Despite the large number of genes that have been associated with limb-girdle muscular dystrophy (LGMD), there are a significant number of patients with LGMD in whom causative genetic mutations have not been identified. Many of these patients are likely to have mutations in novel genes that have not previously been associated with LGMD. In the past, linkage analysis to identify novel causative genes was most useful in large pedigrees that yielded high LOD scores. With the advent of high throughput sequencing technology and zebrafish morpholino techniques, it is now possible to screen for novel LGMD genes among large lists of candidates generated by low, broad, or multiple linkage peaks. The applicant proposes to perform such analyses on pedigrees with LGMD and other muscular dystrophies that do not appear to be associated with previously described genes. Among a number of pedigrees screened to date, the applicant’s team has identified mutations in a novel muscular dystrophy/myopathy gene, and are screening further families. Identification of novel genes will assist in the diagnostic evaluation of these patients, and may elucidate pathogenic mechanisms that may prove useful in designing future therapies.
