Limb-girdle muscular dystrophy (LGMD) is genetically one of the most heterogeneous diseases, with >20 genes identified.1 Moreover, causative mutations remain undetermined in more than half of all LGMD patients, suggesting additional heterogeneity. In Japan for instance, ∼60% of the genetic causes of LGMD remain unknown (YK Hayashi et al., unpublished data). LGMD involves recessive as well as dominant disease alleles on autosomes and the X chromosome,2 and the mutations are widely distributed across the entire length of multi-exon genes. The observed mutation frequency for particular LGMD genes varies among different races or geographic regions. The lack of clinical or laboratory findings that help identify the disease-causing genes and their respective common mutations also hinders efficient gene-screening. It is costly and time-consuming to screen all known disease-causing genes by conventional PCR and Sanger sequencing.

Mutation detection is necessary for definitive diagnosis, specifically for genetic counseling, prenatal diagnosis or any-gene-based therapy, as well as understanding disease pathogenesis and epidemiology. Recent developments in high-throughput sequence capture methods and next-generation sequencing technologies allow for targeted enrichment and resequencing of nearly all exons of protein-coding genes, and have made exome sequencing not only feasible but also extremely cost-effective. Exome sequencing is increasingly being adopted as a diagnostic tool for genetic disease characterized by extreme genetic heterogeneity, as well as for discovery of new causal mutations for unidentified inherited disorders.3

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