19.: Diagnosing the limb-girdle muscular dystrophies using whole exome sequencing: An Australian cohort

Abstract

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic disorders that result in proximal muscle weakness. The weakness typically begins after 2 years of age and dystrophic changes are present on muscle biopsy. The genetic cause of LGMD in Australia remains unknown in approximately 40% of patients resulting in uncertainty for patients with regards to risk in other family members and their long-term prognosis. We reviewed the clinical information on all participants in a large cohort of patients with LGMD who lacked a genetic diagnosis after standard diagnostic testing (n = 53). Whole exome data analysis was performed using the xBrowse web interface (Broad Institute, Cambridge, MA, USA) to filter variants by nature of DNA change. When no variants were identified in known LGMD genes, candidate genes were ranked for biological plausibility, tissue expression pattern and predicted biological effects of sequence changes. Whole exome data analysis was performed on 53 LGMD families. The data received had an average read-depth of >80 and 10-fold coverage in over 90% of the coding regions of the human genome. Mutations were identified in 25 families, in genes not all typically associated with LGMD. Two families were diagnosed with dominant LGMD, eight families with recessive LGMD, four with congenital myopathy, one with myofibrillar myopathy, three with collagen myopathy, two with metabolic myopathy, one with inclusion body myopathy, one family was found to have a mutation in a novel gene and one family presented with a new phenotype in a known gene. Moreover, testing for myotonic dystrophy type 2 identified two additional families with this disorder. Whole exome sequencing identified the genetic cause of 47% of our LGMD cohort of patients who had been extensively investigated and remained without a genetic diagnosis. The diversity of the mutated genes that were identified supports the clinical observation of heterogeneity in this group of muscle disorders and the difficulty clinicians face in diagnosing this subgroup of diseases. Whole exome sequencing and similar next-generation sequencing are likely to be efficient and cost-effective methods for identifying the genetic basis of LGMD. Further study in this cohort may also reveal new genes that cause LGMD in Australia.