes of neuromuscular disorders]

Molecular genetic studies, positional cloning in particular, contributed to progresses in neurology. However, because of a bottleneck of low sequence analysis throughput, large proportions of small families, especially of late-onset hereditary diseases, still remain to be elucidated. The massively parallel sequencers are expected to identify causative genes in such a small but meaningful families and to reveal pathophysiology of the diseases. Multiple system atrophy (MSA) is a neurodegenerative disorder. Pathophysiology of MSA remains largely uncertain despite many studies. Generally, MSA is a sporadic disorder, but there are rare familial aggregations which would provide a strong clue to understand pathophysiology of MSA. With the backgrounds, we analyzed an MSA family with 2 pathologically proven siblings born with consanguineous parents. Linkage study revealed a candidate 70Mb regions in four chromosomes. We carried out whole-genome resequencing of the proband using Illumina GAIIx. Mean depth was 58X, and a total of 3.5 million single nucleotide variations were found. Although the new technologies are highly powerful, to find a mutation from a number of variations, a challenge with bioinformatics should be overcome. Coping with the problem, the high-throughput sequence technologies will further contribute to a breakthrough in neurology.